Download Diabetes, Insulin Resistance and Cardiovascular Disease 8/13/2000

Diabetes, Insulin Resistance and Cardiovascular
Diseases Good through 09/02/2010
By James J. Kenney Ph.D., R.D., F.A.C.N.  Food & Health Communications.
Diabetes, Insulin Resistance and Cardiovascular Diseases ...................................... 1
Introduction ................................................................................................................. 2
Insulin Resistance Usually Develops Long Before Type-2 DM ................................ 4
How Is Insulin Resistance Diagnosed? ....................................................................... 4
How Are Diabetes and Impaired Fasting Glucose Tolerance Currently Diagnosed
and Monitored? ........................................................................................................... 6
Diabetes Damages Both Small and Large Blood Vessels .......................................... 7
Insulin Resistance Can Lead to CVD Even If Blood Sugar Is Normal .................... 11
How Does Insulin Resistance Alter Blood Lipid Metabolism? ................................ 12
Does Insulin Resistance Effect Blood Pressure? ...................................................... 12
Do Low Sodium Diets Impair Glucose Tolerance? .................................................. 16
How Does Insulin Resistance Effect Blood Clotting and Inflammation? ................ 17
Elevated Homocysteine in Type-2 DM Patients ....................................................... 19
What Diet Is Best For People With Metabolic syndrome? ....................................... 19
Do High-Carbohydrate Diets Increase Triglyceride Levels and Reduce Fibrinolysis?
................................................................................................................................... 21
Do High-Carbohydrate Diets Cause a Drop in HDL-Cholesterol? .......................... 26
High-Carbohydrate Diets Reverse Atherosclerosis and Reduce All-Cause Deaths . 28
Risk Factors for the Development of Diabetes ......................................................... 29
Effects of Increasing Age on Insulin Resistance ...................................................... 29
Insulin Resistance and Type-2 DM Are Increasing in Young Americans ................ 30
Genetic Factors Contribute to IR and Type-2 DM?.................................................. 31
Body Weight, Insulin Resistance and Type-2 DM ................................................... 33
Is Type-2 DM Caused by the Typical American Diet and Lifestyle? ...................... 38
Impact of Diet on Insulin Levels and Blood Sugar Regulation ................................ 39
What Type of Diet Is Best for Type-2 DM Patients? ............................................... 41
Do High-Fat Diets Lead to Insulin Resistance and Type-2 DM? ............................. 43
Dietary Fiber Shown to Improve BS Control in Type-2 DM Subjects..................... 46
High-Carbohydrate Foods Have Variable Metabolic Effects ................................... 47
Energy Density More Important Than % Fat ........................................................... 49
Impact of Dietary Fat and Carbohydrate on BS Levels ............................................ 52
Do High-Carbohydrate Drinks Promote Increased Calorie Intake? ......................... 53
Glycemic Index and BS Control in Type-2 DM Patients ......................................... 54
Small Versus Large Meals May Improve Metabolic Control ................................... 60
Comparison of Diets High in Carbohydrate, Fat or Protein in Type 2 DM Subjects 63
Do High-Carbohydrate Diets Cause Hyperinsulinemia and Weight Gain?.............. 64
Debate over High-MUFA vs High-Carbohydrate Diets for Patients with Type-2 DM
................................................................................................................................... 65
Is "Will Power" and a Calorie Controlled Diet the Key to Weight Control? ........... 67
Population Studies Suggest a High-Carbohydrate Diet Best for Type-2 DM .......... 68
1
Is a Low ED, Low GI, and High-Fiber Diet Best For Obese Type-2 DM Patients? 69
Alcohol, Diabetes and Coronary Artery Disease ...................................................... 70
Drug Therapy Alone Is Far From an Ideal Treatment for Type-2 DM .................... 71
Use of Nutritional Supplements in Patients with Type-2 Diabetes Mellitus ............ 75
Chromium and Glucose Tolerance Factor ................................................................ 76
Pharmacological Doses of Vanadium and Glucose Tolerance ................................. 77
Magnesium Supplements for Type-2 DM Patients ................................................... 78
Vitamin E and Vitamin C Supplements .................................................................... 78
Alpha-Lipoic Acid Supplements............................................................................... 80
Folic Acid and Vitamins B-6 and B-12 Supplements ............................................... 80
L-Arginine Supplements and Insulin Resistance ...................................................... 81
Niacin, Blood Lipids and Diabetes ........................................................................... 82
Omega-3 Fatty Acids, Blood Lipids and Type-2 DM .............................................. 83
Conjugated Linoleic Acid (CLA) and Glycemic Control ......................................... 84
Medicinal Herbs and Glycemic Control ................................................................... 84
Summary ................................................................................................................... 85
References: ................................................................................................................ 88
Introduction
Diabetes mellitus (DM) is not a single disease but rather a group of several diseases. All
types of DM are characterized by fasting blood sugar (BS) levels that are too high and/or
excessively high postprandial BS levels. Type-1 DM appears to be an autoimmune
disease triggered perhaps by a viral infection coupled with some genetic predisposition.
In Type-1 DM, regardless of what the trigger is, the patient's own immune system attacks
and destroys the beta-cells of the pancreas (a.k.a., the islets of Langerhans) which
produce insulin and glucagon (a hormone that raises BS levels). As a result, Type-1 DM
patients eventually lose all or nearly all of their insulin producing capacity leaving them
dependent on exogenous insulin (or perhaps some day a beta-cell transplant) for the rest
of their lives. Without insulin their BS levels rise precipitously and ketone production
increases dramatically leading to ketoacidosis. Type-1 DM was once commonly referred
to as insulin dependent diabetes mellitus (IDDM).
Gestational DM typically develops in the third trimester of pregnancy and often resolves
itself after childbirth. Whether or not it should be treated with drugs is debatable.
However, women who experience gestational DM are at increased risk for complications
during pregnancy. In addition, while about 90% of women with gestational DM do have
their BS levels return to the normal range postpartum, they do remain at very high risk of
developing Type-2 DM later in life.
Type-2 DM is by far the most common type of DM in the U.S. and its prevalence is
increasing rapidly both in the U.S. and worldwide. From 1990 to 1998 the prevalence of
Type-2 DM increased by 33%.1 The cost of treating diabetes in the U.S. today is running
at about $100 billion annually. Type-2 DM accounts for about 90% of the 16 million
Americans with DM. Another 20 million have impaired glucose tolerance (IGT), which is
2
pre-diabetic state. By age 75 years about 1 in 5 Americans has developed Type-2 DM.2
Worldwide at least 120 million people have Type-2 DM and this number is projected to
increase to 220 million by 2010.3 Diabetes is among the top 5 causes of death in most
countries even though mortality statistics greatly underestimate the true rate of diabetesrelated mortality because diabetes is often underreported on death certificates.4 5
The American Diabetes Association created the new diagnostic criteria of impaired
fasting glucose (IFG) in 1997, which is often, but certainly not always associated with
IGT. Particularly among the elderly there is considerable discordance between IGT and
IFG. IFG is less sensitive than is IGT for predicting which patients will progress to Type2 DM and also less sensitive at predicting an increased risk of CVD.67 Most patients with
IGT do also have impaired fasting glucose (IFG) and vice versa, but IGT and IFG are not
identical. A large percentage of those with IGT (and a lesser percent with IFG) will
progress to Type-2 DM with time.
Both IGT and Type-2 DM are usually characterized by some degree of resistance to the
BS lowering action of insulin. This is called insulin resistance (IR). IR is also referred to
as a decrease in insulin sensitivity. IR is generally present for many years before fasting
BS (FBS) levels begin to rise above the normal level. Perhaps 20 to 30% of all
Americans have at least a moderate degree of IR.8 While IR is almost always a precursor
to the development of Type-2 DM, many people with IR never do develop Type-2 DM.
This is because the impact of IR on glucose tolerance can be largely overcome by
hyperinsulinemia and some people continue to produce the extra insulin needed to keep
BS levels from rising into the diabetic range. Nevertheless, IR and hyperinsulinemia do
increase the risk of cardiovascular disease even if BS levels remain within the normal
range.
IR, IGT and Type-2 DM and their complications will be the primary focus of this review
because they are so common in the U.S. and elsewhere and because they can often be
treated successfully with only dietary and lifestyle changes. The dietary and lifestyle
changes needed to reduce IR and improve glucose tolerance are basically the same for
most people with the IRS, IGT and Type-2 DM. As will be shown, most research
suggests that treating people with IR, IGT and Type-2 DM optimally usually require
regular exercise and a diet that is very different than that consumed in most modern
societies today.
IR and IGT usually precede the development of Type-2 DM. They can be viewed as early
stages of Type-2 DM. Human population studies suggest that people inherit a tendency to
develop IR, IGT and Type-2 DM. However, epidemiological evidence suggests that
changes in diet and increased physical activity can reduce IR, hyperinsulinemia and the
risk of developing Type-2 DM.9 Increasingly it appears these metabolic disorders are
largely caused by the typical American diet and sedentary lifestyle. This means
improving the diet and increasing the activity level should slow (or perhaps prevent) the
development of IR and reduce the risk of developing Type-2 DM. Indeed, recent research
has shown that improved diet and exercise habits can greatly reduce the chances of
someone with IR and IGT progressing to Type-2 DM.10
3
Insulin Resistance Usually Develops Long Before Type-2 DM
People with Type-2 DM usually have some degree of both resistance to the action of
insulin and also some decrease in the capacity to produce insulin. In some Type-2 DM
patients, the resistance to insulin is more severe while in others the capacity to produce
insulin is severely depressed (although not to the degree seen in Type-1 DM). As a result,
the insulin levels in Type-2 DM patients may be higher than normal, close to normal or
below normal levels. However, even with above normal insulin levels the fasting and/or
postprandial BS levels will be elevated because of resistance to the action of insulin.
Obese middle-aged patients with Type-2 DM have increased basal liver glucose output
despite hyperinsulinemia. Normally, increased insulin levels block glucose output by the
liver. Obese middle-aged Type-2 DM patients also have impaired insulin release from
pancreatic beta-cells in response to rising BS as well as marked IR. By contrast, in
elderly patients with Type-2 DM the primary metabolic defect is a reduced or slowed
clearance of BS by insulin.11 This suggests that most of those who develop Type-2 DM
fairly early in life may have more severe defects in insulin-mediated BS and carbohydrate
metabolism than those who develop Type-2 DM later in life.
Regardless of what age Type-2 DM develops, virtually all patients with this disease will
have some degree of IR. IR is associated with a reduced ability of insulin to inhibit the
output of glucose by the liver and to stimulate the uptake of BS by muscle and fat cells.12
Usually IR exists for many years before Type-2 DM develops. It may be that the greater
requirement for insulin over time eventually wears out the beta-cells of the pancreas.
Alternatively, the insulin resistant state may lead to metabolic changes such as increased
serum free fatty acids (FFA) levels which lead to the malfunction and eventually the
death (a.k.a., aptosis) of the pancreatic beta-cells (lipotoxicity) with a subsequent
reduction in the capacity to produce insulin. Regardless of the cause, as beta-cells lose
their ability to secrete the larger amounts of insulin required because of IR, BS levels
begin to rise above the normal range. The result is often both fasting and postprandial BS
levels increase into the IFG and/or IGT range and eventually into the diabetic range. In
some cases fasting BS levels remain below the DM range but postprandial BS levels rise
excessively high.
How Is Insulin Resistance Diagnosed?
IR is a risk factor for the development of CAD and Type-2 DM. It has been estimated to
occur in 20-30% of the US population. However, there are currently no routine laboratory
procedures for establishing its presence. IR is fundamentally impairment of insulin
signaling, which arises from post-receptor defects in the propagation of the message
normally triggered when insulin binds to the receptor. There are many genes involved in
this process and there are numerous environmental stressors that appear to contribute to
the development of IR. Therefore, it is unlikely that a simple genetic test will soon be
developed to determine who will develop IR.
4
The ability of insulin to move glucose out of the blood and into cells can be determined
directly using the euglycemic, hyperinsulinemic clamp technique. This technique utilizes
a constant rate of insulin being infused for a long enough time to attain steady-state
metabolic conditions. "Glucose clamp" refers to the process of holding plasma glucose
constant by repeatedly measuring BS and then adjusting the rate of infusion of glucose to
maintain a fairly constant BS level. It often takes about 1 1/2 to 2 hours from the start of
the insulin infusion to achieve steady BS level by adjusting the rate of glucose infusion.
This rate of glucose infusion thus becomes a quantitative measure of insulin action to
stimulate glucose uptake and utilization.13
IR can also be estimated using an intravenous glucose tolerance test but this is less
accurate than the "glucose clamp" technique. Both of these tests are difficult to perform,
unpleasant to undergo, and time and labor intensive so their use is currently limited
primarily to research labs.
Decreased insulin sensitivity occurs when a normal amount of insulin moves glucose out
of the blood and into fat, muscle, and liver cells in a slow and inefficient manner. When
muscle, fat and liver cells resist the action of insulin they are said to be insulin resistant.
However, IR does not necessarily lead to a high BS level and the diagnosis of IFG or
Type-2 DM. Indeed, BS levels may still be well within the normal range (<100 mg/dl)
despite IR. This is because the decreased sensitivity to the action of insulin on BS
regulation can be largely overcome if enough extra insulin is secreted. When insulin
output by the beta-cells of the pancreas can no longer keep up with the increased demand
for insulin (due to the IR) then BS levels start to rise above the normal range (60 to 99
mg/dl). However, the necessarily higher insulin levels coupled with the IR have been
associated with a host of metabolic disturbances. This is true even when the fasting BS
level remains in the normal range.
IGT is diagnosed by measuring BS levels after the patient consumes 75gm of glucose
(usually dissolved in flavored water). This is known as the oral glucose tolerance test
(OGTT). IGT is diagnosed when the postprandial BS level is above 140 mg/dl but below
200 mg/dl (the cutoff point for diagnosing diabetes) 2 hours after the oral glucose load is
consumed. Using IFG levels as a surrogate for IGT will often lead to misdiagnosis of
IGT. This is because most people (54 to 67%) with IGT (2 hr OGTT BS > 140 mg/dl and
< 200 mg/dl) still have a normal fasting BS level (<5.55 mmol/L or 100 mg/dl). Indeed,
about 7% of people with Type-2 DM as diagnosed with an OGTT (BS of 200 mg/dl or
more) had fasting BS levels below 100 mg/dl.14 15 16
Another way to determine if someone is likely to have significant IR is to measure risk
factors frequently associated with it. It is clear that measuring the fasting BS level is not
the most accurate way to diagnose IR, IGT and Type-2 DM. The ratio of fasting insulin
level to BS level would be more accurate than using only the fasting BS level. While not
routinely done, the measurement of fasting insulin levels can show the likely presence of
IR even when BS levels are still well within in the normal range. If fasting insulin levels
are high despite a normal fasting BS level then IR is the most likely explanation.17
5
However, using surrogate measure to predict the presence and the degree of IR is still less
accurate than measuring it directly using the insulin clamp technique.
It is clear that screening for IGT and Type-2 DM would be more accurate if both fasting
insulin and BS levels were measured than if fasting BS level alone was used to make the
diagnosis.18 Most studies have shown that the likelihood of progressing from IR and IGT
to Type-2 DM increases with increasing BMI.19 Patients with an increased waist to hip
ratio and a strong family history of Type-2 DM should be presumed to have clinically
significant IR, especially if they also have hypertension (HTN), a low HDL-Chol
(<35mg/dl) and/or an elevated triglyceride (TG) level (>177 mg/dl or 2.0 mmol/L). A
recent study of 185 healthy men found that more than 80% of those with a large waist
(>35 inches or 90 cm) and elevated TG levels (2.0 mmol/L or more) were characterized
by hyperinsulinemia and also had a more atherogenic lipoprotein profile. This
dyslipidemia consisted of small, dense LDL particles that were enriched in apoB 100.20
How Are Diabetes and Impaired Fasting Glucose Tolerance Currently
Diagnosed and Monitored?
In contrast to IR, impaired fasting glucose (IFG) and Type-2 DM are fairly easy to
diagnose using the new American Diabetic Association’s fasting BS cutpoints. However,
focusing primarily on fasting BS levels to diagnose and treat patients with IGT and Type2 DM is not a particularly useful strategy. The Diabetes Intervention Study demonstrated
that after 11 years of follow-up the postprandial BS level was an independent risk factor
for both heart attacks and mortality but that fasting BS alone was not an independent risk
factor for heart attacks and overall mortality.21 Therefore, therapies aimed at lowering 2
hr postprandial BS levels appear to be a more important focus of therapy than fasting BS
levels alone.
When the FBS level is between 100 mg/dl to 125 mg/dl, IFG will be diagnosed. Many
patients with IFG are IR and also have IGT and will go on to develop Type-2 DM.22
There are about 20 million Americans with IGT and this number is increasing each year.
Because IGT is not usually associated with any symptoms, most people who have this
condition are not aware of it. IGT is associated with an increased risk of CVD and is
often a prelude to the development of Type-2 DM. This is why it is a good idea to have
one’s FBS checked regularly once one reaches middle-age. However, even if fasting BS
levels remain in the normal range, those who are overweight, have an increased waist to
hip ratio, have HTN, and/or dyslipidemia should either have an OGTT or a fasting insulin
level measurement, particularly if there is a family history of Type-2 DM.
Many people with Type-2 DM are not aware they have it even though it usually produces
some symptoms like increased thirst and urination. However, because these symptoms
come on so gradually they are often missed or dismissed as being just part of getting
older. Type-2 DM is diagnosed when fasting BS (FBS) is consistently >125 mg/dl (or 7.0
mmol/L) or when a random (non-fasting) BS is >200 mg/dl (11.1 mmol/L) and the
patient has symptoms of Type-2 DM such as increased thirst and urination. DM can also
6
be diagnosed if the BS level is 200 mg/dl (11.1 mmol/L) or higher 2 hours after
consuming a 75 g glucose drink. This is the case even when the FBS level remains below
126 mg/dl or even below 100 mg/dl.
In Type-2 DM patients, the measurement of glycosylated hemoglobin (Hb A 1-c) is
generally regarded as the best measure of average BS control over the last 2-4 months.
Glycosylated hemoglobin is also referred to as glycated hemoglobin. Hb A 1-c is the
result of the chemical bonding of glucose to the amino acids in the Hb molecule. Red
blood cells (RBC) remain in the bloodstream for about 120 days on average and are then
removed and their Hb broken down. So for 4 months glucose is constantly attaching itself
to the Hb molecules in the RBC. The bone marrow is constantly producing new RBC
with "fresh" Hb that is free of attached glucose molecules.
Table 1 shows level of BS control based on Hb A 1c values. In people with normal BS
levels Hb A 1c levels are no more than 5-6%. In people with untreated or poorly treated
diabetes, Hb A 1c values are more than 7%. A diabetic patient with a Hb A 1c is
considered to be in excellent control when HbA1c is below 7%, whereas when Hb A 1c
values of 10 or higher the patient is considered to be in very poor control. The higher the
BS level on average the faster glucose attaches not only to Hb but to other proteins
throughout the body. Over time high BS levels leads to permanent damage to a variety of
tissues and organs. Poorly controlled Type-2 DM patients can also worsen the
dyslipidemia commonly seen in Type-2 DM patients.
Table 1. Glycosylated Hemoglobin (Hb A 1c) as a Biochemical Marker for Average
Glucose Control
Hb A 1c Value
Corresponding
Mean BS Level
Degree of BS Control
< 6%
under 114 mg/dl
Normal for Healthy People
<7%
115 to 147 mg/dl
Excellent
<8%
148 to 180 mg/dl
Good
<9%
181 to 214 mg/dl
Fair
<10%
215 to 247 mg/dl
Poor
>10%
over 247 mg/dl
Very Poor
_____________________________________________________________________
Diabetes Damages Both Small and Large Blood Vessels
Over time, chronically elevated BS levels contribute to the damage to small blood vessels
(microvascular disease) and also damage to the peripheral nerves (neuropathy). HbA1c
gives an accurate measure of the average BS level over the past 120 days (the average
lifespan of red blood cells). The higher the HbA1c and the longer it has been elevated the
greater the risk of neuropathy and microvascular health problems such as nephropathy,
7
retinopathy, and poor microcirulation to the extremities which can lead to infections,
gangrene and amputations.
The first sign of microvascular damage to the kidneys is the appearance of small amounts
of protein (albumin) in the urine. This is known as microalbuminuria. Diabetes is the
number one cause of kidney failure in the U.S. The combination of HTN and poorly
controlled BS levels will lead to microalbumiuria and eventually kidney failure in about
10-20% of patients. Results from a recent population-based study found that
microalbuminuria was associated with death from CAD, cerebrovascular disease, and all
causes combined. These associations were independent of known CVD risk factors and
other diabetes related variables.23
About half of patients with DM develop neuropathy and/or retinopathy within about 25
years. Those with poorer BS control are more likely to see these microvascular
complications develop. Neuropathy primarily effects the long nerves to the feet and
hands. Tingling, pins and needles, burning sensations (similar to having a sunburn) and
eventually numbness in the feet and hands are clinical signs of neuropathy. Damage to
the retina of the eye is the number one cause of blindness in America and is most often
due to diabetes and poor BS control. Cataracts are also more common in people with DM
and can also lead to loss of vision.
The 10y Diabetes Control and Complications Trial showed that tight control of BS levels
(Hb A1c <7% ) compared to poorer control (Hb A1c >9%) lead to a 50-75% reduction in
the occurrence of microvascular disease in Type-1 DM patients.24 The United Kingdom
Prospective Diabetes Study demonstrated conclusively that chronically elevated BS
levels in Type-2 DM patients lead to the same microvascular complications seen in Type1 DM patients. In this study each 1 percent point drop in Hb A1c levels was associated
with a 35% decline in the risk of developing microvascular complications.25
The microvascular complications of Type-2 DM are primarily associated with increased
BS although hypertension (HTN) also plays a major role in the development of
microvascular disease. Hyperglycemia leads to the formation of advanced glycation end
products (AGE), which have been shown to accelerate calcification in microvasular
vessels.26 The combination of HTN and hyperglcemia are particularly damaging to the
retina and kidneys. The microvascular problems, which are characteristic of DM and
result in a lot of morbidity, are not what kills most people with DM. Most Type-2 DM
patients die from damage to their large blood vessels. Macrovascular damage to the large
blood vessels such as the coronary arteries can lead to heart attacks and strokes. The
macrovascular complications of Type-2 DM appear to be primarily due to the
abnormalities of lipid metabolism and BP regulation that are more common in people
with IR. Other CVD risk factors like smoking, inactivity, obesity, elevated homocysteine
levels probably play a similar role in promoting CVD in people with Type-2 DM as they
do in nondiabetic people.
Patients with diabetes have been shown to have an impaired production of vascular
endothelial growth factor-A (VEGF-A) induced chemotaxis of monocytes. VEGF-A is
8
involved in angiogenesis or the growth of collateral blood vessels. This appears to be part
of the mechanism which results in severely compromised blood flow to the lower legs
and feet.27 Claudication or peripheral vascular disease (PVD) is about 10 times more
common in patients with diabetes as in those with normal BS levels. PVD is
characterized by aching pain in the lower legs when walking that dissipates with rest.
This attenuated ability to produce collateral blood vessels when ishemia develops in the
primary blood vessels may aggravate other circulatory problems that are more common
in patients with diabetes.
The risk of dying of a heart attack for people the same age is about 3-5 times greater in
people with DM than those with normal BS levels in the U.S. 28and in Finland.29 In the
US, cardiovascular disease (CVD) accounts for about 2/3 of all deaths in patients with
Type-2 DM. Data from the MRFIT study found that people with Type-2 DM are 3-5
times more likely to die from CHD for any given serum cholesterol level.30 31 Figure 1
below shows the data from the MRFIT study.
Figure #1
Unfortunately, despite the fact that it is the macrovascular complications that account for
most of the increased mortality in patients with Type-2 DM, many clinicians still focus
much more attention on controlling BS than blood lipid and other CVD risk factors
frequently seen in these patients.32 Of course deaths from CAD are nearly doubled in men
with diabetes even after adjusting for other CAD risk factors. In women, CAD risk is
9
increased more than 2 ½ fold after adjusting for other CAD risk factors.33 Because
diabetes is a major risk factor for CVD, the American Heart Association and the National
Cholesterol Education Program recommend that the target for LDL-Cholesterol is less
than 100 mg/dl for patients with diabetes.
IR itself, with or without elevated BS, is characterized by several metabolic disturbances,
which hasten the development of CVD. An estimated 20-30% of the U.S. population has
what has been variously termed the "deadly quartet", "metabolic syndrome", "the
metabolic syndrome" and the "insulin resistance syndrome" (IRS). This syndrome is
generally characterized by IR, hyperinsulinemia, dyslipidemia, central or visceral
adiposity, and often HTN and impaired fasting glucose (IFG) or Type-2 DM.34 IR and the
disturbances in lipid metabolism it causes promote the growth of atherosclerotic plaque
and increases the risk of advanced CVD even in people who do not have IGT or diabetes.
After other known risk factors for CVD have been factored in, both Type-2 DM and IGT
patients appear to have at least twice the risk of developing CVD as those with normal
insulin sensitivity. This suggests that a chronically elevated BS level by itself probably
plays a relatively minor role in the pathogenesis of the large blood vessels
(macrovascular disease). The other metabolic disturbances in lipid metabolism and
perhaps blood pressure (BP) regulation seen in people with IR appear to be more
responsible for the macrovascular damage that leads to increased CVD mortality than the
elevated BS levels alone.35 Other research suggests that much of the increased risk of
CVD seen in patients with Type-2 DM may develop after the onset of overt diabetes.36
This suggests the increased BS and/or factors associated with it also may play a
significant role in the promotion of macrovasular disease.
People with IR often experience higher BS levels after meals than do people with normal
insulin sensitivity. This may be the case even if fasting BS levels remain well within the
normal range. Recently it has been shown that HbA1c levels are positively associated
with an increase in mortality from IHD, CVD, and all causes independently of serum
cholesterol level, cigarette smoking, age, and blood pressure.37 This was true for men
with diabetes (HbA1c >7.0%) but also for nondiabetic men with HbA1c levels between
5.0 and 6.9%. Indeed, 82% of the excess mortality associated with increasing HbA1c
levels occurred in men without diabetes. This is consistent with data from the longrunning Framingham Heart Study that also found a strong positive association between
the prevalence of CHD and increasing HbA1c levels.38 Other researchers have also found
a positive association between increasing HbA1c levels and increased atherosclerotic
disease in both diabetic39 and non-diabetic individuals.40
Regardless of whether or not elevated BS levels plays a major or minor role in the
atherogenic process itself, increased BS must be brought under control to prevent
neuropathy and the microvascular disease that often develop in diabetes patients. While
nearly all Type-2 DM patients have IR and the IRS (a.k.a. metabolic syndrome), this
metabolic syndrome is also present in many people with normal fasting BS levels. Many
will never be diagnosed with Type-2 DM because they continue to produce the extra
insulin needed to keep their BS levels in the normal range. However, even if fasting BS
10
levels remain within the normal range, the IR, increased postprandial BS,
hyperinsulinemia and metabolic disturbances usually associated with it will still greatly
increase the risk of CVD and all-cause mortality.
Insulin Resistance Can Lead to CVD Even If Blood Sugar Is Normal
Metabolic syndrome, which is also called the insulin resistance syndrome (IRS), is a
metabolic syndrome characterized by IR and an increased risk of CVD. However, unlike
Type-2 DM and IGT, the BS levels remain in the normal range. However, even if FBS
remains within the normal range (60-109 mg/dl), one study found that a higher BS level
on admittance to a hospital following a heart attack was associated with a greater chance
of subsequent mortality.41
Many people with the IRS will see their fasting BS gradually rise and many will
eventually develop IGT and Type-2 DM. However, even when IR never leads to IGT or
Type-2 DM, it is still associated with a host of metabolic disturbances which increase the
chances of having or developing a variety of known and suspected CVD risk factors. One
study that followed about 650 people for about 10 years found that the quartile of people
with the greatest degree of IR were several times more likely to have a myocardial infarct
(MI) than the quartile of people with the least IR.42 The Quebec Cardiovascular Study
also found that those with the greatest degree of IR were at least several times more likely
to develop CVD.43 Adverse changes in blood lipids (i.e. elevated triglycerides and
decreased HDL-C), hypertension (HTN), hyperinsulinemia and an increased risk of CVD
are common characteristic of individuals with the IRS.44 It has been estimated that as
many as 1 in 4 apparently healthy Americans are at increased risk of CVD due to
metabolic syndrome.45
Most of the people who have metabolic syndrome are overweight or obese and have a
relatively high waist to hip ratio (men > 0.95 and women > 0.85).46 47 The IRS can occur
in people of normal body weight (BMI <25) and with a waist to hip ratio below the highrisk level. For example, a recent study found that reduced insulin sensitivity was an
independent risk factor for greater thickening of the carotid wall in both obese and
normal weight premenopausal women even though they had normal BP, didn't smoke and
were not diabetic.48 Since increased carotid wall thickening is considered a fairly good
marker of early asymptomatic atherosclerosis, these results suggest that IR promotes
CAD even when BS levels remain in the normal range.
It appears that IRS promotes atherosclerosis independently of other CVD risk factors.
Unfortunately, there are no generally accepted criteria for establishing who has and does
not have the IRS. Nevertheless, a study of 1069 nondiabetic men age 65-74 y found that
those with a clustering of CVD risk factors typical of those associated with IR had an
increased risk of CAD events over a 7 year period.49 IR is usually associated with some
disturbances in blood lipids and/or blood clotting which may account for the increased
morbidity and mortality from CVD seen in both diabetes patients (even if they have good
BS control) and in people with IR even though they have normal glucose tolerance.
11
How Does Insulin Resistance Alter Blood Lipid Metabolism?
IR is not only associated with problems with carbohydrate metabolism and often BS
regulation but also distortions in lipid metabolism. The disturbances in lipid metabolism
with IR frequently lead to a more atherogenic blood lipid pattern. The alterations in LDL
particles is often referred to as Pattern B or Phenotype B which is associated with small
dense, apo B-rich LDL and the more rapid progression of atherosclerosis.50 Typically
HDL-Cholesterol is also depressed and both fasting and postprandial serum triglycerides
(TG) are elevated. LDL-Cholesterol levels are not necessarily elevated but there is
usually a greater proportion of small dense LDL-Cholesterol particles that are more
atherogenic.
In normal individuals, the release of insulin suppresses the action of hormone sensitive
lipase (HSL) in adipocytes. However, in people with significant IR, their adipocytes
resist the action of insulin and so the suppression of HSL is less. HSL breaks down TG
stored within fat cells (aka, adipocytes) into free fatty acids (FFA) and glycerol which are
then released into the blood. Because of this, IR is always associated with an increased
release of FFA and higher FFA levels throughout the day. The increased flux of FFA
from adipocytes to the liver stimulates greater synthesis of TG and VLDL particles by the
liver. As a result, the liver releases more TG-rich VLDL particles into the blood. This is
primarily why serum TG levels are often elevated in people with IR.
Increased serum VLDL particles result in greater transfer of cholesterol esters from HDL
particles. This transfer of cholesterol esters from HDL to VLDL particles is mediated by
cholesterol ester transfer protein (CTEP). As a result HDL-Cholesterol levels usually
drop when VLDL-TG levels rise. It appears that the loss of cholesterol esters from the
HDL particles reduces the binding of apo A-1 to the HDL particle. As a result the apo A1 protein becomes separated from the HDL particle. Once this happens the apo A-1
protein is quickly removed from the circulation by the kidney and broken down. This is
why many people with IRS have lower than average HDL-Cholesterol levels.
CETP also increases the exchange of cholesterol esters from the LDL particles and
increases the transfer of TG to the LDL particles. Lipases found in the muscle, liver, and
adipocytes may then remove the TG from these cholesterol ester depleted LDL particles
resulting in a smaller, apo B-100 enriched LDL particle which is more susceptible to
oxidation and may also more easily get into the arterial wall. These changes make these
smaller, more dense LDL particles considerably more atherogenic than larger LDL
particles.51 52
People with the IRS have a greatly increased risk of cardiovascular disease (CVD). More
than half of those with IRS even without Type-2 DM will die from CVD.
It is clear that the diet that is ideal for people with IR must reduce risk factors for
CVD and it must also reduce the risk of IR progressing to IGT and Type-2 DM.
Does Insulin Resistance Affect Blood Pressure?
12
The coexistence of HTN and diabetes in the same patient has a devastating effect on the
cardiovascular system.53 About 3/4 of the people with Type-2 DM also have HTN. The
current goal for BP control in patients with diabetes is a BP of <130/85 mmHg.54 Most
research suggest that when BP levels are considerably lower than 130/85 mmHg this will
help reduce both microvascular and macrovascular complications commonly seen in
patients with Type-2 DM.55
HTN is more strongly associated with central or visceral adiposity than it is with
peripheral adiposity or BMI.56 No one is sure exactly how or why increasing abdominal
fat and/or hyperinsulinemia and IR might contribute to the development of HTN. There
are a number of theories and proposed mechanisms to explain the tendency to develop
HTN when IR, central adiposity, hyperinsulinemia and/or Type-2 DM are present. It has
been hypothesized that HTN results from IR, hyperinsulinemia because of increased
blood volume expansion secondary to insulin-stimulated sodium and fluid resorption in
the collecting tubules of the kidney coupled with an insulin-induced increase in
catecolamines. 57 58 59 However, other researchers have questioned the validity of this
hypothesis. 60 61 62 63 64 It seems unlikely that IR and hyperinsulinemia promote HTN
primarily by increasing sodium resorption and/or increasing catecholamine release.
Indeed, there is growing evidence that HTN may not be causally related to the IRS.65
More recently it has been proposed that HTN may result from the increase in intraabdominal pressure (IAP) that results from increasing amounts of visceral fat.66 As
visceral fat stores expand pressure inside the abdominal cavity increases. During
pregnancy, the rapid growth of the baby in the third trimester also leads to an increase in
IAP and is also associated with the development of HTN (pre-eclampsia and toxemia). A
recent study in dogs supports the theory that an increase in IAP alone can elevate BP. In
this study, an intra-abdominal balloon was inflated and deflated over a period of 7 weeks.
After 5 weeks with increasing intra-abdominal pressure caused by the inflated balloon the
dogs BP increased from 122/82 mmHg to 155/107 mmHg. When the balloon was
deflated the BP returned to normal within about 2 weeks. The authors concluded that,
"Increased IAP from progressively inflating an intra-abdominal balloon in dogs was
associated with significant increases in systolic and diastolic BP that resolved with
balloon deflation. Increased IAP may be a cause for the systemic hypertension in central
obesity and pre-eclampsia.”67 It is clear that the increase BP in the study with dogs could
not have been due to the metabolic effects of IR, hyperinsulinemia increased FFA, all of
which are associated with increased visceral fat stores. This is because inflating a balloon
to increase IAP but would not be expected to affect these metabolic factors.
A study that compared obese subjects with primarily either central or peripheral fat stores
to a group of lean controls found that renal blood flow was significantly reduced in those
with central obesity presumably due to increased IAP.68 These researchers noted that
plasma renin activity, renal vascular resistance, and microalbuminuria were higher in
those subjects with increased visceral fat stores compared to those with increased
peripheral fat stores. They found that renal vascular resistance increased significantly
with an increasing waist to hip ratio but not with fasting insulin levels.
13
It has been hypothesized that there is a resetting of pressor naturesis in obesity-induced
HTN. This resetting of pressor naturesis might be due to an increased reactivity to pressor
factors such as a reduction in nitric oxide generation by vascular endothelial cells. Or it
may result from an increase in intracellular sodium and calcium in the vascular smooth
muscle cells, which makes them over constrict in response to vasoconstrictive agents
such as angiotensin II and norepinephrine.69 Others have suggested that increased renal
tubular resorption of sodium could be related to histological changes within the
kidney which lead to compression of the renal tubules and vasa recta which leads to more
efficient sodium resorption.70
Another possible mechanism linking IR and HTN to an increased risk of developing
HTN involves the inactivation of nitric oxide (NO) by free radicals. NO is involved in
vasodilation of arteries and arterioles so increased destruction of NO as well as reduced
production could lead to vasoconstriction and increased peripheral resistance. Increased
peripheral resistance to the flow of blood is characteristic of primary or essential HTN. A
reduced ability to produce NO from L-arginine has been observed in patients with IR and
essential HTN.71 The combination of reduced production and increased destruction of NO
could seriously impair the ability of arteries and arterioles to vasodilate.
Enhanced inactivation of NO was induced in rats by a diet high in fat and sugar and this
was shown to correlate with the development of HTN.72 The authors of this study
hypothesized that a diet high in fat and sugar increases the generation of reactive oxygen
species (ROS) or free-radicals that react with NO and inactivate it. In these rats BP rose
gradually for 18 months and was accompanied by increasing nitrotyrosine (NT), which is
produced when ROS react with NO and inactivate it. A reduction in functional vascular
endothelial NO would lead to reduced vasodilation and increased BP due to peripheral
resistance. Increased inactivation of NO in the kidney leads to alterations in renal tubular
epithelial cells that leads to increased sodium retention. A decrease in bioactive NO has
been demonstrated in hypertensive humans.73
One could argue that a diet high in sugar and fat induces omnivorous animals (like rats
and humans) to consume more energy, which over time would lead to increased body fat
stores. Those who store more of this increased body fat in the intra-abdominal region are
more likely to experience a rise in IAP, which leads to hemodynamic changes in the
kidney that increase sodium retention and elevate BP. In addition, such a diet appears to
decrease the ability of blood vessels to dilate by increasing the rate at which NO is
destroyed. Regardless of the mechanism involved, all these theories predict a reduction in
BP with the loss of visceral body fat and a reduction in salt intake. Research has also
shown that a diet composed largely of fruits, vegetables and non-fat diary products
reduces BP, particularly in hypertensive subjects and particularly if dietary sodium is
simultaneously reduced even if no weight is lost.74 However, weight loss has been
repeatedly shown to lower BP even if salt intake is not reduced. 75 76 Nevertheless, how
important weight control is for treating and preventing HTN in the long-term has not
been clearly established.
Obesity has long been associated with an increased risk of developing both HTN and
Type 2 diabetes mellitus (DM).77 It has also long been known that intentional weight loss
14
reduces insulin resistance, lowers blood pressure and helps prevent the development of
Type 2 diabetes mellitus. However, the long-term metabolic effects of intentional weight
loss have been difficult to study because of the difficulty in getting most people to lose
weight and keep it off for many years. An ongoing study in Sweden of obese individuals
who underwent gastric surgery in order to lose weight and keep it off is shedding much
light on the metabolic effects of long-term intentional weight loss.
In this Swedish Obese Subjects (SOS) study, a group of 346 obese subjects who had
gastric bypass surgery were matched with 346 control obese subjects who were drawn
from a registry of 1508 obese potential control subjects. Each experimental subject was
then matched for BMI and 17 other health variables with a control subject. The
experimental subjects then underwent gastric surgery. The average BMI of both groups
was about 41. After 2 years, the control subjects remained at their initial weight while the
subjects who underwent gastric surgery had lost a lot of weight and had an average body
weight 23% lower than before the surgery. Compared to the control subjects, the
experimental subjects who had a 23% weight reduction maintained for 2 years. The
surgical subjects also had a 2.5-fold reduction in the incidence of HTN and a 32-fold
reduction in the incidence of Type-2 DM compared to the control subjects whom had lost
no weight.78 These findings are consistent with those of most other studies that have also
shown a dramatic improvement in IR and BS control when significant weight is lost over
a period of several weeks to several years. Nearly all studies on the relationship between
weight loss and HTN have found a significant drop in BP in hypertensive subjects
whenever weight is intentionally lost and kept off.
More recently, data after 8 years of follow-up of the SOS study have been published.79
After 8 years the average maintained weight loss of those who had the gastric surgery is
16% or about 45 lbs while the weight of control subjects did not change significantly.
The authors concluded, "Whereas this weight reduction had a dramatic effect on the 8year incidence of diabetes (odds ratio 0.16, 95% CI 0.07 to 0.36), it had no effect on the 8
year incidence of hypertension (odds ratio 1.01, 95% CI 0.61 to 1.67). A differentiated
risk factor response was identified: a maintained weight reduction of 16% strongly
counteracted the development of diabetes over 8 years but showed no long-term effect on
the incidence of hypertension." The results of this study suggest that in the long-term
reducing body weight and IR alone are unlikely to prevent or control HTN.
The recent DASH-Sodium clinical trial has demonstrated that the single most important
dietary factor effecting BP is the amount of salt in the diet. Indeed, reducing dietary
sodium from 2400 to 1500 mg/day was shown to reduce BP in both normotensive and
HTN individuals more than reducing dietary sodium from 3300 to 2400 mg/day.80 The
combination of the DASH diet plus restricting sodium intake to 1500 mg/day was shown
to be the most effective strategy for lowering BP in people with and without HTN. While
this study excluded people with Type-2 DM it is unlikely that sodium restriction would
be any less effective in people with Type-2 DM. The one questionable part of the DASH
diet for patients at high-risk for CVD, like people with Type-2 DM, is the sanctioned use
of low-fat dairy products. It would be wise to substitute non-fat dairy products for these
in Type-2 DM patients with a LDL-Cholesterol level greater than 100 mg/dl.
15
It appears that a DASH-style diet that is low in salt, fat and refined carbohydrates and
high in minimally processed fruits, vegetables and whole grains is best for people who
have HTN and IR, IGT and Type-2 DM. In part this is because such a diet promotes
weight loss without hunger, and also corrects electrolyte disturbances involved in the
development of HTN. Losing excess body fat almost always improves insulin sensitivity
and helps to correct the dyslipidemia that frequently results from metabolic disturbances
associated with IR. However, weight loss alone should not be relied on to control BP
with patients with IR, IGT and Type-2 DM. If BP cannot be adequately controlled with
diet and lifestyle changes after 6 months then anti-hypertensive medications must be
utilized.
Do Low Sodium Diets Impair Glucose Tolerance?
HTN is serious and common problem for patients with Type-2 DM. The latest JNC VI
guidelines call for a BP goal for patients with diabetes of below 130 mmHg systolic and
85 mmHg diastolic. In older patients controlling the systolic BP is usually more
challenging but new guidelines state that “risk stratification for major complications of
hypertension (stroke, myocardial infarction, heart failure, kidney failure) is much more
accurate when systolic rather than diastolic BP is used.81 Epidemiological studies have
shown that the rise in systolic BP with age is most closely linked to an excessive intake
of dietary salt.82 Because most Type-2 DM need to reduce dietary salt to help control
their HTN it is important to know what, if any effect changes in dietary salt intake have
on carbohydrate metabolism, IR and BS regulation?
The level of dietary salt in modern diets is much higher than it was during most of human
evolution. It seems likely that the human body is not physiologically adapted to such a
high salt intake. The impact of excessive salt in the etiology of essential HTN is well
established.83 In contrast to numerous studies of the impact of dietary salt on BP, there
have been few studies on the impact of dietary salt on glycemia and insulin levels. One
study examined postprandial BS and insulin levels after feeding either cooked lentils or
white bread either with or without added salt. When salt was added to the lentils the
incremental area under the plasma glucose curve was significantly greater than that for
unsalted lentils (778 mg.min/L vs 200 mg.min/L). When the salt was added to the white
bread the peak BS concentration was significantly higher than when the bread was
unsalted (125 mg/dl vs 114 mg/dl). After consuming both the lentils and bread, plasma
insulin levels were higher 45 minutes postprandially with the salted compared to unsalted
version. The insulin output for the salted compared to the unsalted bread was 39%
greater. The authors concluded that if their results are confirmed by others, they "would
support the recommendation that diabetics, as well as the general population, should
reduce their intake of salt." 84
However, other studies have suggested that the addition of more salt to the diet may
reduce IR, at least in the short-term. For example, one study found that moderately
reducing salt intake about doubled the plasma insulin level in a group of 8 healthy young
(25-40y) subjects even though BS levels were not significantly affected. The much
16
greater insulin to glucose ratio on the lower salt diet led these authors to conclude “... in
younger subjects, moderate dietary salt restriction may have adverse effects on both
vascular and systemic sensitivity to insulin.” 85Another study of 31 patients with essential
HTN and IR compared plasma glucose and insulin responses to a 75g oral glucose intake.
The subjects were either a high-salt (342 mmol/d or 7,866mg sodium/d) or a very-lowsalt diet (34 mmol/d or 782mg sodium/d). This study found that both the BS and insulin
levels were higher on the very-low-salt diet than on the high-salt diet. The results of this
study suggest that a very-low-salt may deteriorate glucose metabolism in patients with
HTN, especially in those with IR, IGT and Type-2 DM. 86 Short-term salt restriction may
impair glucose tolerance in hypertensive patients. Given the conflicting results of the
above studies it is clear that more research is needed to better establish the impact of
altering dietary salt intake on IR, BS levels, insulin levels and carbohydrate metabolism.
It is also clear that some of the discrepancies seen in various studies on the GI of various
foods could be due in part to variations in the amount of salt added to those foods.
The makers of sports drinks have known for many years that the addition of small
amounts of salt to a carbohydrate drink speeds its absorption but high levels of salt can
delay the absorption of fluid and carbohydrate. It seems likely the absorption of dietary
carbohydrate and both the glycemic response and insulin output in response to consuming
various foods could be affected by the amount of salt in those foods. However, excessive
salt intake is strongly linked to the development of HTN, which is common in people
with IR and is found in the majority of people with Type-2 DM. There is a wellestablished and close and partially independent correlation between salt intake and
hypertensive organ disease, which suggests that excess dietary salt is a direct perpetrator
of renal disease and CVD.87 Given the high prevalence of HTN and the very high
prevalence of CVD and renal disease seen in patients with Type-2 DM it seems wise to
encourage them to limit their sodium intake to no more than 1500 mg/d.
Patients with IR, IGT and Type-2 DM should be encouraged to use spices in place of salt.
Indeed, there is even some evidence suggesting that some spices such as cinnamon,
cloves, bay leaves and tumeric may have a potentiating effect on insulin activity.88
Encouraging patients with Type-2 DM to use cinnamon rather than salt in their oatmeal
should help to prevent or treat HTN and may also have a small but favorable effect on
carbohydrate metabolism. It should be noted that dietary sodium that is not accompanied
by chloride has much less impact on BP than sodium chloride. Using MSG, for example
in place of salt in soup is one way to help prevent increased BP.89
How Does Insulin Resistance Effect Blood Clotting and
Inflammation?
Another factor that appears to contribute to the increased risk of CVD seen in people with
IR is an increase in type 1 plasminogen activator inhibitor (PAI-1).90 This is because
PAI-1 is a specific inhibitor of plasminogen activator and so higher levels are associated
with thrombosis. Increasing levels of PAI-1 have been shown to increase the tendency of
blood clots to grow and also to increase the migration of smooth muscle cells in the artery
17
wall. Both thrombosis and the migration of smooth muscle cells within the artery wall
increase the growth of atherosclerotic plaque. PAI-1 is produced by human adipocytes
and its production is greater by visceral fat cells than in subcutaneous fat cells. The
production of PAI-1 increases with increasing body fat cell size.91
An increase in the tendency of blood to clot has long been associated with chronic
inflammation. A study of 1008 men, 40-69y, 1/3 with IGT examined the relationship
between insulin sensitivity and inflammatory markers such as C-reactive protein (CRP),
fibrinogen and white blood cell count. This results of this study suggested that chronic
subclinical inflammation is part of the IRS. Those men with the larger waists, higher
fasting insulin levels and the lower levels of insulin sensitivity (measured directly)
correlated with higher levels of these 3 markers for chronic inflammation.92
Prospectively, elevated CRP has been shown to be a powerful predictor for increased risk
of CAD over the next several years.93 However, whether or not increased CRP causes
atherosclerosis or merely reflects an epiphenomenon accompanying the atherosclerotic
process has not been established.
It is possible that acute phase inflammation may contribute to atherosclerotic plaque
rupture that can trigger a blood clot that shuts off blood supply. This appears to be how
most heart attacks occur. A causal link between the IRS and a chronic inflammatory state
was suggested by a study that showed the increased levels of PAI-1 and fibrinogen in
people with the IRS.94 95 In a population study of healthy women a strong association
between C-reactive protein (CRP), which is a major acute phase protein, and increased
adiposity was observed. Regression analysis revealed that CRP was positively associated
with other characteristics of the IRS such as increased BMI, waist circumference, PAI-1
levels, BP, insulin levels and lower HDL-Cholesterol.96
It has been suggested that chronic inflammation may also contribute to the development
of the IRS and eventually Type-2 DM. According to this hypothesis, stimuli such as
excessive energy intake result in cytokine hypersecretion and eventually lead to IR and
diabetes in genetically predisposed individuals.97 Cytokines such as interleukin-1 and -6,
and tumor necrosis factor-alpha stimulate the liver to produce more acute-phase
inflammatory proteins.98 It appears that excessive energy intake leads to increased
deposits of intraabdominal fat and this may be one key to explaining why IR develops
and why both IR and obesity contribute to a greater risk of developing CVD.
It has been suggested that aspirin therapy reduces the risk of fatal ischemic events in part
by reducing the production of pro-inflammatory cytokines rather than by its anti-platelet
properties.99 More research is needed on the impact of diet on the generation of
proinflammatory cytokines and their potential role in the development of atherosclerosis
and thrombosis. It seems likely that losing excess body fat can ameliorate the chronic
inflammatory state, which should help reduce the risk of developing both atherosclerosis
and Type-2 DM. Weight loss is perhaps most critical in overweight patients with Type-2
DM and other risk factors for atherosclerotic disease, particularly in those who already
have clinical evidence of advanced atheroscerotic disease.
18
Elevated Homocysteine in Type-2 DM Patients
Elevated plasma total homocysteine (tHcy) levels are now a fairly well established risk
factor for CVD.100 In a study of Type-1 and Type-2 DM patients it was only the later who
more frequently had elevated tHcy levels and this was especially true for those Type-2
DM patients with accelerated macrovascular disease.101
In rats, a diet high in fat and/or sugar has been shown to lead to obesity, IR and
hyperinsulinemia and a number of other atherosclerotic risk factors.102 103 104 More
recently a diet high in fat and sugar was associated with alterations of 2 enzymes
involved in Hcy metabolism. This study found that rats fed the diet high in fat and sugar
were hyperinsulinemic and had elevated tHcy levels compared to rats fed a diet low in fat
and high in starch and fiber.105 A low intake of folic acid is often associated with an
increased tHcy level. Whole grains, legumes and many fruits and vegetables are good
sources of this vitamin. Unfiltered coffee has also been shown to raise both LDL-C and
tHcy levels.106
A diet higher in fruits and vegetables has been shown to be associated with a lower tHcy
level in humans.107 The DASH diet, which emphasizes more fruits and vegetables, as
well as increased low and non-fat dairy products, also has been shown to cause a
significant drop in tHcy levels.108 It seems likely that a diet higher in fruits and vegetables
will likely reduce tHcy levels and many other CVD risk factors seen in people with IR,
IGT and Type-2 DM. The consumption of unfiltered coffee should be discouraged.
What Diet Is Best For People With Metabolic Syndrome?
Worldwide there is a growing epidemic of IR and Type-2 DM. This growing epidemic is
particularly evident in human population undergoing rapid cultural and dietary changes
usually from a diet low in fat and sugar and high in fiber to a typical modern diet coupled
with a much more sedentary lifestyle.109
Research in animals has shown that diet-induced IR generally appears before the other
metabolic disturbances associated with the IRS.110 Indeed, not only has a diet high in fat
(particularly saturated fat) and sugar been shown to induce IR in skeletal muscles due to
defects in autophosphorylation and tyrosine kinase activity of the insulin receptors but
these defects were corrected when the animals were switched to a very-low-fat diet high
in fiber and starch.111 So in both humans and animals, IR can be brought on by an energy
dense diet high in fat and sucrose. IR can then be improved by a diet high in fiber and
slowly digested starch and very low in fat. The IR produced by a diet high in fat, sugar
and refined starches may be due largely to the increased energy intake which leads to
increased body fat stores and elevated FFA levels in the blood.
Fischer rats are genetically resistant to developing hyperglycemia. Nevertheless, IR and
the metabolic disturbances associated with it have been induced in these rats simply by
feeding them a diet high in fat and sucrose ad libitum.112 Compared to a control group of
rats fed a low-fat, high-starch diet, those rats fed the high-fat and sucrose diet had
19
increased serum TG and insulin levels, elevated BP, an increased tendency for blood to
clot and increased body weight. These results make it clear that in rats many of the same
risk factors associated with the development of metabolic syndrome and atherosclerosis
in humans can be induced by feeding them a diet high in fat and sugar even though their
BS levels remain in the normal range.
In these studies on rats most of the fat was given as lard with small amounts of corn oil.
More research is needed to determine if the type of fat in the diet promotes IR
independently of the amount of fat or total energy content of the diet. More research is
also needed to determine the relative contribution of sucrose (used in these rat studies),
other sugars relative to different types of starch to the development of IR. It is also
important to determine how much of the IR promoting impact of fats and sugars in the
diet are independent of their impact of ad libitum calorie intake. It may well be that most
or all of the IR promoting effects of diets high in fats and sugars is mediated by their
tendency to increase ad libitum energy intake and promote increased body fat stores.
Another study that examined the effect of switching Type-2DM subjects from a high-fat
(42% kcal) diet with a low P/S (0.3) to a high complex carbohydrate diet (21% fat kcal)
with a high P/S (1.2) and twice as much fiber. The results showed that the average LDLCholesterol dropped by 23%, even though both diets had the same high cholesterol
content (550 mg/d) and were fed isocalorically.113 This study also found no significant
change in HDL-Cholesterol or BS levels. Serum TG changed little in most but did rise
significantly in 2 subjects. It appears that a minority of Type-2 DM patients may
experience at least a transient increase in fasting TG even when high-fiber, highcarbohydrate foods are increased at the expense of dietary fat. However, if the P/S and
fiber are both increased when dietary carbohydrate replaces dietary fat isocalorically,
then most Type-2 DM subjects will experience little change in their TG or HDLCholesterol levels, but their LDL-C will drop markedly. By contrast, if the highcarbohydrate and high-fat diets are fed isocalorically and the P/S remains constant, then it
is more likely that fasting TG will increase and HDL-Cholesterol will fall.114
Nevertheless, both of these presumably adverse metabolic effects on blood lipids
associated with a higher carbohydrate diet would likely be mitigated if the diet was fed ad
libitum and weight was lost. Most research suggests that this is what would happen.
Most carefully controlled clinical trials have shown that a diet composed of less fat, sugar
and rapidly absorbed starches reduces CVD risk factors in people who have IGT and
Type-2 DM.115 Longer term clinical trials in patients who already have IGT have shown
improved diet and more exercise can at least slow the progression from IGT to Type-2
DM.116 117 Of course, IR develops long before IGT is present and by the time IGT is
present beta-cell function has already been impaired.118 Ideally, a healthier diet and
exercise program should be instituted before IR first starts to develop. Unfortunately
there is no cost effective way to diagnose early IR. However, those with a higher BMI
and W/H ratio, lower HDL and higher than average TG and/or HTN and a family history
of Type-2 DM could be presumed to be at high enough risk of having IR to intervene.
20
A diet with a lot of fruits, vegetables, whole grains and 2-3 servings daily of nonfat dairy
products and with a little fish and lean meats or vegetarian alternatives that is also low in
salt, sugar and fat is likely to be ideal for treating most overweight or obese patients with
IR, IGT and Type-2 DM. If instituted early in life and coupled with a moderate amount of
daily activity it seems likely that the growing worldwide epidemic of Type-2 DM could
be largely eliminated.
Do High-Carbohydrate Diets Increase Triglyceride Levels and Reduce
Fibrinolysis?
Higher fasting TG levels are often seen in patients with IR, IGT and Type-2 DM. In
people consuming a typical American diet, higher fasting and postprandial TG levels are
often associated with an increased tendency for blood to clot and/or a reduced ability to
break up those clots (a.k.a. impaired fibrinolysis).
Higher fasting TG levels have been found in many studies that have compared diets high
in carbohydrate with diets high in unsaturated fat in patients with Type-2 DM.119 120
However, most of these studies have lasted only a few weeks. Most epidemiological
studies do not show higher fasting TG levels in human populations consuming highcarbohydrate diets than in those that consume higher fat diets.121 122 The now classic
study of South African prisoners who were switched from a high-fat Western diet to a
low-fat (15%) high-carbohydrate diet showed that fasting TG levels about doubled in
most subjects in the first 3 to 5 weeks but then declined gradually over the next 3-6
months. By the 8th month nearly all subjects had seen their fasting TG levels return to
baseline levels observed on their original high-fat (45%) diet.123
It appears that it may take many months for the body to fully adapt to a diet higher
carbohydrate and lower in fat. So while many studies have shown presumably adverse
effects on blood lipids (increased TG and decreased HDL-Cholesterol), these studies
have typically lasted no more than a few weeks. This does not appear to be long enough
for the body to fully adapt to the higher carbohydrate diet. Figure 2 below shows what
happened to fasting serum TG levels in a group of about 50 postmenopausal women who
were placed on a low-fat, high-carbohydrate diet consisting largely of whole foods.124
21
Figure 2. Effect of increasing dietary carbohydrate at the expense of fat on
fasting plasma triglyceride levels in postmenopausal women.
Adapted from Parks EJ. Am J Clin Nutr 2000;71:424
During the first 4 months of this study dietary carbohydrate gradually replaced dietary fat
in the diet but subjects were required to consume enough calories to prevent weight loss.
During this time fasting serum TG levels rose from 151 to 204 mg/dl. The increase in
fasting TG level was less than that observed by the Stanford study (113 vs 206 mg/dl)
despite a much greater increase in dietary carbohydrate. Part of the reason for this greater
rise in TG levels observed in the Stanford researchers' study was that they used more
refined high-carbohydrate foods (which raise TG levels more than natural highcarbohydrate foods). Another reason was that the Stanford study kept their subjects on
the experimental diets for only 2 weeks. Two weeks is certainly not long enough for the
body to fully adapt to the higher carbohydrate intake. Also, the subjects in this study lost
a little weight during the first 4 months of the study despite the researchers best attempts
to get them to maintain their initial body weights. Weight loss tends to lower TG levels
so even the loss of a few pounds can blunt the TG raising effects of adopting a highcarbohydrate diet.
During the next 8 months of this study the subjects continued to consume the same highcarbohydrate, low-fat (15% of energy). However, during this phase the researchers no
longer tried to control how much their subjects ate or weighed. During this phase the
subjects' calorie intake was ad libitum. During this second phase of the study, average
fasting TG levels gradually returned to their baseline level. Not surprisingly, in this 8
month period the subjects lost another 4.5 pounds consuming a self-selected very-low-fat
diet (ad libitum). It seems clear that if most people were taught to consume a VLFNV
22
diet which consisted largely of natural foods they not only would see their blood lipids
improve and their risk of heart disease fall but they would also lose weight without any
need to count calories.
Stanford University researchers have been leaders in publishing studies that suggest highcarbohydrate diets have adverse metabolic effects on blood lipids. For example, a recent
study found a lower HDL-Cholesterol (39 vs 44 mg/dl) and higher fasting TG levels (206
vs 113 mg/dl) in 8 healthy subjects fed a high-carbohydrate (25% fat) diet compared to
those same subjects fed a high-fat (45% fat) diet for 2 weeks.125 This study also showed
higher postprandial remnant lipoprotein particles (RLP) on the higher carbohydrate diet
compared to the diet higher in unsaturated fat. Increased postprandial and fasting TG
levels are more common in people with IR with or without Type-2 DM. Because some
studies have found an increased risk of CAD in Americans with higher fasting and
postprandial TG levels, the Stanford authors concluded, "Given the atherogenic potential
of these changes in lipoprotein metabolism, it seems appropriate to question the wisdom
of recommending that all Americans should replace dietary saturated fat with
carbohydrate." Is such a conclusion justified?
When a very-low-fat (15% of energy) diet was fed isocalorically with a moderate fat diet
to healthy subjects their fasting TG levels were much higher (188 vs 115 mg/dl) on the
higher carbohydrate diet than on the moderate fat diet. Just as the Stanford researchers
observed in their study, the results of this study also showed that postprandial TG (and
presumably RLP) were also much higher on the high-carbohydrate diet than on the diet
higher in fat (see Figure. 3 below). HDL-Cholesterol was also lower (42 vs 35 mg/dl) in
this study on the higher carbohydrate diet just as it was in the Stanford study. LDL-Chol
was somewhat higher on the VLF (134 vs 128 mg/dl) than the moderate fat diet when
both diets were fed isocalorically. However, when the VLF, high-carbohydrate diet was
fed ad libitum, the LDL-Cholesterol was now lower (119 vs 128 mg/dl) than on the 30%
fat diet. Remarkably, this was despite a much higher PUFA content (11.2% vs 2.5%
energy) and P/S (1.6 vs 0.5) on the 30% fat diet compared to the VLF diet. The P/S ratio
in the Stanford study was also higher on the higher fat diet. And while the fasting TG
levels were still a little higher (130 vs 115 mg/dl) on the VLF fed ad libitum compared to
the moderate fat diet, the postprandial TG level was already considerably lower on the
15% fat diet compared to the 30% fat diet. This is not surprising because diets much
lower in fat result in the production of much fewer TG-rich chylomicrons.
23
Figure 3. Effect of an AHA-Style Diet and a VLF Diet (Fed either Ad Libitum or
Isocalorically with the AHA-Style Diet) on Serum TG
Adapted from Lichtenstein. Arterioscler Thromb. 1994;14:1751
As we have seen, an increased fasting and postprandial TG level may be associated with
more potentially atherogenic RLP. As Figure 3 above clearly shows, even when fasting
TG levels are somewhat higher on a higher carbohydrate diet, they may still be much
lower during most of the day on such a diet. Because most people spend most of the day
in the postprandial state, it seems clinically more relevant to study the impact of dietary
changes on postprandial blood lipids rather than just fasting blood lipid levels. People
spend most of their lifetime in a postprandial state so it may be inappropriate to
generalize the findings about higher fasting TG levels promoting CAD to people
consuming a VLF diet. This is because the postprandial rise in TG levels (and
presumably RLP) will be much less with an ad libitum VLF diet than it would be on an
ad libitum diet with added fats and oils. It should be noted that 90 minutes of brisk
walking reduced postprandial TG levels by 20% and also reduced the rise in postprandial
insulin levels.126 Therefore, the combination of a VLF diet combined with regular
aerobic exercise is perhaps best for reducing postprandial TG levels.
It seems likely that potentially atherogenic RLP would also be lower but these were not
measured in this study. It should be clear that clinicians cannot assume the higher risk of
CVD often associated with higher fasting and postprandial TG levels (in people
consuming high-fat Western-style diets) would be comparable to the risk of CVD with a
similar fasting TG level in people consuming a VLF diet. It seems likely that RLP would
24
fall along with postprandial TG levels on a low-fat diet particularly when it is fed ad
libitum for a long time. This is because such a diet would likely lead to a reduced
chylomicron production and a loss of body fat stores. The long-term effect of highcarbohydrate diets on blood lipids and body weight is an area that deserves more
attention from researchers.
Whether or not elevated serum TG levels are an independent risk factor for
atherosclerotic heart disease has been a matter of scientific debate for many years. A
secondary analysis of data from MRFIT, LRCCPPT and the LRC Prevalence and
Mortality Follow-up Study concludes "with few exceptions no significant interactions
between cholesterol subfractions and triglycerides were found... and triglyceride
measurement did not improve discrimination between those subjects that did and did not
suffer coronary heart disease events."127 These authors also stated that, "Evidence does
not support the routine measurement of serum triglyceride levels for assessing coronary
heart disease risk." In an accompanying editorial, Dr Rubens suggested that high
triglyceride levels, like the presence of other risk factors "should prompt a clinician to be
particularly aggressive about control of other concomitant risk factors such as smoking,
obesity, hypertension, sedentary lifestyle, diabetes mellitus, elevated LDL-cholesterol or
low levels of HDL-cholesterol."128 High TG levels are often associated with lower HDLCholesterol and much of the risk associated with higher TG levels disappears when HDLCholesterol levels are corrected for.
High fasting and postprandial TG levels are often associated with IR and an increased
tendency for blood to clot when people are consuming high-fat diets.129 Short-term
studies often show an increase in fasting TG levels when dietary carbohydrate replaces
dietary fat.130 A study that compared the impact of high- and low-GI diets found that the
low-GI diet lowered both BS and insulin levels throughout the day and improved insulin
sensitivity compared with the high GI diet. Serum TG levels dropped 30% and PAI-1 was
reduced on the low-GI diet compared to the high-GI diet.131 Results suggests that a less
processed and refined diet may help to lower TG levels, reduce thrombosis and increase
fibrinolysis even if it does not lead to weight loss.
A low-fat, high-carbohydrate diet has been shown to reduce blood viscosity of patients
with CVD.132 Compared to an isoenergetic high-carbohydrate meal, a higher fat meal
with either as butter or a MUFA-rich oil has been shown to increase clotting factor VII
activity and inhibit fibrinolysis.133 Compared to a diet high in natural starch-rich foods a
diet high in either fat or sucrose were both shown to increase clotting Factor VII by 10%
in a group of 20 healthy normal weight women 20-51y.134 Epidemiological studies
suggest a 10% increase in clotting factor VII activity is associated with an increased risk
of fatal CAD135 136 137
Overall, research to date demonstrates that higher fasting TG levels induced by replacing
dietary fat with carbohydrate is associated with very different metabolic effects than
higher TG observed in people consuming a typical high-fat modern diet. Higher TG
levels on high-fat, low fiber modern diets are often associated with IR and an increased
risk of CVD primarily because they are associated with exaggerated postprandial
25
lipemia.138 139 By contrast, higher fasting TG levels that result from increasing dietary
carbohydrate primarily from whole foods sources is usually associated with increased
insulin sensitivity, a decreased tendency for blood to clot, weight loss without hunger and
a reduction in most other CVD risk factors. Indeed, long-term compliance with a natural
foods high-carbohydrate diet often results in a drop in fasting and a more marked drop in
postprandial TG levels in the long-term. Clinicians should not assume that a transient or
even prolonged increase in fasting TG level and/or a drop in HDL-Cholesterol level (that
often results from the isocaloric substitution of carbohydrate for monounsaturated fat)
increases the risk of CVD in people with IR, IGT and Type-2 DM.
Do High-Carbohydrate Diets Cause a Drop in HDL-Cholesterol?
Another concern about very-high-carbohydrate diets is that that they may lower HDLCholesterol. However, this drop in HDL-Cholesterol has been shown primarily in shortterm studies in which body weight and/or calorie intake is carefully controlled to prevent
weight loss on the higher carbohydrate diet. However, healthy diets that have a very low
fat content and a very high carbohydrate content generally reduce ad libitum energy
intake and weight loss usually increases HDL-Cholesterol levels. This suggests that
studies that require subjects to consume the same energy intake on both low- and high-fat
diets may not be relevant in the real world conditions where people’s appetites generally
control energy intake.
The Stanford group and others have shown a drop in HDL-Cholesterol and have
suggested that this drop in HDL-Cholesterol seen in their short-term studies (in which
dietary carbohydrate is increased at the expense of monounsaturated fat) should be
expected to increase the risk of CAD in the long run. 140 141 There are 2 reasons to be
skeptical of such a claim. First, there is growing evidence that the drop HDL-Cholesterol
that results from restricting dietary fat intake does not lead to a permanently lower HDLCholesterol. This is because replacing high-fat foods with high-carbohydrate foods
usually reduces ad libitum energy intake. Reduced ad libitum energy intake results in
weight loss and a lower body weight is usually associated with an increase in HDLCholesterol. For example, when a group of hypercholesterolemic men were placed on an
ad libitum VLFNV diet for 3 months their energy intake decreased and they lost about
16.5 lbs. On this low-fat diet, their LDL-Cholesterol dropped from 236 to 139 mg/dl (or 41%) and their TG dropped from 170 to 145 mg/dl (or -15%) but their average HDLCholesterol was essentially unchanged (36 to 37 mg/dL or +3%).142 Those who continued
to consume a very-low-fat intake for another 9 months saw their HDL-Cholesterol
continue to increase. It should be noted that fasting plasma TG levels also fell on average
in this study which is the opposite of what the Stanford group and others have repeatedly
observed in short-term studies where both the high-fat and high-carbohydrate diets were
fed isocalorically. One problem with these studies is that the dietary carbohydrate is
largely refined grains and sugars which have a high glycemic index. One study found that
lower HDL-Cholesterol was associated with high-glycemic index carbohydrates but not
with those with a low-glycemic index.143 The impact of different types of carbohydrate
on blood lipids and the risk of CVD is an area that requires a lot more research.
26
Another study, in which a VLFNV diet was fed ad libitum to patients at high risk of CAD
found that fasting TG levels were higher than in control patients who were fed an AHAstyle diet. Indeed, in many patients the VLFNV diet was shown to result in regression of
atherosclerotic plaque while the AHA-style diet was shown to result in progression of
atherosclerosis in most patients.144 It should also be noted that people who live in
countries where very-low-fat diets are the norm have lower HDL-Cholesterol on
average compared to Americans and yet also have a much lower risk of CAD.145
One reason a lower HDL-Cholesterol on a VLF may not mean the same thing as a low
HDL-Cholesterol on a high-fat diet is that HDL's ability to promote reverse cholesterol
transfer may be impaired by diets higher in fat. It has been shown that the fractional
clearance rate of cholesterol is much faster on VLF diets than it is on diets higher in
fat.146 This means that it is likely that the amount of cholesterol transported back to the
liver from the arteries may not be impaired on a high-carbohydrate diet despite a lower
HDL-Cholesterol level. In animals this reverse cholesterol transport was not impaired
despite a much lower HDL-Cholesterol on a high-carbohydrate diet compared to a highfat diet.147
So while HDL-Cholesterol does often fall initially when most people first adopt a
VLFNV diet, it is not clear that this lower HDL-Cholesterol level necessarily increases
the risk of CAD. Furthermore, in most patients, the adoption of a VLFNV diet will
usually result in weight loss in the long run and this weight loss will eventually result in
HDL-Cholesterol returning toward baseline levels or even higher levels in some patients.
One study found that HDL-cholesterol and apo-A-1 levels may remain modestly
depressed even after 8 months of consuming an ad libitum very low-fat in most
postmenopausal women if the amount of weight lost is modest (only 5-15lbs). However,
in this study most of the dietary carbohydrate came from high-glycemic index foods with
a low to modest fiber content.148 However, even if only modest amounts of weight are
lost it is likely that fasting TG level will return close to the baseline level even though
HDL-Cholesterol levels remain modestly depressed.
By contrast, research suggests that high-fat energy dense diets promote excessive energy
intake and weight gain.149 Weight gain will often lead to IR, increased fasting and
postprandial TG levels, lower HDL-Cholesterol levels and a shift towards more small,
dense LDL particles. Of course, whatever the short-term impact of high-carbohydrate or
high-fat diets on body weight and blood lipids is less important than their impact on the
atherosclerotic process and on morbidity and mortality from CVD and other causes. One
should not become so preoccupied with short-term changes in blood lipids to lose sight of
the long-term metabolic consequence that have been demostrated clinically and observed
in human population studies. This research proves beyond a reasonable doubt that highcarbohydrate diets consisting largely of minimally processed foods rarely leads to
clinically significant atherosclerosis and often leads to regression of pre-existing
atherosclerotic lesions.
27
High-Carbohydrate Diets Reverse Atherosclerosis and Reduce AllCause Deaths
Ornish observed significant progression of atherosclerosis on a AHA-style diet even in
most patients taking cholesterol-lowering medication while those on a very low-fat, highfiber diet experienced regression even though none were taking cholesterol-lowering
drugs.150 Nevertheless, some have claimed that very low-fat diets per se may be
dangerous for the general public because they cause adverse lipid changes that promote
atherosclerosis.151 But if high-carbohydrate diets are more atherogenic than diets higher
in fat, what are we to make of the studies that reported regression of atherosclerosis in
most patients who already have advanced coronary artery disease (CAD) when they
followed a very-low-fat, near vegetarian diet? 152 153 154 155 Indeed, it was shown long ago
that a VLFNV diet reduced all-cause mortality in a group of individuals at high-risk of
CVD compared to a typical American diet.156
By contrast, many of those who claim high-carbohydrate diets are dangerous also insist
that a diet high in monousaturated fats improves blood lipids and is, therefore, beneficial
in treating patients with atherosclerosis. However, there are no studies showing reversal
of atherosclerosis on a low-carbohydrate, high-monounsaturated fat diet. Indeed, a sudy
that examined the atherogenic potential of lipoprotein particles harvested from 19 Type-1
DM subjects found a greater number of large VLDL particles in those fed a highmonounsaturated fat diet compared to those fed a high-carbohydrate diet. Larger VLDL
particles are usually associated with small, dense LDL particles that are believed to be
more atherogenic. Since both the high-monounsaturated fat and high-carbohydrate diets
had the same amount of SFA, cholesterol and fiber and were fed isocalorically the results
of this study suggest that diets higher in monounsaturated fatty acids and lower in
carbohydrate may be more atherogenic. The authors of this study concluded “that in
normolipidenmic, nonobese fasting patients with type 1 diabetes, a high carbohydrate diet
versus a high monounsaturated fat diet results in fewer circulating big VLDL particles
and therefore perhaps a lower atherogenic potential”.157
Human studies of lipoprotein metabolism have shown that bigger VLDL particles often
lead to the generation of more atherogenic IDL and small dense LDL particles.158 Two
recent studies that used nuclear magnetic resonance spectroscopy to measure changes in
atherosclerotic lesion showed that large VLDL particles were associated with more
advanced atherosclerotic lesions159 and a greater atherosclerotic disease risk.160
Claims that high-carbohydrate diets necessarily promote atherosclerosis are questionable
given that such a diet was shown to reverse atherosclerotic lesions in most people even in
those who had higher fasting triglyceride levels. Claims that high-monousaturated fat
diets are preferable to high-carbohydrate diets for most people is not supported by
credible clinical research using hard clinical end points (e.g. angiograms, heart attacks,
overall mortality). However, the impact of VLFNV diets on atherosclerosis, CAD and
all-cause mortality in patients with Type-2 DM has not been adequately studied in wellcontrolled long-term trials. This is an area where more research is clearly needed before
any firm conclusions should be drawn.
28
Risk Factors for the Development of Diabetes
The major risk factors for the development of Type-2 DM include older age, obesity,
family history of Type-2 DM, a prior history of gestational diabetes, IGT and/or IR,
physical inactivity and a rich Western-style diet with a lot of fat, sugar and other refined
carbohydrates. Type-2 DM is more common in modern industrial societies than in third
world countries even though it appears people of European origin are less genetically
prone to develop Type-2 DM than many ethnic groups of African, Asian, Pacific
Islanders and Native Americans decent.
The worldwide incidence of Type-1 DM in multivariant analysis was shown to have an
inverse relation to energy intake from vegetable products and positively correlated with
energy intake from animal sources.161 Studies of both experimental animals and humans
suggest that a high intake of dietary protein, particularly from animal origin is somehow
involved in the development of Type-1 DM.162 Conversely, it may be that modern diets
with a lot of animal products may lead to excessive energy intake. There is some
evidence that over nutrition and hyperinusulinemia early in life may lead to an increased
risk of developing Type-1 DM.163 164
It seems clear that the typical modern diet rich in animal products, fat, refined
carbohydrates and low in fruits, vegetables, whole grains and legumes plays a significant
role in promoting all types of DM.
Effects of Increasing Age on Insulin Resistance
Most often Type-2 DM develops in people after age 40y. Given that IR and Type-2 DM
both increase dramatically with age in America and most other industrialized countries it
became widely believed that the aging process itself played a major role in their
development.165 By age 75y about 20% of Americans will have Type-2 DM.166 However,
in rats the impact of aging process alone on the development IR appears to be quite
modest when the diet is high in starch and fiber. On the other hand, when the rats
consume a diet high in fat and sugar, IR is already quite severe by early midlife.167
Studies of humans also suggest that most of the increase in IR seen in older people is
associated with differences in diet, body weight, body fat distribution, fitness level and/or
activity level. 168 169 170
Aging is associated with a greater proportion of body fat stored in the abdominal region.
Increased intra-abdominal fat is most closely linked to the development of IR and Type-2
DM.171 This makes it difficult to separate the effects of aging from those caused by
excessive calorie intake and inactivity over a prolonged period of time.
The prevalence of IR, IGT and Type-2 DM all increase dramatically as people age but
there are many reasons for this. The aging process itself is associated with only a very
modest reduction in the capacity to produce insulin and a somewhat delayed insulin
action. However, in the absence of increased visceral fat stores, insulin sensitivity does
not appear to be much impaired by the aging process alone.172 The age-related increase in
29
IR seen in many older Americans appears to be primarily due to a rich Western-style diet
and increased visceral fat stores.173 Also, the level of physical activity in many elderly
people is very low, even by American standards. This is why it is very difficult to
separate the effects of the aging process itself from those of diet and lifestyle factors. In
addition, the elderly are more likely to be taking drugs that can raise BS and/or increase
IR (eg. beta-blockers and corticosteroids).
Because the American population is becoming fatter on average and there is a growing
percentage of Hispanic immigrants who are more predisposed to develop Type-2 DM on
a Westernized diet than other Americans, the incidence of Type-2 DM is also increasing
dramatically in those younger than 40 y. The 1995 Dietary Guidelines for Americans
recommended that body weight should not increase by more than 10 lbs after the
attainment of adult height.174 Unfortunately, most Americans do not attain this goal and
average body weight has been increasing in all modern societies.175 176
The primary defect in BS regulation seen in older patients with Type-2 DM is resistance
to insulin mediated glucose uptake by skeletal muscle cells and adipocytes. By contrast,
in middle-aged obese patients with Type-2 DM there is not only IR but also impaired
glucose-induced insulin release from the beta-cells and altered regulation of liver glucose
output resulting in an increased release of glucose into the blood. Both older and middleaged patients with Type-2 DM have a limited first phase release of insulin in response to
rising BS following a meal. However, the second phase of insulin release is more likely
impaired in middle-aged obese patients with Type-2 DM than in older patients with
Type-2 DM.177
To summarize, it is clear that the prevalence of IR and Type-2 DM does increase with
age. However, this is primarily the case in technologically advanced countries where
sedentary behavior is the norm and the diet is rich in fat, sugar and other refined
carbohydrates. This is largely because body weight and particularly intraabdominal fat
stores increase with time (or age). While there are a small percentage of people who
develop significant IR due to genetic factors that trigger biochemical changes even with a
healthy lifestyle, it is primarily the age-related increase in body fat, particularly in the
abdominal area combined with decreasing physical activity that account for most of the
IR seen in older Americans.
Insulin Resistance and Type-2 DM Are Increasing in Young
Americans
The prevalence of Type-2 DM in people younger than 40 y is increasing in virtually all
technologically advanced societies. In the U.S. this increase is most notable in minority
populations and particularly those who migrate to the U.S. as children, teenagers or
young adults from Third World countries. There are also many younger people with IR
and a normal FBS who will eventually develop Type-2 DM as they age. Unfortunately,
there is no easy way to determine who these future Type-2 DM patients will be.
30
Virtually all Type-2 DM patients and most people with IGT have IR. In order to develop
Type-2 DM an individual who already has IR must also lose some of their capacity to
increase insulin output in response to a rising BS level. When insulin output starts to
decline, perhaps due to prolonged over stimulation of the beta cells, it creates a relative
deficiency of insulin even though insulin output may still be higher than normal. The
ability of IR to provoke beta-cell failure in genetically susceptible people may be a
critical step in the development of Type-2 DM.178
Those who have the IRS and never develop IFG, IGT or Type-2 DM continue to produce
enough extra insulin to overcome the IR and thus prevent FBS levels from reaching
abnormally high levels. Nevertheless, IR (and the hyperinsulinemia that must accompany
it when BS levels are normal) still increase the risk of coronary heart disease even when
dyslipidemia and HTN are not present 179 180. IR sets the stage for the development of
Type-2 DM and also is by itself a major risk factor for the development of CVD (even in
those with normal FBS levels). Unfortunately, IR often escapes clinical suspicion in its
early stages because FBS, blood lipids and BP in younger individuals may all still be
within the "normal" range.
The goal of nutritional management of patients with IFG and Type-2 DM is to normalize
BS regulation and reduce risk factors for CVD and kidney disease. There is no known
diet that can increase the capacity to produce insulin by the beta-cells of the pancreas in
Type-2 DM patients. Nevertheless, most Type-2 DM produce as much or more insulin
than most slender and normal weight people of the same age. This is because the body's
need for insulin increases dramatically with increasing BMI. Both reducing excess body
fat and increasing physical activity improves insulin sensitivity in obese Type-2 DM
patients.181 Because both exercise and weight loss reduce IR, they usually reduce
hyperinsulinemia and improve BS regulation and blood lipid levels and lower BP. This is
why a healthy diet, exercise and weight loss should be the cornerstones of the treatment
plan to reduce the risk of developing CVD in patients with IRS with or without Type-2
DM.
Genetic Factors Contribute to IR and Type-2 DM?
Although Type-2 DM does not follow the classic Mendelian pattern of inheritance, there
is little doubt that genetic traits strongly influence its development. In studies of identical
twins, the concordance rate is nearly 100%. This means that if one identical twin
develops Type-2 DM the other will also. By contrast, the concordance rate for Type-1
DM in identical twins is only 50% which means that if one twin develops Type-1 DM
there is a 50-50 chance that the other twin will as well.182 Of course, identical twins
reared in the same or very similar environment usually end up adopting very similar diets
and other lifestyle characteristics. In order to separate the impact of genes from
environment it would be necessary to rear the twins in very different environments and
this has not been done. However, in a few rare cases where one twin became obese and
the other did not it is always the thinner one who avoids Type-2 DM or at least develops
it much later in life. This suggests that even a strong genetic predisposition to develop IR
31
and Typoe-2 DM can prevent or at least delay its development for many years by
adopting a healthy lifestyle that prevents the development of excessive visceral fat stores.
In the US, the incidence of Type-2 DM is highest among Native Americans and Pacific
Islanders and higher among people of Asian or African decent than those of European
decent. Hispanic Americans are not a racial group but many have ancestry from these
higher risk groups and so the incidence of Type-2 DM is also high in Hispanic
Americans. It has been postulated that the increased tendency for IR and Type-2 DM to
develop in these ethnic groups is related to a "thrifty" genotype which favors the
deposition of visceral fat in modern societies.183
Pima Indians living in Maycoba, Mexico consume a minimally processed highcarbohydrate (63% of calories), low-fat (23% of calories) diet. This diet is composed
largely of beans, potatoes, corn tortillas supplemented with some fruits and vegetables
and small amounts of lean animal protein.184 Even though the Mexican Pimas are from
the same genetic line as the Pima Indians of Arizona they weigh an average of 60-65 lbs
less and only rarely develop Type-2 DM before the age of 50y. By contrast, the Arizona
Pimas have the highest incidence of Type-2 DM of any population ever studied. By age
50y more than half of all the Arizona Pimas have developed Type-2 DM. The differences
seen in these two groups of Pimas coupled with the fact that obesity and Type-2 DM
were uncommon among the Arizona Pimas before World War II certainly suggests that
the adoption of a diet high in sugar, refined flour and fat promotes the development of
obesity and Type-2 DM in those who are genetically predisposed.
Type-2 DM is a complex metabolic disorder that involves many different biochemical
abnormalities. These many different biochemical abnormalities plus the clinical variation
among Type-2 DM patients make it clear that this disease has a polygenic hereditary
component. Many of these abnormalities are present for many years before Type-2 DM
develops. However, once hyperglycemia develops both insulin secretion and insulinmediated glucose utilization become even more compromised than in the prediabetic
state. The magnitude of the decrease in insulin receptor kinase activity correlates with the
degree of elevation in FBS. However, the defect in insulin receptor kinase activity is
usually normalized after weight reduction and other measures that reduce BS. This
indicates that this metabolic defect is secondary and not primary.185
The role of genetics in determining the risk for developing IR and Type-2 DM is
complicated by the fact that the perinatal environment may influence the tendency to
become obese 186 and develop IR.187 Lower birthweight is independently associated with
a greater tendency to develop IR as an adult. Undernutrition during the first two
trimesters of pregnancy puts the child at an increased lifelong risk of becoming obese.
While the tendency to develop Type-2 DM is clearly inherited, the precise nature of the
genetic defects remain largely unknown except for a few genetic syndromes associated
with severe insulin resistance (IR).188
Genetic factors clearly predipose people to problems with IR. Indeed many close
relatives of people with Type-2 DM have been shown to have IR even though their FBS
32
levels are well within the normal range.189 Many of these relatives are destined to develop
Type-2 DM if they follow a typical American diet and sedentary lifestyle. Neither the
genetic factors that predispose one to develop Type-2 DM nor age are considered
modifiable risk factors. However, it has been shown in animals that at least some
biological aspects of the aging process can be slowed down by reducing energy intake.190
Pharmaceutical companies are now working on ways to modify or manipulate genes
which may some day lead to ways to more successfully treat or prevent IR and Type-2
DM. For now, the treatment of IR and Type-2 DM should focus on more easily modified
risk factors.
Body Weight, Insulin Resistance and Type-2 DM
Both average body weight and the prevalence of obesity are continuing to increase in all
ethnic groups in the U.S.191 This has ominous implications for the development of IR,
IGT and Type-2 DM because the association between obesity and particularly increased
visceral body fat stores is well established.192 Indeed, after controlling for genetic factors,
a study of twins found that the only factor to be independently related to fasting plasma
insulin level was the BMI.193
It has long been known that in the obese, insulin levels are usually elevated in both
normal and most diabetic individuals, both postprandially and in the fasting state.194 The
relationship between body weight and the average fasting insulin levels is shown in
Figure 4. It is clear that fasting insulin levels are on average much higher in people who
are overweight or obese compared to those who are close to ideal body weight or
underweight. However, there are some people who are overweight who actually have
lower insulin levels than some people who are close to ideal body weight. This is because
there are many people in America who have quite a bit of IR even though they are close
to or at a “healthy” body weight (BMI 18-25). For many of them a truly ideal body
weight may be even more slender, at least in terms of their risk of developing IR and
Type-2 DM and CVD.
For any given individual, the loss of body weight almost always lowers fasting insulin
levels and weight gain almost always raises fasting insulin levels because weight gain
increases IR. Significant IR is rare in very thin individuals but when it does occur weight
loss is not a viable option. In slender individuals with Type-2 DM exercise and to a
limited extent dietary changes can still increase insulin sensitivity and improve BS
control.
33
Figure 4. The Average Fasting Insulin level of People of Different Body Weights
A prospective study of 114,281 female nurses by Harvard researchers examined the risk
of developing Type-2 DM and its association with body mass index (BMI).195 In this
study, nurses who were in general good health and between the ages of 30 to 55 y were
followed for 14 years. At the start of this study all subjects had normal FBS levels.
During this 14 y follow-up period 1,917 nurses were diagnosed with diabetes. The results
of this prospective study on nurses are shown in Figure 5.
Figure 5 shows that the relative risk of developing Type-2 DM increases dramatically
with increasing BMI. These data provided compelling evidence that the relative risk of
developing Type-2 DM in women is very low if they are close to ideal BMI (19 to 22 if
maximum longevity is the criteria for "ideal"). Compared to the thinnest women (BMI <
22.0), the heaviest women were 93.2 times more likely to develop diabetes over a 14 y
period. However, even within the "normal" weight group those with a BMI of 24.0-24.9
were still 5 times more likely to develop diabetes than those who had the lowest BMI
(<22.0). Women who were overweight but not obese (BMI 25.0 to 29.9) were from 8 to
25 times more likely to develop diabetes during the ensuing 14 y follow-up period
compared to those with a BMI <22.
Figure 5. Impact of Increasing BMI on the Risk of Developing Type-2 Diabetes Mellitus
in Women
34
This study also showed that even after adjusting for present body weight, the women who
had gained 5.0 to 7.9 kg after age 18 y were nearly twice as likely to develop diabetes as
those whose weight had remained fairly constant (+ or - <5.0 kg). In addition, those
women who had lost 5 kg or more since they were 18 y cut their risk of developing Type2 DM by 50% or more. This means that a woman with a BMI of 24 to 24.9, who had
gained 5.0 to 7.9 kg since she was 18 y, would actually be about 4 times more likely to
develop Type-2 DM than a woman with the same BMI but who had been heavier as a
teenager and had lost 5 kg or more and kept it off. She would still be about 2.5 times as
likely to develop Type-2 DM as a women who was weight stable since age 18 y and had
a BMI of less than 22.0. By contrast, a women with a BMI of 24.0 to 24.9, who had
gained 5 to 7.9 kg since age 18 y would have about a 10 times greater risk of developing
diabetes than a woman whose BMI had been stable and below 22.0 throughout her
lifetime.
It should be noted that even in those with a strong genetic predisposition to progress from
IGT to Type-2 DM, the risk of becoming diabetic can likely be dramatically reduced or at
least postponed to a much older age by a healthier diet and regular exercise which result
in long-term weight control.196 Logic dictates then the best diet for the prevention and
treatment of IR, IGT and Type-2 DM is one that is least likely to lead to a positive energy
balance over time. This research leads to the inescapable conclusion that both reduced
insulin sensitivity and the development of Type-2 DM are largely the result of an
excessive calorie intake over time leading to the storage of excess body fat in genetically
predisposed individuals. Increased stores of visceral fat require the beta-cells of the
pancreas to produce much higher insulin levels 24 hours a day, year after year in order to
keep BS levels in the normal range. Eventually, for reasons that are not clear, the
nutritional stress of a rich diet, particularly when coupled with inactivity takes its toll and
the insulin-producing beta-cells. In some people these beta-cells can no longer keep up
35
with the increased demand caused by the IR for greater and greater amounts of insulin.
When insulin production can no longer be ratcheted up enough to meet the growing
demand due to IR then BS levels begin to rise. Usually, postprandial BS levels start to
increase while fasting BS levels remain well within the normal range. With time this is
eventually followed by higher fasting BS levels as well. Over many years, both fasting
and postprandial BS levels drift high enough for IGT (or IFG) and finally Type-2 DM to
be diagnosed.
There is evidence that those who gain weight later in life are more likely to develop
hyperinsulinemia than those who gain weight earlier in life.197 This may be part of the
reason that Type-2 DM is so prevalent among people in developing countries that
undergo rapid industrialization and adopt a more modern diet and lifestyle or in those
who migrate from Third World countries to the U.S. It seems obvious that the best way to
prevent or at least slow the loss of insulin sensitivity and the development of Type-2 DM
is a diet and lifestyle that minimizes the gain of body fat after age 18 y.
A meta-analysis of studies of Australian Aborigine showed that the adoption of a modern
Western-style diet coupled with inactive lifestyle resulted in hyperinsulinemia, weight
gain, Type-2 DM, dyslipidemia and HTN. However, when the Aborigine returned to the
hunter-gatherer lifestyle of their youth they showed striking improvement in both
carbohydrate and lipid metabolism. This shows that the negative impact of a Western
lifestyle can be at least partially reversed if a lifestyle more in sync with what the human
body is designed for biologically is adopted.198 To a large extent then, Type-2 DM is a
disease caused by an inactive lifestyle coupled with a typical Western diet that is high in
fat and refined carbohydrates. Such a lifestyle often promotes weight gain, obesity and
eventually Type-2 DM in genetically susceptible individuals.
The loss of a modest amount of excess body fat often leads to an improvement in BS
levels in people with IFG and Type-2 DM.199 Energy restriction has been shown to
improve glycemic control and blood lipids and this improvement is independent of the
macronutrient content of the diet. A study of Type-2 DM subjects found that the loss 6.6
kg reduced fasting BS by 14%, insulin by 27% and HbA1c by 14% after 8 weeks. This
study also found that the drops in BS, insulin and HbA1 levels were similar whether the
diet was very high in carbohydrate (10% fat en.) or high in either saturated or
monounsaturated fat (32% fat en.).200 It is well known that lowering BS levels can at least
partially reverse both IR and the decline of insulin secretion which are partially induced
by glucose toxicity.201 The first phase of insulin secretion in response to a meal tends to
deteriorate more rapidly in the presence of higher BS levels.202
A study of obese subjects found that those who lost weight following gastric surgery and
then maintained an average weight loss of 16% for 8 years had a greatly reduced risk
(odds ratio = 0.16) of developing Type-2 DM compared with control subjects who had a
similar initial weight and age but who did not have the surgery and maintained a constant
body weight.203 It seems clear that the primary focus of medical nutrition therapy for the
treatment and prevention of Type-2 DM should be avoiding excessive energy intake. Of
36
course calorie restriction without changing diet composition usually results in chronic
hunger, which undermines long-term weight control efforts.
Research of Japanese and Japanese –Americans suggests that a modern Western-style
diet and lifestyle consumed from early in life causes an up regulation of pancreatic betacell function and this eventually leads to enhanced insulin secretion in adulthood. This
may set the stage for the development of hyperinsulinemia, Type-2 DM and CVD later in
life.204 If this is the case then the best way to reduce the incidence of Type-2 DM in the
US and other developed or developing countries would be to have people alter their
eating behavior and physical activity level to avoid stressing human physiology to the
breaking point. Both the prevention of obesity and the permanent loss of excess body
weight will reduce IR and help prevent the development of Type-2 DM and to do this
successfully may mean abandoning the modern diet and sedentary lifestyle to which an
increasing number of the World’s population has become accustomed.
Most researchers believe that the typical modern Western diet and lifestyle promotes IR
and the development of IR, IGT and Type-2 DM primarily because it leads to increased
body fat stores. However, even subtle adverse changes in both carbohydrate and lipid
metabolism have been observed in just 2 weeks on a modern, high-fat diet in both Pima
Indians and Caucasians.205 In this study, the researchers compared the metabolic response
to either a typical high-fat, Western-style diet or a diet consisting largely of the traditional
for Pima Indians of the American Southwest. The traditional Pima diet was high in fiber
and starches and low in fat. To avoid confounding by difference in energy intake on the
two diets the subjects were required to maintain the same body weight during the two
week study period. They found that insulin levels and FBS levels were significantly
higher on the high-fat diet than on the high-fiber, high-carbohydrate traditional Pima diet.
Even though this study found no significant change in IR on the modern diet compared to
the traditional Pima diet, they did find impairment of noninsulin mediated glucose uptake
and a reduced effectiveness for increased BS to trigger insulin release. Overall, they
found "the ability to compensate for a particular degree of insulin resistance was
diminished on the modern diet."
It is known that most Pima Indians and a large percentage of Americans will develop IR,
IGT and Type-2 DM on a typical high-fat, refined carbohydrate modern diet. Diets high
in fat (and particularly saturated fat) and refined carbohydrates (particularly sugar) have
been most closely linked to the development of IR, while diets high minimally processed
high-carbohydrate foods are most often associated with increased insulin sensitivity. 206
No doubt the main reason for this is that most Pima Indians in the US as well as a large
percentage of other Americans consume excessive calories end up overweight eating
diets loaded with fatty meats, dairy products and refined carbohydrates.
Some popular diet book authors have suggested that high-carbohydrate diets cause
hyperinsulinemia and this leads to IR and increased body fat stores. In fact, studies of
Pima Indians have shown that those with IR and high insulin levels were actually less
likely to gain weight over time than Pima Indians with less IR and lower fasting insulin
levels.207 IR appears to be largely the result of excessive energy intake, inactivity and
37
weight gain rather than the cause of weight gain. Indeed, IR results in the increased
release of FFA from adipocytes and increased fat oxidation.208 This may be because IR
slows the uptake of glucose and the storage of glycogen in muscle cells making these and
other tissues more dependent on FFA as an energy source. Since IR reduces the body’s
ability to store fat, IR may be a physiological adaption to prevent even more excessive
energy stores.209
More than anything else, IR, IGT and Type-2 DM are the consequence of a chronically
excessive calorie intake and increased body fat stores, particularly in the abdominal
region. A typical Western diet has also been shown to produce subtle adverse changes
carbohydrate metabolism even when calorie intake is controlled. It seems obvious that
the human body is not biologically designed to function optimally in the modern world
where the diet is unusually rich (relative to what humans evolved on). It is also clear that
the large amount of physical activity, which was required by our ancient ancestors for
survival and for which the human body is physiologically designed, is increasingly no
longer part of the modern lifestyle. If the growing epidemic of obesity and Type-2 DM is
to be stopped people may have to adopt a diet and lifestyle that is drastically different
from what most Americans have now become accustomed.
Is Type-2 DM Caused by the Typical American Diet and Lifestyle?
Expecting that people accustomed to a typical Western diet and lifestyle will adopt the
diet and lifestyle of a hunter-gatherer is certainly out of the question for most Americans.
On the other hand, most clinicians who deal with overweight patients soon realize that
advocating only moderate changes in diet and exercise habits is fairly ineffective even
with good compliance for treating most overweight individuals with IGT or Type-2 DM.
In part this is because moderate changes in diet do not usually make much of an impact
on BS or blood lipids or body weight. By contrast, people who were successful at losing a
lot of body weight and keeping it off were nearly all found to have made major changes
in both their diets and activity levels.210
There is also reason to believe that advocating major changes in diet are more likely to
lead to permanent dietary changes that reduce the risk of degenerative diseases like Type2 DM and CVD than the advocacy of more modest changes.211 This may be true in part
because major changes in diet often produce more dramatic improvements in disease
symptoms and objective clinical data than do more modest dietary changes. It seems
likely that the dramatic improvement in the disease process may make the patient feel
more empowered and more motivated to continue with major diet and lifestyle changes.
By contrast, modest changes in diet and lifestyle often have such little clinical impact that
the patient comes to believe that diet doesn't matter much and comes to rely more on
medical interventions. It may also be true in part because backsliding is easier when the
dietary changes made were minor.
Indeed, there is reason to question the ethics of health professionals if they do not fully
inform their patients/clients about what the scientific research suggests is the most
promising therapeutic approach. If patients choose not to follow the best therapeutic
38
advise to prevent or treat disease that should be their choice (after all, they will be the one
paying the price for their decision). If a health professional decides for the patient that the
patient would not benefit from accurate information that requires difficult changes in diet
and lifestyle then many would argue that that health professional has not lived up to
his/her duty to fully inform this/her patient.
Impact of Diet on Insulin Levels and Blood Sugar Regulation
In order to understand the impact of diet on BS and insulin levels it is helpful to
understand the role of insulin in regulating BS levels. The transport of glucose across cell
membranes requires a group of homologous transmembrane proteins known as GLUT-1,
2,3,4 and 5. The GLUT-4 protein is located primarily in muscle cells and adipocytes. A
reduction in the number of GLUT-4 transporters slows the transport of glucose from the
bloodstream into these cells. It is now clear that impaired insulin-stimulated glucose
transport into the muscle and fat cells plays a major role in the pathophysiology of IR and
the development of Type-2 DM.212
In the short-term, the impact of dietary carbohydrate has a much greater impact on
postprandial BS levels than does either dietary fat or protein. Dietary protein blunts but
prolongs the BS response to a meal, which may be advantageous for Type-1 DM where
large swings in blood glucose levels can make BS control more difficult.213 Figure 6
shows that in normal people, foods high in protein and fat trigger the release of insulin.
Surprisingly, even foods with little or no carbohydrate still cause a fairly substantial
insulin response despite the fact that they have little effect on BS.214
39
Figure 6. Insulin Index of Foods. This figure shows that in normal people, foods that are
high in protein and fat trigger the release of insulin.
40
These researchers showed that the increase in insulin output following the consumption
of 240 kcal of foods (which varied widely in their ratio of macronutrients) varied more
than 3-fold. But the amount of insulin released did depend solely on the grams of
carbohydrate in each food. Note that two high-carbohydrate foods, namely potatoes and
jellybeans caused the greatest increase in insulin secretion. However, a Mars candy bar
which has a fairly high fat content produced a much greater increase in insulin secretion
than 3 other high-carbohydrate foods, namely All Bran cereal, oatmeal or whole wheat
pasta, all of which have more grams of carbohydrate. By contrast, peanuts which had the
highest % fat of the foods tested triggered the smallest increase in insulin output. The
increase in insulin excretion caused by beef or fish was actually higher than that triggered
by 240 kcal of All Bran, oatmeal or brown pasta even though the former have no
carbohydrate at all.215
The data from this study make it quite clear that the body's production of insulin (and
presumably its need for insulin) cannot be precisely predicted from either the grams of
carbohydrate in a food or the amount of energy in the food. Nor can the amount of insulin
needed to maintain a healthy BS level in someone with Type-2 DM be predicted by
examining the amount of insulin released to a given amount of a food in normal subjects.
People with Type-2 DM and others with a lot of IR require much more insulin to keep BS
levels from rising too high after a meal than those without IR.
The results of the Holt study refute the simplistic notion that eating more protein and fat
and less carbohydrate will dramatically reduce the need for insulin and/or reduce insulin
secretion. Indeed, increased dietary protein not only triggers insulin secretion, it also
increases glucagon output. Patients with Type-2 DM already have increased glucagon
levels that stimulate the release of glucose from the liver. Higher protein diets also
accelerate the loss of kidney function (common in diabetes patients) so the long-term
risks and benefits of a higher protein and lower carbohydrate intake for patients with
diabetes should not be promoted unless further evaluation can show both safety and
efficacy.
In general, the total energy content of the meal consumed has a far greater impact on the
release of insulin than the ratio of fat to carbohydrate to protein in the meal. Of course, in
the long run the frequent consumption of high calorie meals, regardless of their
macronutrient composition coupled with inactivity will lead to increased BMI and body
fat. As BMI increases IR develops and the risk of developing IGT and Type-2 DM
increase dramatically. It seems clear that the diet, which is best at preventing weight gain
and promoting weight loss is likely to prove most beneficial for treating patients with IR,
IGT and Type-2 DM.
What Type of Diet Is Best for Type-2 DM Patients?
While the impact of diets, which vary in the ratio of fat to protein to carbohydrate on BS
levels and insulin sensitivity, have been studied by several research groups the results
have been inconsistent. Part of the reason for these inconsistent results is that the
experimental design most appropriate to evaluate the impact of diet on IR is still a matter
41
of scientific debate.216 It seems likely that the ratio of macronutrients in the diet is less
important than other dietary factors such as energy balance (and energy density) and the
amount of saturated fatty acids (SFA), trans fatty acids (TFA), cholesterol, salt, glycemic
index and fiber.
One thing that is clear is that the typical modern diet and sedentary lifestyle promotes the
development of Type-2 DM in nearly everyone who is genetically predisposed to this
disease. The impact of this disease is greatest in Pima Indians, a group who have a
particularly strong genetic predisposition to develop IR and Type-2 DM. However, 100
years ago Type-2 DM was a virtually unknown disease among Pimas living in the
Southwest North America when they lived as subsistence farmers and consumed a highcarbohydrate, high-fiber diet.217 Today, the prevalence of Type-2 DM among Arizona
Pimas is the highest of any human population in the world. About 1/2 of all Pimas over
the age of 35y now have Type-2 DM.218
Obviously, the Pima Indians have not changed genetically in a few generations so this
recent rapid rise in the prevalence of Type-2 DM and obesity must be attributable to a
change in their environment. It seems clear that the adoption of a more modern lifestyle
with a diet higher in fat and refined carbohydrates and a lower level of physical activity
are largely responsible. One study with 123 subjects who had IGT and were followed for
1-3 years showed that dietary fat intake was an independent risk factor for the
progression from IGT to Type-2 DM.219
People of European origin appear to be considerably more resistant on average to the
physiological stress placed on the BS regulating mechanisms by a rich diet and sedentary
lifestyle than the Pima Indians. However, people of European origin are not immune to
developing IR or Type-2 DM. A study of non-diabetic Pima Indians and Caucasians fed
them either a traditional Pima-style diet (70% carbohydrate; 15% protein; 15% fat) or a
typical modern diet (50% carbohydrate; 20% protein: 30% fat). The results showed that
glucose-mediated glucose disposal, beta-cell function, and glucose tolerance deteriorated
significantly in just 2 weeks on the modern diet compared to the traditional Pima diet.220
The decrease in insulin sensitivity was similar in both the Pima Indians and the
Caucasians subjects. Some researchers claim it is not a high-fat modern diet per se that
causes these adverse metabolic effects but rather the excessive energy intake that
frequently accompanies such diets. Of course, if a modern diet causes excessive energy
intake that may be part of the mechanism by which such diets lead to IR, IGT and Type-2
DM.
Total energy intake is almost certainly the single greatest dietary variable influencing the
development of IR and Type-2 DM. In short-term studies, diets high in unsaturated fats
or carbohydrates appear to have a similar impact on insulin sensitivity when fed at the
same energy level.221 The American Diabetes Association's latest guidelines recommend
replacing SFA with cis-monounsaturated fatty acids (MUFA) or carbohydrate.222
Total energy intake is probably much more important than the ratio of carboyhdrate to
unsaturated fat in the diet for treating and preventing complication associate with IR.
42
Recent research has suggested that tumor necrosis fator-alpha (TNF-alpha) may play a
role. TNF-alpha could represent a local adipostat that causes a down regulation of
adipocyte LPLase thus triggering IR and making it more difficult for fat cells to remove
TG from the blood.223 A recent study of obese, but otherwise healthy subjects who
followed an energy restricted diet for 3 months and lost an average of 9.3 kg suggest that
TNF-alpha may play a role in the development of IR.224Increased TNF-alpha has been
linked to increased IR225 and dyslipidemia.226
So what really matters most in terms of insulin sensitivity and BS regulation in the longterm is energy balance. It seems likely that any diet that leads to a positive energy
balance (and increased visceral fat stores), particularly when coupled with an inactive
lifestyle will markedly increase IR in genetically susceptible individuals. Over time, such
a diet and lifestyle will eventually result in the development of IGT and Type-2 DM in
those who are genetically predisposed to lose their capacity to maintain the very high
insulin levels needed to keep BS in the normal range when IR is present. By contrast,
switching to a diet with a higher satiety value that results in reduced energy intake and
weight loss will reduce IR and lower BS levels in most patients with IGT and Type-2
DM. A high satiety diet combined with increased daily activity appears to be the best way
to prevent and treat IGT and Type-2 DM.
Do High-Fat Diets Lead to Insulin Resistance and Type-2 DM?
In rodents, diets higher in fat have been shown to induce IR by reducing GLUT-4
expression in adipocytes.227 A reduction in GLUT-4 action in muscle cells with high-fat
diets appears to result from defective insulin signaling by phosphoinositide-3 kinase.228
Defective function of the GLUT-4 transporters in skeletal muscle cells and adipocytes
appears to be the cause of impaired glucose uptake or IR. The defective insulin signaling
of GLUT-4 transporters appears to be caused by an increase flux of free fatty acids (FFA)
to these tissues that diverts glucose into the hexosamine pathway.229 However, it is likely
that diets higher in fat cause these metabolic problems primarily by increasing ad libitum
calorie intake.230
In human subjects, high-fat diets have been implicated in the development of IR and
problems with BS regulation since the 1930s. 231 232 It has been known for a long time
that glucose tolerance tends to deteriorate when the ratio of dietary fat to carbohydrate
increases in the diet.233 In the short-term diets higher in fat increase postprandial free
fatty acid (FFA) levels. In the long-term high-fat diets often lead to increased body fat
stores which also result in elevated FFA in the blood. An increase in FFA in the blood
also appears to increase IR in muscle cells. An increase flux of FFA to the beta-cells has
been shown to dramatically increase the fat content in the beta-cells in rats. This
increased intracellular fat appears to delay insulin secretion when BS levels rise.
However, it also enhances insulin output in the short term but may lead to death of betacells in the long-term just as a build up of fat in liver cells leads to their death and
cirrhosis.234
43
A study of 1173 men and women found that insulin sensitivity deteriorated over time in
those who consumed more dietary fat (regardless of the type of fat), particularly in
individuals at increased risk of developing Type-2 DM because of obesity.235 A study that
examined insulin sensitivity in women found a reduced insulin sensitivity on a high (50%
of calories) fat diet and increased insulin sensitivity on a low (20% of calories) fat, highcarbohydrate diet.236
In contrast to the research implicating high-fat diets with the development of IR, there are
also many studies which have found that high-carbohydrate diets lead to higher BS
levels, higher insulin levels and/or adverse effects on blood lipids in patients with Type-2
DM compared to diets higher in unsaturated fat. 237 238 239 All of these studies have lasted
no more than a few weeks. Nevertheless, the results of studies such as these have lead
some researchers to advocate a diet high in unsaturated fat and lower in carbohydrate to
treat people with IR and Type-2 DM.
However, in all of the studies that have shown these presumably adverse metabolic
effects of diets higher in carbohydrate and lower in UFA, the researchers have required
their subjects to consume the same number of calories (and/or maintain the same body
weight) on both the high-fat and high-carbohydrate diets. In several such studies the
authors stated that they had difficulty getting people to eat as many calories on the highcarbohydrate diet as they ate willingly on the higher fat diet. As we have seen in both
animals and humans increased energy intake quickly results in a reduction in insulin
sensitivity and this may be the primary reason that high-fat diets usually lead to the
development of the IRS.
As discussed earlier, when research subjects were allowed to consume a highcarbohydrate diet ad libitum (rather than isocalorically with the high-fat diet) most of the
supposed negative metabolic effects associated with the high-carbohydrate diet largely
disappeared. This made the higher carbohydrate diet appear to be superior to the diet
higher in monounsaturated fat diet, at least in terms of reducing CVD risk factors 240 241.
It appears that it is more the consumption of calories in excess of what is needed to
maintain a healthy body weight rather than the macronutrient mix itself which is
primarily responsible for the development of metabolic problems referred to as metabolic
syndrome or the IRS.
There is some evidence that the type of dietary fat, as well as the amount of fat in the
diet, may influence the action of insulin. Some researchers have suggested that
polyunsaturated fats are more readily used for energy than SFA or TFA, perhaps because
they are also more easily mobilized by lipolytic stimuli from adipocytes. In theory, this
could make them less fattening than more saturated fatty acids. In addition, when PUFA
are incorporated into cellular membranes they appear to have some beneficial effects on
insulin action and the risk of developing Type-2 DM. 242 243 244 There must also be a good
balance between the omega-6 and omega-3 PUFA to improve cellular membrane
function and help avoid the development of IR.245
44
In subjects with Type-2 DM omega-3 fatty acid supplements have been shown to cause a
deterioration in glucose tolerance in the short-term.246 247 However, this effect of fish oil
supplements may be transitory.248 Results from the Oslo Diet and Exercise Study found
that adding fish to a low-fat diet and combining this with regular aerobic exercise
reduced IR.249 In general, fish oil supplements in Type-2 DM subjects tend to lower
serum TG levels but may also raise LDL-Cholesterol levels a little. However, the LDL
particles become larger and should be less atherogenic. Fish oil supplements have little or
no impact on BS control.250 There seems little reason to discourage patients with Type-2
DM from taking fish oil supplements provided they come from a reliable source.
However, too little information is currently available as to what would be an appropriate
amount.
Much more research is needed before one can be certain about what the ideal amount and
ratio of both omega-6 and omega-3 PUFA in the diet should be for Type-2 DM patients.
Based on what is currently known the diet should have about 4-8% of calories form
PUFA with a ratio of omega-6 to omega-3 (a.k.a. n-6 to n-3) of about 4 to 1 or less. A 4
to 1 ratio of n-6 to n-3 is a much lower ratio than the 20 to 1 ratio found in the typical
American diet and more in line with what was common in the diets of paleolithic huntergatherers.251 More appropriate levels of PUFA can be attained by following a low-fat,
DASH-style diet in which fatty fish and other seafood displace much of the red meat and
poultry.
Figure 7 shows the result of a study examining the impact of covertly increasing dietary
fat by adding fats and oils and replacing high-fat foods with lower fat alternatives.
The results of this study found that human subjects increased their ad libitum energy
intake and gained weight as the percentage of dietary fat increased.252 In this study the
45
subjects were fed foods to which fats and oils were covertly added. As can be seen from
Figure 7, ad libitum calorie intake increased significantly as the percentage of calories
from fat increased.When all the foods consumed by research subjects had between 15 and
20% fat calories the average daily calorie intake was only 2087 kcal/d. When the foods
they consumed contained 45-50% fat calories, the same subjects consumed more than
2700 kcal/d on average. The results of this study certainly suggest that the addition of
refined fats and oils to low-fat foods tends to increase ad libitum energy intake and
promote weight gain over a 2 week period.
The authors of a review on dietary fat and obesity argued that "dietary fat plays a role in
the development obesity". They based their conclusion on numerous studies of both
experimental animals and people.253 Other researchers have argued that "Diets high in fat
do not appear to be the primary cause of the high prevalence of excess body fat in our
society, and reductions in fat will not be the solution." 254 In fact, both arguments appear
to be correct.
Focusing on the % fat calories in the diet while ignoring other dietary factors and activity
levels will probably not prove to be very successful as the sole strategy for treating and
preventing obesity and the IR that frequently accompanies it. Nevertheless, reducing
dietary fat should probably be one part of a comprehensive dietary make over which,
when coupled with increased physical activity, is probably ideal for creating a negative
energy balance and promoting weight loss. So for most overweight Type-2 DM patients,
reducing dietary fat (and particularly SFA and TFA) is an important therapeutic strategy
for promoting weight loss without requiring patients to count calories and go hungry.
Dietary Fiber Shown to Improve BS Control in Type-2 DM Subjects
Since the 1970’s there has been growing interest in the potential of diets higher in fiber to
reduce a wide variety of degenerative diseases. Dean Burkitt and his associates found
higher rates of obesity, cardiovascular disease and Type-2 DM in human population
groups that had adopted a modern diet high in fat, sugar and refined grains conmpared to
those groups who consumed a more Spartan diet high in dietary fiber. Dr. Burkitt
hypothesized that a lack of dietary fiber in the modern diet was likely a major
contributing factor for the development of obesity, Type-2 DM and cardiovascular
disease.255
In the 1990s, researchers spent a lot of time doing studies that compare the impact of
diets high in carbohydrate or MUFA in people with Type-2 DM but no real consensus
has developed. This probably because the ratio of carbohydrate to fat in the diet is not a
particularly important factor in determining insulin sensitivity or BS control in short-term
studies that tightly control calorie intake. While a lot of attention has been paid to the
type of fat recommended, relatively little attention has been paid to the type of
carbohydrate in the diet. Those who tout a Mediterranean-style diet usually focus on its
high MUFA content. However, a true Mediterranean diet is rich in fruits, vegetables,
beans and grains that are rich sources of dietary carbohydrate and fiber.256
46
Increasing dietary fiber has received far less attention but is probably a more important
factor than the ratio of fat to carbohydrate in the diet. The most recent American Diabetes
Association recommendations suggest increasing dietary fiber to 20-35 g per day largely
because of the cholesterol-lowering impact of soluble fiber. The latest American Diabetes
Association recommendations considered the impact of dietary fiber on BS control to be
inconsequential.257 This is probably an incorrect assertion.
A recent randomized, crossover study with Type-2 DM patients who followed either a
moderate fiber diet (24 g/d) or a high-fiber diet (50 g/d) isocalorically showed that not
only did the high-fiber diet improve blood lipids but it also significantly lowered both
preprandial and postprandial BS levels throughout the day.258 Since the high-fiber diet in
this study had the same amount of SFA, cholesterol and total fat, protein and
carbohydrate, it is clear that dietary fiber well in excess of what the American Diabetes
Association is currently recommending is likely to benefit most patients with IGT and
Type-2 DM.
Short-term studies that closely monitor energy intake probably underestimate the longterm benefits of increasing dietary fiber. This is because an increase in dietary fiber is
usually associated with greater satiety that leads to reduced energy intake and as loss of
excess body fat.259 There is convincing scientific evidence showing that reducing body
fat stores improves insulin sensitivity and reduces IR. Losing weight is also beneficial for
lowering BS, blood lipids, BP and the risk of CVD. For these reasons the diet for
overweight Type-2 DM patients or those with IGT or IR should emphasize the intake of
fiber-rich foods such as whole grains, beans, fruits, vegetables, nuts and seeds. While
some studies have shown beneficial effects of dietary fiber supplements there is
insufficient evidence that they are safe and effective in long-term clinical trials so the
emphasis should be on food sources of fiber rather than supplements.
High-Carbohydrate Foods Have Variable Metabolic Effects
While it has long been recognized that various sources and types of dietary fat can have
very different metabolic effects, many researchers and clinicians fail to recognize the
very different impact of various sources and types of dietary carbohydrate have on BS,
blood lipids, insulin levels and satiety. This has led some to pronounce diets very high in
carbohydrate calories as undesirable for patients with diabetes and IRS.
In general, more processed and refined foods have both a higher GI and ED than more
natural foods and appear to provide less satiety.260 But is it the higher insulin response or
the greater ED of such foods that is primarily responsible for their lower satiety value?
This is consistent with the observation that the potato, which causes a relatively high
glycemic response and insulin score or output compared to many other foods, is also a
very high satiety food.261 If insulin is a satiety hormone then foods that produce more
insulin per calorie may actually be preferable for weight loss. In any case, a foods ED
appears to be a far more important factor than its GI in determining its satiety index.
Since foods with a high satiety index are likely to lead to lower total calorie intake when
consumed ad libitum, clinicians should focus more on a foods ED than its GI.
47
In general, more processed and refined high-carbohydrate foods have a higher ED and a
lower satiety value than less processed plant foods.262 The combination of a low-fat,
high-fiber diet consisting largely of minimally processed plant foods will most likely
prove to be best for promoting weight loss and improving BS control in Type-2 DM
patients. In part, this because such a diet can readily create a negative energy balance
without increasing hunger. However, just because a diet has a higher ratio of
carbohydrate to fat does not necessarily mean that it will always be superior for
promoting weight loss and improving BS regulation and overall health in Type-2 DM
patients.
For many years it has been clear that dietary sucrose and particularly fructose have a
deleterious impact on insulin action when consumed in large amounts by experimental
animals. Results of trials in humans have been less consistent but several have shown
adverse metabolic effects in people with IR.263 Fructose was shown to elevate LDLCholesterol levels in a double-blind crossover design study of healthy human subjects.264
However, a more recent study suggests that this hyperlipidemic effect may not persist in
healthy individuals. However, this study did show that a diet in which 14% of the glucose
calories were replaced with fructose resulted in a sustained increase in serum TG levels
throughout the day of 32% in healthy men.265 Higher fasting and postprandial TG are
associated with more small dense LDL particles that are believed to be more atherogenic.
Of all adults, normal weight, premenopausal women appear to be the least susceptible to
the dyslipidemic impact of diets higher in fructose or sucrose. Nevertheless, a study of 20
healthy, normal weight women between ages 20 and 51y showed that replacing saturated
fat with sucrose did not have favorable effects on blood lipids. In this study the women
were fed either a diet high in fat (46% en.) and SFA or two low-fat (26% en) diets, one of
which was high in starch and the other high in sucrose (23% en). Both the high fat diet
and the high starch diets had only about 2% of energy as sucrose. All 3 diets were fed ad
libitum and the high starch diet had about 50% more fiber than the other two diets.
Compared to the high-sucrose diet the high-starch diet reduced LDL-Cholesterol about
9% and fasting and postprandial TG levels by 15 and 30%, respectively. Clotting Factor
VIIc was also reduced about 10% as was ad libitum enrgy intake. The authors stated that
“These results suggest that diets high in sucrose are more atherogenic and thrombogenic
than diets high in starchy foods.”266
Both fructose and sucrose have been shown to adversely effect blood lipids. They also
appear to increase TG levels more in people who already have elevated serum
triglyceride levels many of whom have IR, Type-4 hyperlipoproteinemia and/or Type-2
DM. 267 268 269 270 Most data also suggests that diets high in sucrose, fructose and refined
grains will have a high calorie density and low in fiber content and satiety value. It seems
likely that diets higher in sucrose and fructose are undesirable for most people with IRS,
IGT or Type-2 DM. Unfortunately, postion papers on sugar from the American Diabetes
Association and the American Dietetic Association play down or deny these well
established adverse metabolic effects of fructose and sucrose.
48
All of the studies that have shown presumably adverse metabolic effects from diets
higher in carbohydrate and lower in fat have at least one of several serious design failures
that make their results largely irrelevant to the real world. These design problems include
one or more of the following: (1) The high-fat and high-carbohydrate diets are fed
isocalorically and/or body weights are artificially controlled by manipulating energy
intake; (2) The higher carbohydrate diet(s) had a much higher sugar content (sucrose
and/or fructose) than the higher fat diets; (3) The higher carbohydrate diet did not have a
higher fiber content than the higher fat diet and/or (4) The time frame of the study is too
short to allow the subjects to fully adapt metabolically to each of the experimental diets.
In the future researchers must be more careful not to generalize about the adverse
metabolic effects produced by diets higher in carbohydrate when most of the increased
carbohydrate is from refined sugars and/or refined grains and the s to all highcarbohydrate diets. Clearly, research shows that not all high carbohydrate foods have the
same metabolic impact in either healthy subjects or those with IR, IGT and Type-2 DM.
Energy Density More Important Than % Fat
Weight loss is a very effective strategy for reversing many of the metabolic problems
associated with IR, IGT and Type-2 DM. Many researchers have advocated reducing the
percent of calories from fat because of research suggesting high-fat diets promote
obesity. Three meta-analyses of dietary intervention trials have consistently shown an
association between a greater intake of dietary fat and increased energy intake and a
higher BMI.271 272 273
There are two main reasons that reducing dietary fat usually promotes weight loss
without increasing hunger. First, diets lower in fat will usually have a lower calorie
density or energy density (ED) than diets higher in carbohydrate. Second, diets higher in
carbohydrate and fiber and/or protein tend to provide more satiation and satiety when fed
at the same calorie level than diets higher in fat. Feeling satiated on fewer calories leads
most people to consume fewer calories at meals and/or increase the time between meals.
This is because it takes longer after a high satiety meal for hunger signals to become
strong enough to trigger eating behavior. In the long run, people who feel satisfied with
fewer calories will weigh less.
However, one must be careful not to focus only on the % of energy from dietary fat. For
the past 20 years the incidence of obesity and average BMI for Americans has been
increasing but the % of dietary fat has been decreasing.274 It seems clear that only
reducing the % of calories from fat will not necessarily reduce ad libitum energy intake
and prevent excessive body fat stores from accumulating over time. Clearly Americans
are becoming more sedentary and are smoking less and these factors could be offsetting
the beneficial effects of reducing dietary fat. In addition, the food industry over the past 2
decades has produced a large and growing number of “low-fat” and “fat-free” products
such as cakes, cookies, candies, frozen yogurts, chips, etc. and often marketed these
products as beneficial for aiding weight loss. These products generally have a high ED,
little or no fiber and an apparently low satiety value.
49
Even when fed ad libitum, a high-carbohydrate, low-fat diet does not always lead to a
decreased energy intake compared with a diet higher in fat. It has been shown that if the
energy density (ED) of a high-fat diet and high-carbohydrate diet is the same, the ad
libitum energy intake on both diets will be similar.275 It has been shown that on both a
20% and 40% fat diet, that it is primarily variation in the ED of the two diets that leads to
differences in ad libitum energy intake and changes in body weight.276 277 Figure 8 shows
that on two diets with the same macronutrient composition and a similar palatability that
ad libitum energy intake was much greater on the high than the low ED diet.
Figure 8. Effect of Energy Density on Ad Libitum Energy Intake with Diets with the
Same Macronutrient Composition
Stubbs RJ, et al. Int J Obesity 1998;22:885-92
Not surprisingly, this study also showed that the subjects were gaining body weight on
the high ED diet but they were losing weight on the low ED diet even though both diets
had the same % of calories from fat, carbohydrate and protein and on both diets the
subjects were allowed to eat as much as they wanted.
Of course, the addition of refined fats and oils to any food invariably increases that food's
ED. This is because ounce for ounce refined fats and oils have more calories than
anything else. On top of this, it should be recognized that most naturally occurring highfat foods have a high to very high ED. For example, avocados and olives have 2-5 times
the ED of high-carbohydrate fruits. Fatty meats, fish and poultry have about double the
ED of very lean cuts and varieties. Processed fatty meats like bologna, bacon and hot
dogs can have up to 7 times the ED of shrimp or flounder prepared without fat. Potato
chips, French fries and Pringles have 4-8 times the ED of boiled or baked potatoes.
Whole milk has twice the ED of skim milk and fat-free cheeses have 1/5 to 1/2 the ED of
full fat cheeses. Butter and margarine have 3,250 kcal/lb while all refined fats and oils
50
(eg. olive oil, lard and corn oil) have a little more than 4000 kcal/lb. By contrast, 1 pound
of sugar has 1725 kcal. So outside a research lab it is unlikely that someone eating a highfat diet will be consuming a low ED diet.
It is very difficult to consume a high-fat, low ED diet because so many high % fat foods
and all refined fats and oils have such a high ED in comparison to most low-fat foods. By
contrast, fresh fruits, vegetables, legumes, many minimally processed whole grain foods
(eg. pasta, corn, barley, brown rice, oatmeal, etc.) non-fat dairy products and very lean
meat, poultry and seafood have a very low to moderate ED (65 to 650Cal/lb). It is
precisely because diets higher in fat are generally more calorie dense compared to diets
higher in carbohydrate and fiber, that the former are more likely to lead to a positive
energy balance and weight gain.
Weight gain, particularly after age 18 y is the primary modifiable risk factor for the
development of metabolic problems such as IR, IGT and Type-2 DM. Indeed, a study of
individuals who were at increased for developing Type-2 DM because they were already
overweight, showed that a high intake of dietary fat worsened insulin sensitivity.278
Others have shown that the habitual consumption of a high-fat diet impaired insulin
sensitivity as measured by an intravenous-glucose-tolerance test in both lean and obese
subjects. However, this association weakened and became statistically insignificant after
adjustments for body weight.279 So it appears that diets higher in fat tend to increase IR
and the risk of developing Type-2 DM primarily because they tend to promote an
increase in ad libitum energy intake and increased body fat stores over time.
There can be little doubt that reducing the amount of high-fat, high ED foods will help
prevent the consumption of excess energy intake. Excessive energy intake over time
results in weight gain, increases IR and promotes the development of IGT and Type-2
DM in genetically predisposed individuals. While reducing the percent of dietary fat
helps lower the ED of the diet it should not be the primary focus for patients who need to
lose excess body fat. Rather than fat the focus should be on eating foods with a low ED
that are high in fiber. More soups and salads and more fruits and vegetables should be the
main focus. Three recent books that may be beneficial for people trying to adopt a
healthy weight loss diet are (1) “Volumetrics: Feel Full on Fewer Calories” by Dr
Barbara Rolls; (2) The “Calorie Density Solution” by Robert Pritikin, and (3) “Eat More
and Weigh Less” by Dr. Dean Ornish.
Switching to nonfat dairy products and low-fat meat, fish and poultry will help to lower
energy density and reduce saturated fat in the diet. However, if the % of energy from
dietary fat is reduced then the percent of calories from protein and /or carbohydrate must
increase. Some researchers have expressed concern about diets with a higher % of energy
as carbohydrate and/or protein in place of unsaturated fat. This is because the absorption
of both dietary carbohydrate and protein stimulate the release insulin whereas dietary fat
does not in healthy individuals. Of course postprandial BS levels rise much more in
response to diets higher in carbohydrate than diets higher in protein. However, the impact
of dietary carbohydrate on postprandial BS levels can vary considerably in both normal
and diabetic individuals depending on the amount and type of carbohydrate-rich food
51
consumed. Also, while dietary fat alone does not stimulate the release of insulin, adding
fat to high-carbohydrate foods usually does increase ad libitum energy intake and may
also influence BS levels even if it is substituted isoenergetically for carbohydrate.
Impact of Dietary Fat and Carbohydrate on BS Levels
Many clinicians and the American Diabetes Association recommend that patients with
diabetes focus primarily on the grams of carbohydrate in their meals in order to predict
how high BS levels will go and how much insulin they will need to maintain normal BS
levels. These recommendations are based largely on very short-term studies. However,
Figure 9 shows the results of a study that examined the impact on BS following ingestion
of either 2 slices of white bread (WB) or one slice of bread with added fat in a group of
lean, healthy subjects.280 Note that BS levels rise much more after consuming 2 slices of
WB than it does after consuming just one slice with the added fat even though both meals
contained the same amount of energy. However, when these subjects consumed a
standard meal 4 hours later those who had eaten the higher carbohydrate meal (2 slices of
WB) earlier now experienced a significantly lower BS response than those who had
consumed the bread with added fat. Clearly, the lower glycemic response that results
when fat replaces carbohydrate isocalorically is largely negated by the exaggerated
glycemic response to the very next meal.
Figure #9 - Impact of an isocaloric breakfast of bread or bread with fat and a standard
lunch on postprandial BS levels.
52
White bread is probably not a particularly good high-carbohydrate food for people with
IR, IGT and Type-2 DM. This is because it has a high ED, is rapidly absorbed and
provides a relatively low level of satiety. The effect of consuming isoenergetc breakfast
with either white bread or spaghetti on BS, insulin and serum TG levels following a
standard meal 4 hours later was observed in a group of 10 healthy normal weight
volunteers. The results of this study showed that the insulin, BS and postprandial TG
response to the standard lunch meal were all significantly lower following the more
slowly digested spaghetti breakfast than the white bread breakfast.281 The authors of this
study concluded that “Improved glucose tolerance and lowered serum TG levels can
appear in the course of a single day. As insulin resistance and raised postprandial TG
concentration are known risk factors for cardiovascular disease, the present study adds
evidence for a beneficial role of a low-GI diet.”
It should be clear from these two studies that there is a carry over effect from what is
consumed at one meal to the following meal(s). The “benefit” of a reduced postprandial
BS response following a meal with more fat and less carbohydrate at breakfast is largely
lost later in the day because of the exaggerated postprandial BS excursion at the
subsequent meal(s). However, the lower BS level and reduced postprandial lipemia
following a lower GI breakfast results in improved glucose tolerance and lower serum
TG levels at a subsequent meal. This suggests that reducing the BS excursion by
increasing dietary fat is of questionable benefit but consuming a more slowly digested
high-carbohydrate meal may have lasting physiologically beneficial effects particularly
for people with IR, IGT and Type-2 DM.
Of course, the main reason to reduce dietary fat in meals is to reduce the ED of the diet
and increase the satiety value of the food consumed. This should promote weight loss
without hunger. The addition of refined fats and oils to foods always increases the ED
and reduces the satiety value whenever fat is added to another food. In the long run it is
far more important to reduce excess body fat in an overweight or obese patient with IR,
IGT and Type-2 DM than it is to focus only on how high the BS goes after a single meal.
However, there are some low-fat, high-carbohydrate foods that have little satiety value
even though they may have a low ED as well as little or no fat.
Do High-Carbohydrate Drinks Promote Increased Calorie Intake?
One particularly poor way to consume dietary carbohydrate is in the form of drinks. Soft
drinks, sport drinks and fruit juices. These beverages all contain sugar and are essentially
devoid of dietary fiber. Research suggests sucrose and fructose both may increase IR
when substituted isocalorically for starch. However, when consumed in water these
sugars have very little satiety value and so are likely to promote weight gain. Indeed, the
same amount of sugar added to the the diet as jelly beans was shown to depress ad
libitum calorie intake of other foods but this was not the case when the same amount of
sugar was added as a drink.282 Since the late 1970s, the increasing incidence of obesity
and Type-2 DM has been roughly paralleled by an increased consumption of sugar-rich
drinks.
53
It should be noted that adding water to sugar greatly reduces the ED. However, in this
case the lower ED of the food clearly does not result in a higher satiety value. By
contrast, the addition of water to solid foods has been shown increase its satiety value and
reduce ad libitum energy intake. A study that fed the same food to a group of people as
either a chicken casserole or as chicken soup found that the ad libitum energy intake was
36% greater with the casserole than with the soup. This is not surprising because the
casserole had a higher ED than the soup. However, simply drinking the same amount of
water that was added to the casserole ingredients to make the chicken soup was shown to
have no impact on ad libitum energy intake.283 These data suggest that drinking water
(and probably other energy-free drinks) with a meal does not increase satiety or reduce ad
libitum energy intake.
When the water is incorporated into the food, as it was when the casserole was converted
into a soup or when pasta or rice are cooked it lowers the foods ED and helps to curb
appetite. But when a beverage is consumed with a meal it does not increase satiety. It
seems likely that other forms of liquid calories such as beer, wine, distilled spirits, mixed
drinks and milk shakes and "protein drinks" may have little satiety value and so adding
them to the diet may increase ad libitum energy intake and promote weight gain.
Although more research is needed in this area before any firm conclusions should be
drawn, it seems likely that avoiding calorie-containing drinks will help prevent excessive
calorie intake.
Paradoxically, increasing the water content of solid foods, which reduces ED, may help
reduce ad libitum energy intake and so promote weight loss. Long-term weight loss
usually increases insulin sensitivity and lowers BS levels in Type-2 DM patients.
However, in both normal and well controlled patients with diabetes the addition of 300
ml of water to a solid meal significantly increased the postprandial glycemic response.284
So long-term the addition of water to solid foods may aid weight loss and reduce
metabolic disturbances associated with IR. However, in the short-term, Type-2 DM
patients may experience an increased postprandial BS level when water is added to solid
foods to make, for instance soups. Of course, if fewer calories are consumed this effect
will be clinically insignificant.
The addition of sugar containing drinks (including fruit juices) to a meal may promote
increased calorie intake and result in much higher postprandial BS levels. The addition of
sugar or other calorie-rich sweetener to a hot breakfast cereal will increase the ED and
reduce the satiety value. This will result in increased postprandial BS levels in the short
term and weight gain in the long run. Therefore, patients with Type-2 DM should be
encouraged to use sugar substitutes (ie, aspartame, sucralose, saccharin, etc.) to sweeten
foods and beverages rather than sugar, honey, maple syrup, etc.
Glycemic Index and BS Control in Type-2 DM Patients
Not all foods or even all high-carbohydrate foods have the same impact on BS levels. The
rise in BS after consuming a given food or meal is known as the glycemic response. The
glycemic index (GI) is a measure of the glycemic response from foods containing 50 g of
54
carbohydrate relative to the glycemic response to a standard food (usually glucose or
white bread). Figure 9 illustrates the effect of a high- and low-GI high-carbohydrate food
on the glycemic response. Because people with IGT or Type-2 DM experience an
exaggerated rise in BS levels after eating a meal high in carbohydrate, it seems logical to
choose those high-carbohydrate foods that have the least impact on postprandial BS
levels in order to reduce postprandial BS levels.
Figure 10. Illustration of the Glycemic Response of a High- and a Low-Glycemic Index
High-Carbohydrate Food
GI is defined as the incremental area under the blood sugar response curve elicited by a
50g available carbohydrate portion of a food expressed as a percentage of that after the
same amount of carbohydrate from a standard food taken by the same subject. In most
studies either glucose (a.k.a., dextrose) or white bread has been used as the standard. In
simple terms, the GI is a measure of how high ones BS goes after consuming a specific
amount of carbohydrate from various foods.
In normal rats and in rats with streptozotocin-induced diabetes it has been shown that
diets with a high-GI starch content resulted in increased body fat stores and reduced
insulin sensitivity whereas substituting low-GI starch resulted in smaller body fat stores
and improved insulin sensitivity.285 If the GI of foods consumed by people effect body fat
stores and/or insulin sensitivity this should be an important factor in planning meals for
Type-2 DM patients.
The role of high- and low-GI foods and a high-carbohydrate diet in the treatment of
obesity, Type-2 DM, and CVD is currently a matter of intense scientific debate. One of
the most contentious issues regarding dietary recommendation for people with Type-2
DM and/or IR is the impact of diets with different GIs. Stanford researcher Dr. Reaven
55
was recently quoted as saying "the last thing I'd worry about is glycemic index." By
contrast, Harvard nutritional epidemiologist Simin Liu said the work of GI "is the most
fascinating and promising area in nutrition research today." 286 With conflicting opinions
like this it is not surprising there is a lot of confusion about the proper role of GI in the
prevention and treatment of Type-2 DM.
The GI of over 600 foods has now been tested.287 Since the typical supermarket now
carries more than 6000 different food items, it is likely that many people consume a lot of
foods with an unknown GI. Also, people increasingly eat foods prepared away from
home and there is little information about the GI of such foods. In addition, how food
items are cooked and prepared at home or in restaurants can also influence the GI. In
general, cooking, food processing and refining of plant foods tends to increase the GI
compared to foods that are closer to their natural raw state.288 The glycemic load of the
average American women’s diet has been shown to have increased significantly in the
1980s and is likely to continue to increase as more highly refined and processed highcarbohydrate foods replace more natural whole foods in the American diet.289
The American Diabetes Association does not currently recommend the use of GI in
planning meals for diabetics and has claimed that it does not work well for mixed
meals.290 However, the scientific evidence for this position is not strong because the GI of
a mixed meal can be predicted fairly accurately from the weighted average of GI of the
foods in that mixed meal.291 292 Nevertheless, the ADA recommends that the first priority
in planning a diet for diabetics should be given to the amount of carbohydrate rather than
its source. As we've already seen this is far from an ideal strategy. For most overweight
Type-2 DM patients the dietary emphasis is probably best placed on strategies that have
shown promise for reducing ad libitum energy intake without increasing hunger. This
means consuming a diet with a higher satiety value so people feel satisfied with fewer
calories.
When comparing foods of similar macronutrient content, those foods with a lower GI
usually also provide greater satiety than those foods with a higher GI. Even in studies that
controlled for ED, fiber, and palatability, foods or meals with a lower GI generally reduce
subsequent energy intake in human subjects.293 People with IR are likely to experience an
even greater rise in BS and insulin levels after a high-GI meal than active people with a
high degree on insulin sensitivity. The higher insulin levels will then cause a larger and
more rapid fall in BS in those with IR. There is some evidence that a large and/or rapid
fall in BS may trigger hunger.294 If this is so it may be one reason that consuming lower
GI foods in place of high-GI foods may prolong satiety which could aid weight loss.
Another factor that may be contributing to increased food intake after a high-GI meal
compared to a low-GI meal is that the higher insulin levels suppress serum FFA levels.
As a result, when the BS falls rapidly there is no other readily available alternative fuel
source for the body's tissues.295 However, some higher GI foods like a baked potato,
carrots and beets are quite satiating on an equal calorie basis to many other foods with
lower GIs. By contrast, some low GI foods with a high fat content like whole milk, nuts,
ice cream and cheesecake have a fairly low satiety value.296 This suggests that GI may be
56
useful when choosing between two high-carbohydrate foods with a similar ED but not
when choosing between foods that have very dissimilar macronutrient compositions.
Indeed, when subjects were fed either a low or a high-GI breakfast researchers found that
not only were their insulin, BS, FFA and TG levels lower after the low-GI meal but these
values were also lower after a standard lunch meal that was fed four hours later.297 298
It seems likely that the improvement in glucose tolerance to a second meal following a
low glycemic index meal is due to metabolic changes that result from the delayed
digestion and absorption of dietary carbohydrate. The slower absorption of carbohydrate
would be expected to suppress the release of FFA from adipose tissues. Elevated plasma
FFA levels increase glucose intolerance by impairing insulin mediated glucose disposal
and by enhancing liver glucose output.299 Higher plasma FFA levels also increase the
production and release of VLDL-TG from the liver.300 In theory this could increase serum
TG levels and perhaps lower HDL levels.
Back in the 1930's it was demonstrated that spreading out the glucose load (the amount of
glucose delivered to the bloodstream over a set period) reduced insulin requirements in
diabetics.301 This reduction in the body’s need for insulin may be due to a diminished
release of counter-regulatory hormones such as glucagon and catecholamines which are
related to the prolonged suppression of free fatty acid levels seen when glucose enters the
bloodstream more slowly.302 Increased levels of FFA exert a lipotoxic effect on the
pancreatic beta-cells which reduces their release of insulin.303 304 The well known “dawn
phenomenon” of an exaggerated BS response following breakfast may be due largely to
the high FFA levels present after an overnight fast. Indeed, a high carbohydrate snack
with a low-GI was shown to improve both fasting and postprandial BS levels the next
morning in a group of Type-2 DM subjects.305
It appears that a diet consisting of a lot of highly processed and refined high-carbohydrate
foods such as breads, dry cereals, crackers, cookies and cakes would lead to a rapid rise
in BS and an increased need for insulin. However, because the carbohydrate in such
foods is absorbed so quickly and trigger the release of more insulin it can be expected
that BS levels would eventually drop precipitously following such a meal. A rapid drop
in BS levels would trigger the release of glucagon and catecholamines. These hormones
would increase the release of FFA from adipose tissue. Elevated FFA may then increase
glucose intolerance at the following meal.
.
Research has shown a reduction in glycosylated hemoglobin when patients were fed a
low-GI compared to a high-GI diet.306 More recently, research has shown improved BS
control and a reduced number of hypoglycemic events in a group 32 Type-1 DM patients
fed a low-GI diet compared to a group of 31 control Type-1 DM patients fed more
refined foods. The Type-1 DM subjects who complied well with the high-fiber, low-GI,
natural foods diet had significantly lower HbA1c than those who consumed the control
diet after 24 weeks.307
57
Not surprisingly, a study of overweight Type-2 DM patients found a similar degree of
weight loss after six weeks on both a high-GI and low-GI meal plan when energy intake
was the same.308 Knowing only a food’s GI is not adequate for determining what impact
the consumption of that food would have in the long-run in a type-2 DM patient.
However, it seems likely that when choosing among foods with a similar macronutrient
content and ED, those that have a lower GI may help to improve metabolic control in
patients with IR, IGT or Type-2 DM.309
The addition of water to food or a meal usually increases the GI of that food or meal.310
However, as we have seen, the addition of water to solid foods (to make soup) increases
the satiety value of the meal and reduces subsequent ad libitum energy intake. By
contrast, when food is delivered in liquid form with little or no fiber then it appears to
provide very little satiety. Clearly the interaction between water and GI and ad libitum
energy intake is complicated. It appears that drinks with calories are a bad idea for
overweight Type-2 DM patients but adding water to high fiber foods may help increase
satiety even if it does not favorably effect GI. In the long run losing excess body fat is a
higher priority than how high the BS rises after a single meal.
A group of Type-2 DM subjects who were randomly assigned to receive dietary advice
on how to follow either a calorie-restricted diet, a modified fat diet (higher in MUFA)
diet or a high-carbohydrate diet for 18 months. After 18 months there were virtually no
differences between these 3 diet prescriptions with respect to nutrient intakes, body
weight, blood lipids or BS control.311 This suggests that dietary advice to restrict calories,
or to either increase or decrease the % energy from MUFA or carbohydrate has little
long-term impact on important health parameters for most Type-2 DM patients. By
contrast, the effect of dietary advice based on GI was for subjects recently diagnosed with
Type-2 DM produced more encouraging results. In this study the researchers found that
advice based on the GI and the type of dietary carbohydrate rather than on the grams of
carbohydrate resulted in the subjects consuming more dietary fiber. It also showed that
advice based on the GI of foods rather than the grams of carbohydrate improved blood
lipid levels and also improved BS control.312 In long-term clinical trials, low-GI diets
have been shown to modestly improve BS control and blood lipid levels in Type-2 DM
subjects.313 The results of these studies suggest that focusing on the type of dietary
carbohydrate consumed may be more important that the grams of carbohydrate consumed
or the % of energy from unsaturated fat or carbohydrate. It has long been known that
dietary advice to reduce calorie intake is usually futile if it requires subjects to eat less of
their customary diet.
The absorption of carbohydrate is slower with low GI-foods and the rise in BS is blunted
in comparison with higher GI-foods. Alpha –glucosidase inhibitors are a new class of
drugs used to control BS levels. Acarbose (brand name Precose) and miglitol (brand
name Glyset) work by inhibiting the intestinal enzymes that breakdown starches. In effect
they convert a high-GI meal into a lower GI meal. They can also cause bloating, gas, and
diarrhea. A recent study compared a group of 23 older but recently diagnosed Type-2
DM subjects took acarbose for one year with a similar control group. Weight change was
similar in both groups. Nevertheless, those taking acarbose experienced about a 30%
58
improvement in insulin sensitivity and lower HbA1c levels than observed in the control
subjects.314 This suggests that highly refined and processed foods with a high-GI may
impair insulin sensitivity and this impairment is at least partially reversible if the diet is
altered to contain larger amounts of low-GI foods.
Since most Type-2 DM patients are overweight and at heightened risk for CVD, a diet
with a lower ED, less saturated and trans fatty acids, less cholesterol, less salt and more
fiber should probably take precedence over either the grams of carbohydrate or the GI of
the diet. In my opinion, both GI and grams of carbohydrate should be secondary factors
that come into play only after these more important dietary goals have been achieved. It
would be absurd to add Swiss cheese to a Type-2 DM diet in place of an orange simply
because the cheese has a lower GI. It would also be counterproductive to equate whole
and skim milk even though a serving of each has the same amount of carbohydrate. In
both these cases, the serum LDL-cholesterol would rise and the patient would have more
trouble losing weight because of the higher SFA, cholesterol and ED of the cheese and
whole milk compared to the orange and skim milk.
Increased exercise or activity should be a top priority for most overweight Type-2 DM
patients. Increasing physical activity is probably more important than either counting
grams of carbohydrate or meticulously avoiding all high-GI foods. With normal weight
Type-1 DM patients it is likely that consistency in both the type and amount of dietary
carbohydrate will help improve BS control.315 However, when choosing between two
food items with a similar macronutrient content and ED or between two methods of
preparing the same food, it is probably preferable to choose the food or the method of
food preparation that will lead to a lower GI.
Data from the Health Professionals Follow-up Study examined the relationship between
diet and the risk of developing Type-2 DM in 42,000 men. This study showed a positive
relationship between the risk of developing Type-2 DM and the GI of the diet even after
adjusting for BMI, family history of Type-2 DM, physical activity, and total energy
intake.316 A study of 6 overweight Type-2 DM subjects examined the effects of feeding
either a high-GI or low-GI diet for two 6-week crossover periods. In this study both diets
had a similar amount of fiber and macronutrients and both resulted in a similar amount of
weight loss. Nevertheless, serum TG levels were 22.4% lower at the end of the low-GI
diet than the high-GI diet.317
An increase in fasting TG levels that often occur when high-GI carbohydrate replaces
low-GI carbohydrate in the diet is disturbing. This is because such changes are often
associated with a more atherogenic lipoprotein profile. Research has shown that highcarbohydrate diets tend to raise fasting TG levels primarily by increasing VLDL
production in the liver.318 This increased VLDL production can lead to adverse changes
in other blood lipoproteins like reduced HDL-Cholesterol and apo A-1 levels and an
increase in the amount of small, dense LDL particles. Such chances in blood lipoprotein
levels could increase the risk of CVD.319 People with IR appear to experience greater
adverse changes in their blood lipoprotein levels compared to people without IR when the
59
diet is higher in sugar and high-GI starchy foods. This is particularly true when energy
intake remains the same on the higher-carbohydrate diet.320
Many researchers have questioned the wisdom of recommending a very highcarbohydrate, low-fat diet for individuals that have IR, IGT and Type-2 DM. This is
primarily because of their concern about the potentially adverse metabolic changes seen
in people with IR whenever dietary carbohydrate is increased at the expense of
unsaturated fat.321 Indeed, the consumption of more high-GI, high-carbohydrate foods has
recently been shown to be associated with an increased risk of CHD in US women.322 If
no weight is lost as a result of adopting a higher carbohydrate, lower fat diet then there is
very good reason to question the wisdom replacing unsaturated fat with refined
carbohydrates that have a high-GI.
It seems likely that encouraging patients with IR, IGT and Type-2 DM to consume more
low-GI, high-carbohydrate foods and less high-GI high-carbohydrate foods will improve
their metabolic control and reduce their risk of CVD. In large part this is likely due to a
reduction in ad libitum energy intake as most low-GI, high carbohydrate foods have a
much higher satiety value than most high-fat foods. It also seems likely that increasing
the consumption of a diet with a lower GI load may help prevent or at least delay the
onset of the development of Type-2 DM and/or CVD in people with IGT and IR. An
excellent discussion of the arguments for and against the incorporation of information
about GI for diabetic patients can be found in the March/April 1999 issue of Nutrition
Today. A book that may be useful for patients trying to lower the GI of their diet is “The
Glucose Revolution” by Drs. Brand-Miller, Colagiuri, Wolever and Foster-Powell.
Small Versus Large Meals May Improve Metabolic Control
In theory, if the main metabolic benefits of consuming low-GI foods is that they spread
the absorption of glucose out over a prolonged period of time then one could accomplish
much the same metabolic benefits by consuming smaller but more frequent meals. An
epidemiological study found a significantly lower TC and LDL-C but no difference in
HDL-C in people who ate smaller, more frequent meals.323 This suggests that smaller but
more frequent meals may be beneficial for people at high risk for CVD such as people
with IR, IGT and Type-2 DM.
A study that examined the effect of consuming the identical diet as either 17 evenly
spaced small meals daily or as 3 meals daily found that “nibbling” diet did lower LDLcholesterol by 13.5% and apo B by 15.1% compared with the gorging diet after two
weeks. The mean BS levels, FFA and serum TG levels were similar on the two diets but
the mean serum insulin level was 27.9% lower in those consuming 17 vs 3 meals daily.
However,neither the BS and serum insulin levels were effected by consuming the two
diets when an intravenous glucose tolerance test was conducted at the end of each diet
period.324 The authors of this study hypothesized that eating smaller but more frequent
meals may be useful in treating dyslipidemia, diabetes and possibly obesity. This is
60
because they believe the metabolic effects of smaller more frequent meals may be similar
to consuming lower GI-meals.325
A controlled study using either 3 or 6 evenly spaced isoenergetic liquid meals found that
when subjects consumed 6 smaller but more frequent meals they had significantly lower
cholesterol levels than when they had just 3 meals daily. The researchers also found that
cholesterol synthesis was reduced with increased meal frequency. They also observed
lower GIP (a hormone that stimulates insulin release) levels and lower insulin levels
throughout the day in subjects consuming 6 vs 3 meals daily. Similar changes were
observed if the subjects were fed the liquid meals ad libitum or at a constrained energy
level.326 Another study of healthy subjects found that when they consumed 9 meals daily
compared to when they consumed 3 larger meals they had modestly lower levels of total
cholesterol, LDL-Cholesterol and HDL-Cholesterol by 6.5%, 8.1% and 4.1%,
respectively.327 However, this same research group in a study using free-living subjects
with high serum cholesterol levels found switching from 3 to 9 meals a day had little
impact on blood lipid in a group of hyperinsulinemic and hypercholesterolemic
subjects.328
It is still too early to draw any firm conclusions about what are the metabolic benefits and
risks of increasing meal frequency, particularly in hypercholesterolemic individuals with
IR. No studies to date have shown any adverse metabolic changes associated with
increased meal frequency in healthy or diabetic subjects provided that energy intake
remained the same on the two diets. Because IR, IGT and Type-2 DM and dyslipidemia
can all result from excessive energy intake and increased body fat stores the most
important consideration regarding snacking is whether or not it effects long-term energy
balance. Some studies have found an association between snacking between meals and
obesity.329 330 By contrast, another group of researchers found that increasing meal
frequency was associated with lower body weight in men, but not women.331 Other
researchers, on the basis of both animal and human research have also suggested that that
larger but less frequent meals increases the risk of obesity, as well as heart disease and
diabetes.332 Snacking is most likely to prove beneficial for patients with IR, IGT, and
Type-2 DM if the snack foods consumed are primarily fruits and vegetables and other
low-fat, low-salt, high-fiber and high satiety foods.
On a lower ED diet people may get hungry more often and should have available healthy
snack foods like fresh fruits and vegetables to nibble on between meals. This can’t hurt
and it may help. However, snacking when not hungry should be strongly discouraged.
A recent study examined the impact of a snack consumed after a standard lunch but
before the subjects became hungry again. The researchers fed subjects a snack (400 kcal)
at various times after a 1300 kcal lunch even though they were not hungry. They found
that the subjects did not reduce the amount of food consumed at their diner meal. The
snack also did not increase the time before the subjects requested their diner meal.333 The
data from this study suggests that snacking when not hungry may promote increased
calorie intake and weight gain over time. When ED, highly palatable food is readily
available it may be eaten because it is mealtime and people are hungry. However, such
foods may also be consumed simply for their sensory pleasure even when people are not
61
hungry.334 It seems obvious that human beings did not evolve physiological mechanisms
to prevent overeating when rich, highly palatable food is readily available and easy to get
24 hours a day and 365 days a year.335
Another study examined the impact of feeding an isoenergetic preload consisting of 1/3
of the subject's average daily calorie intake either as a single meal or as several small
meals. This study showed that obese men consumed 27% fewer calories at their next
meal (which was given 5 1/2 hours after the single test meal) when the same food was
divided into several small meals compared to when it was consumed as a single meal.336
The results of this study suggest that eating smaller but more frequent meals may help
people feel satisfied while consuming fewer calories.
Another potential advantage in eating smaller but more frequent meals is that stomach
capacity is likely to shrink. A study that examined the stomach capacity of people on a
very-low-calorie diet for 4 weeks found it was reduced by 27 to 36% compared to control
subjects who maintained their usual eating habits.337 This study suggests that people who
regularly eat smaller (but more frequent) meals will begin to feel more satisfied with less
food over time.
It is clear that more research is needed to clarify the metabolic impact of snacking or
increasing meal frequency on body weight, BS, and blood lipids. For example, are the
metabolic benefits of eating smaller but more frequent meals blunted when the diet
consists largely of low glycemic index foods? Eating more natural foods high in fiber and
with a low glycemic index should be encouraged based on what is already known. Many
natural foods with a low glycemic index also have a low ED. Low calorie dense meals
have been shown to result in the consumption of fewer calories at each meal that over
time might lead to an increase in meal frequency. It seems likely that eating more of such
such foods over time will naturally lead to a meal pattern that is likely to improve glucose
tolerance and lower insulin levels, fasting and postprandial triglycerides and LDLcholesterol level. These metabolic changes should dramatically reduce the risk of
atherosclerosis, heart attacks and strokes in the long run.
People who are overweight should be discouraged from either starving (not eating when
hungry) and stuffing (eating when not hungry). Skipping meals and going hungry appears
to increase the desire for foods with a high calorie density. This is detrimental for weight
control because foods with a high calorie density generally provide less satiety. When
people feel less satiated when they consume a smaller quantity of calorie dense foods
compared with low calorie dense foods, they usually compensate by consuming more
food and calories. Eating large but infrequent meals also may promote obesity and
contribute to the development of Type 2 diabetes mellitus in genetically susceptible
people. All of these metabolic changes have been associated with an increased risk
atherosclerotic disease. Because increased physical activity may blunt many of the
adverse metabolic effects of large meals composed largely of high glycemic index foods
it should be encouraged particularly in patients who do not adopt a healthy eating plan.
62
Eating until one is uncomfortably full ("stuffed") will likely increase stomach capacity
over time. This could lead to the consumption of even larger meals and more metabolic
stress. Consuming large but infrequent meals has been shown to raise serum cholesterol
(mainly LDL-C) and it also appears to promote insulin resistance.338 Increased
postprandial plasma triglyceride levels have been associated with an increased risk of
coronary heart disease.339
It seems reasonable to discourage overweight people from snacking or eating meals when
they are not hungry. The one exception to this rule would be breakfast. A healthy
breakfast such as a hot whole grain cereal with fresh fruit and NF milk is the one meal
people should be encouraged to every day even if they not hungry. Focusing on what
people eat and getting them to eat only when hungry the rest of the day is likely to prove
more beneficial than focusing on how much they are eating (counting calories) in the
long term.
Comparison of Diets High in Carbohydrate, Fat or Protein in Type 2
DM Subjects
Dr. O'Dea compared the metabolic effects of 2 very-low-fat (VLF) diets (about 10% fat
calories) to a very-high fat diet (55% fat calories - Diet 3) and a very-high protein diet
(62% protein calories - Diet 4).340 In this study the researchers attempted to feed all 4
diets isocalorically to Type-2 DM men for 2 weeks each. One VLF diet had 45g of fiber
(Diet 1) and the other had 20g of fiber (Diet 2). As one would expect on very high fat and
protein diets, the fiber content was fairly low (14g and 13g, for Diets 3 and 4
respectively). Also, as one would expect the P/S was considerably higher and cholesterol
content considerably lower on the two high-carbohydrate diets than on either the high-fat
or high-protein diets. This study better reflects real world eating because most natural
foods that are high in fat and/or protein come primarily from animals. In general, the P/S
is much lower for animal based foods than it is for naturally occurring high-carbohydrate
plant foods. Of course, dietary cholesterol is found only in foods derived from animals,
while dietary fiber is derived only from plants. In this study, the researchers used real
foods and did not attempt to artificially manipulate the P/S or the SFA, cholesterol and
fiber content of the four different experimental diets.
Unfortunately, these researchers did attempt to get their subjects to consume the same
calorie level on each of the four experimental diets. Comparison of a 75g OGTT before
and after 2 weeks on these four diets showed that glucose tolerance improved on the two
high-carbohydrate diets (more so Diet 2 - which was high in fiber) and the high-protein
diet but deteriorated significantly on the high-fat diet. The higher insulin response
following the high-fat diet clearly showed that this diet increased IR. Others have also
shown that diets higher in fat, even in lean young men fed the same calorie level, those
who were unfit and had higher fasting insulin levels (and presumably some IR) and were
more likely to experience a positive fat balance on a diet with a higher % of fat. The
authors suggested that unfit individuals with a propensity towards IR may have an
impaired ability to oxidize fat under isocaloric conditions and this "may be an important
mechanism by which these individuals differ in their propensity to gain weight over
63
time.341 Insulin sensitivity and glucose tolerance improved on both the high-fiber Diet 2
and the high-protein Diet 4. This improved insulin sensitivity was demonstrated by a
significant drop in FBS on these two diets compared to the subjects' usual diets. By
contrast, there was no significant change in insulin sensitivity or FBS on the lower fiber,
high-carbohydrate diet. It is hard to escape the conclusion that diets with a higher ratio of
fat to carbohydrate have a greater propensity to promote fat storage in people who appear
to be genetically predisposed to develop IR and Type-2 DM.
This study showed that at least in the short-term, diets very high in protein may improve
insulin sensitivity as much as a diet high in carbohydrate and fiber and low in fat.
However, aside from the authors of a variety of fad diet books, there appears to be little
support for diets very high in protein. Diets high in animal protein have been shown to
increase kidney stones. 342 343 344 High protein diets also increase the loss of calcium in
the urine and appear to increase the risk of osteoporosis.345 Diets high in animal protein
and low in carbohydrate are generally fairly high in SFA and cholesterol and increase
LDL-Chol and probably increase the risk of CVD. There is also evidence linking diets
high in animal protein with an increased risk of at least some types of
cancer.346
Do High-Carbohydrate Diets Cause Hyperinsulinemia and Weight
Gain?
Some diet book gurus (e.g. Atkins, Sears, Somers and the Eades) have claimed that highGI foods cause an increased insulin output and this hyperinsulinemia leads to IR and
weight gain. Some dietitians have made similar claims.347 This theory appears too
simplistic. There is no compelling evidence that IR leads to weight gain or that a food's
GI is a particularly important factor in determining that food's impact on satiation, satiety,
hunger, ad libitum energy intake or body weight. Pima Indians with IR and high insulin
levels were actually found to be less likely to gain weight than Pimas with less IR. 348 In
fact, IR appears to be largely the result of excessive calorie intake, inactivity and weight
gain rather than its cause.349
So IR and high insulin levels are due to more to weight gain rather than being the cause
of weight gain. Confusing correlation with causation is a failure in logic. It appears that
despite the claims of diet book gurus (and even one RD), high insulin levels are far more
the result of excessive calorie intake rather than the cause of excessive calorie intake.
Many high GI, high-carbohydrate foods do cause a relatively large release of insulin
compared to low GI-foods. The association of high-GI foods with increased body weight
probably has more to do with their high ED, low fiber content, and low satiety value
rather than to the greater insulin output they trigger.
Weight gain is caused by energy intake in excess of energy output. IR is associated with
an increased release of FFA from adipocytes and increased fat oxidation.350 Since it
appears that IR reduces the body's ability to store fat, IR appears to be a physiological
adaption which limits additional weight gain.351 For more information about GI, obesity
and popular fad diet books claiming that high-carbohydrate diets promote obesity see
64
Kenney JJ. Do high glycemic index foods cause obesity? A look at the false claims made
in Sugar Busters and The Zone diet books. 352
To summarize, weight loss is the surest way to reduce IR and lower BS levels in
overweight or obese patients with IGT or Type-2 DM. Both protein and carbohydrate
stimulate the release of insulin. Of course dietary carbohydrate increases BS levels much
more than does protein. Therefore, replacing carbohydrate with protein calories has the
advantage of lowering BS levels, at least in the short-run in people with IGT or Type-2
DM. However, there is concern that high-protein diets in the long-run may increase the
risk of kidney stones, speed the loss of renal function, contribute to the development of
osteoporosis and perhaps some types of cancer. Also, most high protein foods are high in
saturated fat and/or cholesterol and so would raise serum cholesterol levels and increase
the risk of coronary artery disease (CAD).
Reducing dietary fat has the advantage of reducing the diet's ED and promoting weight
loss without hunger. Reducing the diets ED by increasing dietary fiber and increasing the
water content of solid foods also appears to be beneficial. Eliminating or reducing
energy-containing drinks may also help prevent weight gain and aid weight loss.
Choosing lower GI high-carbohydrate foods makes sense if the foods have a similar
macronutrient and ED. However, reducing the % of energy from dietary fat and replacing
it with carbohydrate will tend to increase both BS and the need for insulin, at least in the
short-run, unless it leads to weight loss. The isocaloric substitution of refined
carbohydrates for unsaturated fat will negatively impact glucose tolerance and also result
in potentially adverse changes in blood lipids.This observation has led to a long running
debate between those who advocate a diet high in monounsaturated fatty acids (MUFA)
and those who advocate a high-carbohydrate diet for patients with Type-2 DM.
Debate over High-MUFA vs High-Carbohydrate Diets for Patients with
Type-2 DM
In 1988, Dr. Garg and others compared a high-carbohydrate diet with a diet high in
MUFA.353 These researchers stated that their results "suggest that the partial replacement
of complex-carbohydrate with MUFA in the diet of patients with NIDDM does not
increase the level of LDL-C and may improve glycemic control and the levels of plasma
triglycerides and HDL-C".
In a letter to the editor, I suggested that the results of Dr. Garg's study had little clinical
relevance because his experimental design required his subjects to consume both the
high-carbohydrate and high-MUFA diets at the same calorie level (isocalorically or
isoenergetically). I pointed out that in the real world people eat until they are satiated and
that high-fat diets are generally less satiating than high-carbohydrate diets.354 In rebuttal
to my letter, Dr.Garg claimed "contrary to their belief, fat (is) more satiating than
carbohydrate" and "weight loss cannot be achieved by promoting satiety but by... will
power..." 355 As we shall see, both of these claims lack scientific merit.
65
An epidemiological study of the U.S. population showed that an increased ratio of dietary
fat to carbohydrate is associated with increased BMI in middle-aged men.356 The
mechanism whereby an increased percent of calories from fat promotes obesity is not
known. However, it is likely related to the fact that high-fat foods tend to have a higher
ED than low-fat foods rather than simply the ratio of the nutrients themselves.357 In fact,
even under the best of circumstances, dietary fat has been shown to be no more satiating
than dietary carbohydrate.358
Other researchers have pointed out that "because carbohydrate foods have a lower ED
than fat foods (on average) and because of their greater satiating capacity, the free intake
of high carbohydrate foods is likely to be self-limiting." 359 360 Simply put, high-fat foods
generally have less fiber and a higher ED than high-carbohydrate foods. Therefore, in the
real world of clinical practice a high-fat diet is likely to be less satiating and lead to a
greater calorie intake than a high-carbohydrate diet. Over time these increases body fat
stores, IR and a greater risk of CVD and Type-2 DM.
As dietary fat increases, it is likely that the ED of the diet will increase and this will
increase ad libitum calorie intake in most people. This clearly calls into question the
clinical relevance of studies in which the subjects were required to maintain the same
body weight on both high-fat and high-carbohydrate diets. However, it is primarily in
studies in which the researchers require that the high-fat and high-carbohydrate diets be
consumed isocalorically and/or that body weight be kept constant that the adverse
metabolic changes on higher carbohydrate diets have been demonstrated. For a more
detailed discussion of the role of dietary fat, carbohydrate and ED on ad libitum calorie
intake see my CPE article.361
Research has shown that the single most important dietary variable that most impacts
satiety and ad libitum calorie intake is ED. Since fat has a much higher ED than
carbohydrate and most high-fat foods have a much higher ED than most highcarbohydrate foods, any recommendation to increase dietary fat at the expense of
carbohydrate is likely to lead to a higher ED diet. A higher ED diet is likely to increase
ad libitum calorie intake and so promote weight gain in the long-run. Since excessive
calorie intake and increased adiposity are major factors promoting the development of IR
and eventually Type 2 DM in genetically susceptible individuals, it seems wise to
question the clinical utility of diets higher in fat for patients with IR and/or Type-2 DM.
It should also be noted that the studies suggesting deleterious effects of highcarbohydrate diets in Type-2 DM subjects have lasted a few days to no more than 6
weeks. The authors of a study of 91 Type-2 DM subjects lasting 6 months stated “our
data suggest that the results of of studies lasting only 6-12 weeks may not represent the
long-term effects of high-carbohydrate diets on cardiovascular risk in subjects with type 2
diabetes.”362 These authors fed their subjects either a high or low-GI breakfast cereal or
replaced the cereal with monounsaturated oils. These authors noted that the higher
MUFA-diet compared to the two high-carbohydrate diets resulted in higher serum FFA
levels and lower insulin levels. They conclude “the increase in plasma insulin and the
66
reduction in free fatty acids associated with the higher carbohydrate intake may reduce
the rate of progression of diabetes.”
Diets higher in MUFA and lower in carbohydrate lead to higher plasma FFA levels.
Higher FFA levels have been shown to cause an increased hepatic glucose output and a
slower clearance and utilization of glucose by peripheral tissues.363 Elevated plasma FFA
levels in animals have also been shown to impair insulin secretion.364 Likewise, an
increase in body fat stores elevates plasma FFA levels and leads to impaired clearance of
glucose by peripheral tissues (i.e. IR). There is no doubt that obesity contributes to IR,
IGT and Type-2 DM. Since a diet higher in fat and lower in carbohydrate leads to similar
metabolic changes it may be involved in the development of Type-2 DM in genetically
susceptible individuals if followed over a prolonged time period even if it does lead to an
increase in body fat stores.
Is "Will Power" and a Calorie Controlled Diet the Key to Weight
Control?
Dr. Garg also suggested that "will power" and a calorie-restricted diet were the key to
weight control. No one debates that reducing calorie intake is necessary to affect weight
loss. However, there is compelling evidence that the use of will power to restrict calorie
intake may create what psychologists have termed "restrained eaters". There is also
compelling evidence which suggests that restrained eaters are prone to developing serious
eating disorders.365 Contrary to Garg's claim that "will power" is the key to weight loss,
most research suggests that few people can adhere long-term to a calorie level which is
significantly below what their appetite demands.366
In some cases, the authors of studies showing adverse metabolic effects on a highcarbohydrate vs a high-MUFA diet have admitted it was difficult to get subjects to eat as
many calories on the high-carbohydrate as on the high-fat diet. For example, Morgan et.
al. concluded that a "low-fat diet enriched with olive oil provides advantages over a verylow fat diet in control of serum lipids among persons with hypercholesterolemia". They
made this conclusion even though these same authors noted that on the 10% fat diet, their
"subjects found it difficult to eat enough food to maintain weight". To prevent weight
loss on their high-carbohydrate diet, Morgan et al required their subjects to consume a
concentrated refined carbohydrate drink.367 In a letter to the editor, I pointed out that
increased adiposity was a significant component in the deterioration of blood lipids and
that the addition of fat to low-fat foods has been shown to increase body weight. I also
pointed out that research has proven that a VLFNV diet can reverse atherosclerosis,
which is something diets higher in fat have not been shown to do.368 In response, one of
the authors stated that "in many ways we agree with the sentiments expressed by Kenney
regarding the advantages of VLF diets.”369 In fact, the main advantage of a high-MUFA
diet compared to a high-carbohydrate diet occurs primarily in short-term clinical trials in
which MUFAs are replacing primarily refined, high-GI carbohydrate-rich foods in an
isoenergetic exchange. This is a very artificial and largely clinically irrelevant situation.
Unfortunately, both researchers and clinicians have often based their dietary
recommendations and advice on just such short-term clinical trials.
67
Population Studies Suggest a High-Carbohydrate Diet Best for Type-2
DM
If we look at population studies it seems clear that high-fat diets seem to promote
obesity.370 By contrast, a VLFNV diet that is high in fiber coupled with a moderate
activity level is likely to prevent both obesity and Type-2 DM in most people. For
example, the Pima Indians living in Arizona have the highest incidence of Type-2 DM in
the world. They consume a fairly typical Westernized diet with about 30-35% fat calories
become obese and by age 50y the majority have developed Type-2 DM. By contrast, the
Pimas living in the Sierra Mardres Mountains of Northern Mexico still grow most of their
own food and consume a high-carbohydrate diet which consist largely of potatoes, corn,
beans, squashes, peppers and small amounts of fruit and animal products. They are more
active, weigh 60-65 lbs less than their American "cousins" and rarely develop Type-2
DM before age 50y.371
Adopting a less processed and refined diet with far less concentrated calories, more fiber
and less fat and increasing daily activity may be necessary for most people to lose weight
and keep it off without chronic hunger. Such a diet coupled with regular aerobic exercise
should improve insulin sensitivity and help to prevent or more effectively treat Type-2
DM. An examination of many of the traditional foods utilized by native Australians and
Pacific Islanders showed that most produced much lower GI and insulin levels than did
high-carbohydrate foods typical of modern Westernized societies.372
The introduction of a Western diet to Australian Aborigine and Pacific Islanders has
resulted in a dramatic increase in the incidence of obesity and Type-2 DM.373 374 By
contrast, when obese native Hawaiians with Type-2 DM were switched from a diet
consisting largely of modern foods to one composed of a traditional Hawaiian foods that
were low in fat (7% of calories) and had a low ED (376 kcal/lb) for 21 days their ad
libitum energy intake dropped from 2594 to 1509 kcal/day and their FBS improved
dramatically.375
A very-low-fat, near vegetarian (VLFNV) diet is likely superior to a more
Mediterranean-style diet with added olive oil for the prevention of both obesity and
Type-2 DM precisely because the VLFNV diet would generally have a lower ED, higher
fiber content and greater satiety value than a diet with added olive oil. Thus in an ad
libitum feeding situation, a VLFNV diet would be more likely promote weight loss
without hunger than would a diet with more added fats and oils. Indeed, it is diets high in
fat (particularly saturated fat) and refined carbohydrates (particularly sugar) that are most
closely associated with the development of obesity and IR, while diets high in unrefined
carbohydrates are usually associated with improved insulin sensitivity.376
It would be inappropriate to draw firm conclusions from population and migration studies
alone. In general, as a population becomes more affluent, not only does its intake of fat
and animal products increase but the source of dietary carbohydrate also shifts from more
natural foods to more refined and processed foods. There is also usually a marked
reduction in physical activity associated with increasing affluence. Clearly, part of the
68
reason that the Mexican Pimas are protected from obesity and Type-2 DM is their greater
activity level.377 So while one can conclude that a more affluent or Westernized lifestyle
as a whole promotes obesity and the development of Type-2 DM in genetically
predisposed individuals, it is not scientifically justifiable to put all or even most of the
blame on an increasing percent of calories from fat. A person's activity level as well as
the amount and types of both dietary fats and carbohydrates appear to be important
environmental factors leading to obesity, IR, Type-2 DM and CVD.
Is a Low ED, Low GI, and High-Fiber Diet Best For Obese Type-2 DM
Patients?
A study that compared a low ED diet consisting primarily of minimally processed plant
foods that are high in fiber and low in fat compared to a typical high-fat, low-fiber
American diet found that the ad libitum caloric intake was dramatically lower on the low
ED diet (3000 vs 1570 Cal/day).378 In this study the satiety ratings of the high and low
ED diets were similar and overall food acceptance on the two diets was similar. In this
study the high ED diet had 681 cal/lb and the low ED diet had only 318 cal/lb. For more
information about why a high-fat, high ED diet coupled with a sedentary lifestyle
promotes obesity.379
Unfortunately, it is quite a challenge to plan acceptable meals that average only about
300-400 calories per pound and have a high fiber content. Such meal plans require more
nutrition knowledge than most Americans possess. They also would require more
culinary skill than most Americans possess to make them sufficiently palatable to
compete with more typical American fare. This is because the palatability of foods tends
to increase with increasing ED even though ED is the primary determinant of ad libitum
caloric intake.380 Because ED is the primary determinant of ad libitum caloric intake, the
creative use of herbs, spices and noncaloric sweeteners and other flavor enhancers to
increase the palatability of a low ED, high-fiber diet is one key to preventing and treating
hyperadiposity (the attainment of body fat stores associated with increased morbidity and
mortality). Reducing body fat stores is the best way to reduce IR and improve BS
regulation in overweight Type-2 DM patients.
Biological functions in animals are generally better when they consume their natural
diet. It is probably safe to assume the same is true for humans. Modern Westernized diets
appear to be somewhat incompatible with the natural biological functioning of the human
body. A high-fiber, and low ED meal plan, consisting largely of lower GI plant foods and
low-fat meats, fish and poultry is much more comparable to what our ancient ancestors
were consuming while humans were evolving from more ape-like creatures to homo
sapiens than is the modern American diet. Therefore, it is probably better to assume that
such a diet is what the human body is biologically designed to handle.381
The effectiveness of a very-low-fat, near-vegetarian diet consisting largely of high-fiber,
minimally processed foods coupled with regular exercise was evaluated in 60 patients
with Type-2 DM who completed a 26-day residential program at the Pritikin Longevity
Center. Of the 23 patients who entered the program on oral hypoglycemic agents, all but
69
2 were off these drugs after 26 days. Of the 17 patients who entered the program on
insulin, all but 4 were off insulin at the end of 26 days. Two of these 4 had their insulin
dosage cut in half. Despite these major reductions in BS-lowering medications (insulin
and oral agents), the average FBS of these 60 patients was reduced from an initial 194.9
down to 144.6 mg/dl after 26 days. Average body weight fell by 4.3 kg and this coupled
with increased activity probably account for much of the improvement in BS
regulation.382
There is also evidence that a diet high in cereal fiber and with a lower GI reduces the risk
of developing Type-2 DM. A study that followed 65,000 + healthy women (age 40-65y)
for 6 years found that the relative risk of developing Type-2 DM was 2 1/2 times greater
in those women who were consuming the most cereal fiber and the lowest glycemic
load.383 This remarkable reduction in the risk of developing Type-2 DM occurred even
after adjusting for age, BMI, smoking, physical activity, family history of diabetes,
alcohol intake and total energy intake. The results of this study certainly suggest that a
diet low in cereal fiber and with a high-GI can significantly increase the risk of
developing Type-2 DM.
Foods with a low-fat content that also have a high-fiber content and a low ED and GI are
most likely to promote weight loss because they also generally have a high satiety value
and reduce ad libitum energy intake. Such foods also tend to increase insulin sensitivity
and reduce the risk of developing Type-2 DM and CVD. This advice is consistent with
the recently updated recommendations of The Diabetes and Nutrition Study Group
(DNSG) of the European Association for the Study of Diabetes. This report specifically
states that "Advice concerning the reduction of energy dense foods and, in particular,
those high in fat will usually help to achieve weight loss without the need for precise
energy prescription." It is only after this strategy fails that the DNSG recommends
resorting to a calorie-restricted diet.
At least in Europe, most leading experts on diet and weight control have come to
recognize the very poor prognosis for long-term weight control typically seen when "how
much" is eaten is the primary focus of dietary advice rather than "what" is eaten. This
report also focuses on the type of fat and the type of carbohydrate rather than the % of
energy from each. They specifically state "Foods with a low glycaemic index (e.g.
legumes, oats, pasta, parboiled rice, certain raw fruits) should be substituted when
possible for those with a high glycaemic index since they may help to improve glycaemic
control and lipid levels."384 Substituting such foods for more refined and processed foods
will likely improve insulin sensitivity and lower HbA1c over time even if weight is not
lost. However, such a change in diet will also likely lead to significant weight loss which
will further improve insulin sensitivity and BS control as well as improve blood lipids
and other CVD risk factors.
Alcohol, Diabetes and Coronary Artery Disease
70
The use of alcoholic beverages by patients with Type-2 DM has been the subject of
considerable debate over the years. For many years it has been known that for those
consuming a modern diet, the regular consumption of moderate amounts of alcohol are
associated with a significant reduction in overall mortality due primarily to a reduction in
deaths from CVD mortality.385 However, the consumption of more than 2 drinks per day
in men is associated with an increased risk of cancer, cirrhosis of the liver, accidents and
other causes of death that offset the reduction in CVD deaths.386 In women, even 2 drinks
per day are associated with an increased risk of breast cancer.
Alcohol is energy dense and liquid, two factors usually associated with little satiety value
and increased ad libitum calorie intake. However, while alcohol consumption is often
positively associated with increased BMI in men, it is usually negatively associated with
BMI in women. Nevertheless, alcohol consumption was associated with an increased
WHR that was independent of BMI in both men and women.387 An increased WHR is
often associated with IR and an increased risk of CVD so it is clear that the relationship
between alcohol and IR and CVD risk is complex.
In both men and women with diabetes there is a several fold increase in the CVD
mortality compared with nondiabetic individuals the same age.388 CAD alone is
responsible for more than 2/3 of the deaths of people with diabetes.389 A recent large
prospective study of men showed a similar reduction in CAD mortality in men with
Type-2 DM as in those without diabetes.390 Similar results in a large prospective study of
women and led the authors to conclude “Although potential risks of alcohol consumption
must be considered, these data suggest that moderate alcohol consumption is associated
with reduced CHD risk in women with diabetes and should not be routinely
discouraged.”391 There is also growing evidence which suggest several possible
mechanisms whereby light to moderate alcohol intake may reduce the cellular damage
that can contribute to CVD.392
Alcohol does inhibit gluconeogenesis in the liver and so can increase the risk of
hypoglycemic events in Type-2 DM patients on insulin and oral agents. Sulfonylurea
drugs can to some degree mimic the impact of Antabuse and so Type-2 DM patients on
these agents may develop nausea with the consumption of alcohol. However, most of the
beneficial effects of alcohol on CVD risk in Type-2 DM patients is likely to accrue with
as little as 3-4 drinks per week. As long as no more than one alcoholic beverage is
consumed with a meal there is little danger of hypoglycemia or other adverse effects but
this is still probably enough alcohol to cut the risk of CVD events by about 50%.
Drug Therapy Alone Is Far From an Ideal Treatment for Type-2 DM
Until 1995, sulfonylureas and insulin were the only drugs approved by the FDA for
treating patients with Type-2 DM. Since then several new classes of drugs have become
available to treat Type-2 DM patients. Today, most patients with Type-2 DM eventually
end up taking several drugs to help control the multiple metabolic problems frequently
seen in Type-2 DM patients. The use of several drugs becomes necessary because no
71
single drug can correct all of the metabolic problems typically seen in most patients with
Type-2 DM for very long. Indeed, most Type-2 DM patients eventually require several
different drugs simply to control BS levels. Unfortunately, relying too heavily on drugs to
control the metabolic problems caused by a faulty diet and lifestyle often gives many
patients an excuse not to deal directly themselves with what is to some extent a selfinflicted illness.
The newest class of drugs used to treat Type-2 DM patients are the glitazones
(a.k.a.,Thiazolidiones) which were approved for use by the FDA in 1997. Thiazolidiones
(e.g., rosiglitazone, pioglitazone) increase insulin sensitivity in skeletal muscle cells. It
should be noted that much the same effect of Thiazolidiones can often be achieved with a
daily aerobic exercise bout lasting 45 minutes to an hour. Like exercise Thiazolidiones
tend to lower BP, improve dyslipidemia, endothelial function and improve coagulation
and fibrinolytic parameters. Troglitazone has also been shown to improve insulin
secretory dynamics in subjects with IGT and prevent the development of Type 2 DM in
women with a history of gestational DM.393 Regular exercise has been shown to increase
the storage capacity of muscle cells for both glycogen and TG. Exercise also increases
blood flow to skeletal muscle and increases the enzymatic capacity for oxidative
metabolism of both fats and glucose.394 Unfortunately, much of the impact of exercise on
insulin sensitivity of muscle cells, like that of thiazolidiones, is lost a day or two after
withdrawal of treatment (either drugs or exercise). Like triazolidiones, exercise has many
other favorable health benefits besides improving insulin sensitity of skeletal muscles.395
The major drawback to the use of glitazones is they do tend to promote weight gain by
causing fluid retention and increasing body fat stores. However, early research suggests
this is due to expansion of subcutaneous fat stores and not visceral fat stores so this may
be more of a cosmetic problem than a health problem. All patients taking glitazones
should be counseled to intensify diet (decrease salt and ED and increase fiber) and
exercise efforts in order to limit fluid retention and increased body fat stores.396
One thiazolidione (troglitazone, brand name Rezulin) has already been taken off the
market due to serious liver damage. While this complication was rare, patients taking this
class of drugs should be monitored closely for liver function at least every two months
for the first year. Symptoms of liver damage such as dark urine, nausea, vomiting,
abdominal pain, fatigue and loss of appetite should warrant an immediate visit to the
physician for liver function testing.
Another new class of drugs to treat Type-2 DM patients are the meglitinides. Currently,
there is only one drug from this class has been approved by the FDA. It is repaglinide,
brand name Prandin. These drugs work much like the sulfonylureas in that they stimulate
increased insulin release from the beta-cells. They should only be taken before a large
meal because of their proclivity to cause hypoglycemia. Because this class of drugs is so
new there exist little information about their possible adverse effects, particularly with
long term usage.
All drugs have toxic side effects so the more drugs taken and the higher drug dosages
required to treat metabolic problems associated with Type-2 DM the greater the potential
72
for adverse side effects. Most physicians rationalize that they rely on drugs to treat
patients with Type-2 DM because the patients do not comply with medical advice to
exercise more and lose weight. This is circular reasoning because physicians often fail to
adequately educate their patients as to how to alter their diet and exercise habits to
significantly impact the metabolic problems seen in Type-2 DM patients. However,
sentiment is shifting in the medical community. Chronic disease care is fundamentally
different than acute care. Today, more than 95% of diabetes care is actually done by the
patient because physicians have little direct control over their patients between office
visits. For diabetes care to succeed, patients must be given accurate information about
how various choices will likely effect their health and well-being in the long term.397 In
many cases compliance failure is due more to a failure to sufficiently educate the patient
about the realities of how what they eat and how active they are impacts their long term
health than it is to actual indifference of patients to their long term well being.
Some oral antidiabetes agents (sulphonylureas) and insulin, which lower BS levels and
help to prevent the health problems associated with elevated BS can actually worsen IR
and promote weight gain.398 The newer meglitinides, which also enhance insulin output
may also promote weight gain. Metformin (a biguanide) works primarily by reducing the
release of glucose from the liver. Another new class of drugs used to treat Type –2 DM
are the alpha –glucosidase inhibitors. These drugs work in the intestines by slowing the
digestion and absorption of carbohydrate. In effect acarbose and miglitol can convert a
high-GI meal into lower GI meal. However, they also may cause a lot of bloating, gas
and diarrhea. Recently, a case of lympocytic colitis was linked to the use of acarbose.399
Like metformin, the use of alpha-glucosidase inhibitors is usually associated with some
weight loss, perhaps because they cause unpleasant gastrointestinal symptoms whenever
large meals are consumed.
Improving glycemic control in Type-2 DM patients may improve dyslipidemia but BS
control with drugs does not restore blood lipid levels to normal.400 Weight gain and IR
both hasten the progression of atherosclerosis. On the other hand, some drugs (i.e. betablockers) used to treat hypertension (HTN), which frequently accompanies the IRS, can
elevate BS and increase the risk of developing Type-2 DM in patients who are IR.401
Drugs used to treat high total cholesterol (TC) or LDL-Cholesterol levels and/or high TG
level have no beneficial effects on BS regulation. Drugs that help raise HDL-Cholesterol
also do not improve BS regulation. Indeed niacin (1-3 g/d), which is the most effective
drug for increasing a low HDL-Cholesterol (more common in people with IR and Type-2
DM), can sometimes increase BS levels in diabetics.
Another problem with controlling BS levels with drugs is that they do not address the
underlying cause of the disease that is a typical Western diet usually coupled with a very
sedentary lifestyle. Perhaps as a result of most physicians giving only lip service to diet
and exercise as a potentially effective therapeutic strategy for controlling not only BS but
also the other metabolic disturbances that are usually associated with Type-2 DM most
patients find their disease progresses fairly rapidly on pharmacotherapy alone. Indeed, a
study of over 4000 people age 25-65 y, who were recently diagnosed with Type-2 DM
found that initially most could keep their fasting BS level below 140 mg/dl with a single
73
drug. However, after just 3 years only about half could maintain their fasting BS level
below 140 mg/dl using a single drug. By 9 years only 1 in 4 patients could maintain their
fasting BS level below 140 mg/dl with one BS lowering drug. 75% required multiple
drugs just to keep fasting BS below 140 mg/dl after 9 years.402 The results of this study
suggests that most people with Type 2 DM advised to follow a moderate diet and placed
on a BS lowering drug will see their body's ability to control BS levels deteriorate rapidly
over time.
Another potential concern for the Type-2 DM patients taking metformin in combination
with a sulfonylureas was an apparent increase in overall death rates with this combination
of drugs in the UK Prospective Diabetes Study.403 However, when used alone metformin
does reduce IR and lower BS levels primarily by reducing the release of glucose from the
liver. Unlike sulfonylureas and insulin, metformin does not promote weight gain and
often tends to promote weight loss. While no drug has been approved by the FDA for
treating IR in people who have normal BS levels, the results of a recent study suggests
that metformin has some beneficial effects in such people. A recent study examined the
impact of metformin given to a group of 22 very obese nondiabetic men and women for
24 weeks and instructed not to change their diets. They experienced a drop of 37% in
fasting insulin levels and lost an average of 12 lbs. They also experienced a modest drop
in total and LDL-cholesterol and this correlated with the amount of weight lost and the
reduction in waist circumference.404 Of course, more dramatic improvements in weight
reduction with a healthy high-fiber diet coupled with regular exercise would likely
produce much greater improvements in blood lipids and insulin sensitivity in obese
subjects than simply taking metformin. Intentional weight loss was shown to reduce
overall mortality in people with Type-2 DM.405
Another concern about the use of metformin is reduced absorption of vitamin B-12.
About 10-30% of those on metformin have shown evidence of reduced B-12 absorption.
A recent study suggests that this impairment of vitamin B-12 absorption in those taking
metformin can be reversed with a calcium supplement.406 Low vitamin B-12 status can
impair mental function, elevate homocysteine level and may even increase the risk of
breast cancer.407 Vitamin B-12 status in older patients with Type-2 DM should be
carefully monitored.
It seems likely that drug treatment of diabetics which controls BS levels, but does not
also reduce IR and/or the metabolic disturbances associated with it, will have little
favorable impact on the risk of developing lesions in the large blood vessels that
ultimately kill most people with Type-2 DM. On the other hand, if the dyslipidemia is
effectively treated with drugs but BS is not adequately controlled, then complications like
blindness, neuropathy, kidney failure and limb amputation due to gangrene will
eventually develop in most Type-2 DM patients. Ideally, the treatment of patients with
Type-2 DM and IGT should not only normalize BS levels but also correct the
dyslipidemia and other metabolic disturbances that speed up the progression of
atherosclerosis and increase the risk of a heart attack, stroke or other macrovascular
event.
74
The most effective way to reduce IR is to reduce excessive body fat stores. However,
aggressive lowering of BS with drugs (sulfonylureas and/or insulin) often promotes
weight gain in diabetics. For example, the combination of insulin therapy and
troglitazone or sulfonylureas in Type-2 DM patients usually results in weight gain.408 409
By contrast, the use of metformin with insulin in Type-2 DM patients does not appear to
promote weight gain and may aid weight loss.410 Meridia has recently been approved for
long term (up to 2 years) use for treating obese patients. However, its proclivity to raise
BP makes it of questionable for most patients with Type-2 DM. No other weight loss
drug is currently approved for long term use primarily because of concerns about safety.
Taking drugs to produce weight loss in the short term is unlikely to have much long term
impact of body weight in patients with IR, IGT and Type-2 DM.
Even though diabetes appears to be caused primarily by a rich, modern diet and a
sedentary lifestyle in genetically predisposed people treatment today usually involves
primarily pharmacotherapy. In effect, drugs are being used to treat the metabolic
disturbances caused by a modern diet coupled with a sedentary lifestyle. Type-2 DM
patients should be informed of the scientific information regarding the potentially
beneficial impact of diet and exercise on their overall metabolic control. For patients who
have advanced Type-2 DM with marked beta-cell failure and for those who either fail to
sufficiently to improve their diets, or adequately increase their activity level and/or lose
sufficient excess body fat, the use of insulin and other drugs will at least partially
counteract some of the metabolic defects resulting from a modern diet and sedentary
lifestyle. However, all drugs have potential adverse side effects and in many cases BS,
BP and blood lipids can be adequately controlled without resorting to pharmacotherapy.
This is most likely the case in the highly motivated overweight or obese patient with
early Type-2 DM. There is clearly a genetic component to the development of Type-2
DM. As a result IR and IGT can often be demonstrated in close relatives of patients with
Type-2 DM. The evidence is mounting that if a healthier diet and exercise program is
instituted before the development of Type-2 DM it can be prevented or at least delayed.
The use of pharmacotherapy to treat such patients lacks proof of long term safety and
efficacy.
Use of Nutritional Supplements in Patients with Type-2 Diabetes
Mellitus
There is growing interest in the potential benefits of various food supplements for
treating patients with IR, IGT and Type-2 DM. These diseases appear to develop in
genetically susceptible individuals when they consume a rich modern diet composed of
large quantities of calorie dense foods rich in refined fats, sugars and grains. The primary
nutritional stress placed on the body by such foods, particularly when coupled with an
inactive lifestyle is a positive energy balance and the storage of excess body fat.
However, refined and highly processed foods are also depleted in many vitamins and
minerals and are also low in fiber and other phytochemicals. It seems likely that a lack of
some of these biochemicals may contribute to the health problems seen in people with IR,
IGT and Type-2 DM. It is also possible that the physiological stress placed upon the body
75
by dyslipidemia, HTN, increased BS and increased body fat stores, particularly in the
abdominal area may increase the need for some nutrients. What follows is a discussion of
some of the food supplements for which research suggests are most likely to have
beneficial effects in patients with IR, with or without elevated BS.
Chromium and Glucose Tolerance Factor
Since the 1950's it has been known that chromium is involved in the clearance of glucose
from the blood. A deficiency of chromium was shown to impair glucose tolerance.411
Chromium exist in several forms but the most common are the trivalent and hexavalent
forms. The hexavalent form is toxic when inhaled (leading to bronchitis and asthma) and
long-term exposure to hexavalent chromium may lead to skin and lung cancer.412 By
contrast the trivalent form is found primarily in the soil and is picked up by plants and
bound in organic complexes and does not appear to be carcinogenic. Most foods have
between 20 and 500 micrograms/kg of primarily trivalent chromium. Processing and
refining of grains and sugars results in the loss of most of this organically bound trivalent
chromium.
Chromium is believed to function in the body as part of an organic complex called the
glucose tolerance factor (GTF) but the precise composition of this GTF is still a matter of
debate.413 In modern societies, the refining of plant foods has led to a drop in chromium
intake and this has been associated with an increasing incidence of IR and IGT and Type2 DM as human populations switch from traditional foods to those that are highly refined
and processed. This has led to speculation that chromium or GTF deficiency may be
playing a role in the development of these health problems. The Estimated Safe and
Adequate Dietary Intake for trivalent chromium is 50 to 200 micrograms/day.414 The
average daily intake for Americans is less than 50 micrograms daily which suggest that
many people are obtaining a suboptimal intake of this nutritional mineral.415 However,
newer research suggests that the actual chromium requirement for healthy adults is much
lower, perhaps only 25 mcg/d - a level that most Americans usually get.416
The feeding of yeast produced GTF trivalent chromium was shown to improve glucose
tolerance in one study of elderly subjects.417 However, these results have not been
replicated. A prospective double-blind study, crossover study with a wash-out period in
28 Type-2 DM patients found that 200 mcg of chromium picolinate supplements for two
months had no significant effect on FBS or HDL-Chol and LDL-Chol levels but did
significantly lower serum TG levels.418 A review of 15 studies, which examined the
impact of chromium supplements on insulin sensitivity concluded that chromium
deficiency does increase IR and that chromium supplements do improve IR in those who
are deficient. However, they also concluded that clinically significant chromium
deficiency is uncommon and that intakes as low as 20 mcg/d may be adequate to prevent
overt chromium deficiency.419
Losing body fat and increasing muscle mass could improve glucose tolerance and lower
BS levels in patients with IGT or Type-2 DM. Some have claimed that chromium
picolinate supplements cause the loss of body fat and an increase in lean tissue. The
76
promoters of chromium picolinate supplements have been making such claims for many
years. However, claims that chromium picolinate or other chromium supplements
promote the growth of muscle and/or the loss of body fat are not supported by any
credible scientific research.420 There is also some evidence suggesting that chromium
picolinate can cause DNA damage and could possibly be carcinogenic.421 Most recent
studies show no beneficial effects of chromium picolinate or other chromium compounds
in healthy human subjects.422
High-dose (1000 mcg/day) of supplemental chromium did reduce insulin requirements in
a group of Type-2 DM patients.423 However, 1000 mcg of chromium is well above the
recommended intake and so represents a pharmacological (aka "nutraceutical") dose.
Indeed, this same study showed that a 200 mcg dose of chromium had no significant
effect on glucose tolerance. It is possible that people with Type-2 DM may require more
chromium than healthy individuals. One study showed that Type-2 DM patients had 33%
less chromium in their blood and yet were losing almost twice as much chromium in their
urine as nondiabetic subjects.424
Whether or not high doses of chromium are justifiable for treating patients with IR and
Type-2 DM requires more research on the risk and benefits of nutraceutical doses. There
have been some reports of chromium toxicity. For example, chromium picolinate caused
DNA damages in an in vitro experiment but other forms of chromium did not. It does not
appear that other forms of chromium pose much danger in trials lasting no more than a
few months.425 However, more research is needed on the long-term safety and efficacy of
high doses (>200 mcg/day) of chromium supplements before they could be recommended
for routine use in patients with IR, IGT and Type-2 DM.
Recent research in rats has identified a low molecular weight chromium compound that
does have some apparently favorable effects on lipid and carbohydrate metabolism and
body composition.426 This chromium compound does not damage DNA and has not been
shown to cause other adverse effects in rats. However, a lot more testing is needed on this
and other chromium compounds before their efficacy in treatingType-2 DM patients is
established.
Pharmacological Doses of Vanadium and Glucose Tolerance
The physiological role of vanadium in human nutrition is not yet clearly defined and it
has not yet been deemed an essential trace mineral. However, it does appear to be
essential in rats and goats. If vanadium does prove to be essential in human nutrition it
seems unlikely that more than 1-2 mg would be required and this amount is easily
attainable from food so it seems unlikely that there is any need for a supplement of this
mineral. Nevertheless, supplements of vanadium (usually as vanadium sulfate) containing
1-5mg elemental vanadium are widely available.
Treatment of people with Type-1 and Type-2 DM with sodium orthovanadate has been to
lower insulin requirements but has no effect on endogenous insulin levels.427 Another
study found a reduction in FBS and HbA1c with no changes in plasma insulin levels in a
77
group of Type-2 DM patients.428 A 100 mg dose of vanadyl sulfate was also found to
improve glucose tolerance in a group of Type-2 DM patients.429
At doses far above any possible nutritional or physiological range, vanadium does mimic
the impact of insulin by increasing the rate at which tissue take up glucose.430
Unfortunately, the levels of vanadium supplementation needed to produce this
pharmacological action are far above any nutritional requirement431 are close to the toxic
level.432 Therefore, the use of vanadium supplements to treat patients with IR, IGT and
Type-2 DM does not appear to be clinically justifiable. Much more research needs to be
done on the long-term safety and efficacy of any kind of vanadium supplement before it
should be advocate for the treatment of Type-2 DM patients.
Magnesium Supplements for Type-2 DM Patients
An abnormally low intracellular concentration of magnesium is induced by the typical
modern diet, alterations in glucose regulation, and/or a high-insulin state, which may
contribute to the development of IR, HTN and electrolyte disturbances. 433 434 Magnesium
supplements (480 mg/d) have been shown to reduce BP in subjects with HTN.435
Hypomagnesia is a common finding in diabetic patients in poor control and is associated
with late stage complications. A prospective study that followed 35, 988 older Iowa
women who were initially free of diabetes for 6 years observed 114 new cases of Type-2
DM. The results of this study support a protective effective of whole grains, cereal fiber
and magnesium from the development of Type-2 DM.436 A study of otherwise healthy
subjects found that those with low magnesium levels responded to a glucose challenge
with higher BS and insulin levels.437 However, these studies do not address whether low
magnesium intake is a causal factor in the development of Type-2 DM. Nor is not known
whether or not magnesium supplementation will reduce the risk of developing Type-2
DM or if magnesium supplements will reduce the long-term complications associated
with Type-2 DM.
In experimental animals, magnesium supplements do correct the insulin resistance that
has been induced by a high-fructose diet.438 This suggests that IR may potentiate
magnesium deficiency and increased magnesium intake may help to protect against the
IRS and perhaps the development of HTN and Type-2 DM. More research is needed
before any firm conclusions should be drawn about the benefits of taking magnesium
supplements for patients with IR, IGT and Type-2 DM. However, based on current
research it seems reasonable to recommend that all Americans consume more whole
grains and other magnesium-rich foods (i.e., beans and dark green vegetables) and limit
their intake of refined sugars and grains. Patients who do not improve their diets may
benefit from a daily supplement of 250 to 450 mg of magnesium.
Vitamin E and Vitamin C Supplements
Increased oxidative stress and enhanced oxidation of LDLs is believed to contribute to
the excess mortality from CVD seen in Type-2 DM patients.439 In vitro glucose promotes
78
ldl oxidation, and glycated LDL particles are very susceptible to to oxidative
modification.440 These findings suggest that people with Type-2 DM may have a greater
need for dietary antioxidants than people with normal BS levels.
Vitamin E is an essential fat-soluble vitamin. Its main function appears to be to protect
cellular membranes from oxidative damage caused by superoxide, hydroxyl and peroxyl
free radicals. Vitamin E may also protect LDL particles from oxidative modification.
Modified LDL particles are believed to play a role in atherogenesis.441
A study of patients with Type-2 DM showed that their monocytes released more
superoxide and interleukin-1 beta which promoted more inflammation. They also found
that diabetic monocytes caused more adhesion to endothelial cells lining the artery walls.
This same study also showed that taking 1200 I.U. of alpha-tocopherol for 3 months
reduced this proinflammatory action by monocytes.442
There is some evidence that oxidative stress may be involved in the genesis of the
neuropathy and microvascular complications associated with diabetes 443 444 445 Two
studies showed that a pharmacological dose of vitamin E (900 mg dl-alpha-tocopherol)
improved whole body glucose disposal and glucose tolerance in Type-2 DM subjects.446
447
A 6 month double-blind controlled study of 21 Type-2 DM patients with mild to
moderate neuropathy found that 900 mg of supplemental vitamin E daily had no
significant effect on glucose tolerance, FBS or HbA1c levels but did significantly
improve some measures of nerve function.448 In a study of 25 elderly patients with Type2 DM a pharmacological dose of vitamin E (900 mg/d) found small but statistically
significant effects on BS, HbA1c, and blood lipids but no effect on beta-cell response to
BS level. The authors concluded that "Daily vitamin E supplements seem to produce a
minimal but significant improvement in metabolic control in type 2 diabetic patients.
More studies are necessary before conclusions can be drawn about the safety of vitamin E
during long-term administration.” 449
Vitamin C (ascorbic acid) is a water soluble vitamin involved in several hydoxylation
reactions and may also be involved in the release of insulin from the pancreatic betacells.450 Ascorbic acid can also act by reducing free-radical oxidative damage. Vitamin C
may reduce the accumulation of intracellular sorbitol, which may ameliorate the
secondary effects of hyperglycemia such as neuropathy and cataract formation. In doses
of 250 to 600 mg (L-ascorbic acid), vitamin C can RBC sorbitol levels and may have
positive effects on protein glycation.451 However, in healthy people, megadoses of
vitamin C (2gm/d) for 2 weeks resulted in delayed insulin release following an oral
glucose challenge.452 Because people with Type-2 DM already have a delayed insulin
response to rising BS levels, there seems to be no rationale for recommending megadoses
of vitamin C for type-2 DM patients. It should also be noted that megadoses of vitamin C
can also throw off some laboratory measures of glucose in urine and blood.
It should be kept in mind that natural foods are much higher in a wide variety of
phytochemicals that have potent antioxidant effects. For example, 500 ml of tomato juice
79
daily was shown to slow the oxidation of LDL nearly as much as 800 IU of Vitamin E in
diabetic patients. However, while the tomato juice did not reduce CRP (measure of
inflammation) in this study, the 800 IU vitamin E supplement did reduce CRP nearly
50%.453 Whether or not large doses of supplements of vitamin E would still be beneficial
if one consumed a DASH-style diet is not clear. More research is needed on the impact of
vitamin E and C supplements on patients with Type-2 DM. However, preliminary
research suggests that supplements of vitamin E in the 400 to 1000 mg/d may some
beneficial effects on neuropathy and free-radical damage that may contribute to CVD in
patients consuming a typical modern diet. High doses of Vitamin C are not warranted for
treating Type-2 DM at this time but doses up to 250 mg/d are probably safe, even if not
beneficial. Patients should be warned that supplements are not a substitute for a healthy
diet, exercise and weight loss. There is growing evidence that an overall healthy diet
pattern reduces the risk of CAD and this reduction in risk is at least partially independent
of specific nutrient intake.454
Alpha-Lipoic Acid Supplements
Alpha-lipoic acid is a fat soluble biochemical that is synthesized by the body. It is
involved in a variety of biochemical reactions in a variety of cells. It also has potent
antioxidant activity that can squelch a variety of free-radical reactions. Like vitamin E it
is believed to function in protecting cellular membranes from oxidative damage. In a 4
week controlled clinical trial with 40 subjects, lipoic acid (1200 mg/d) supplementation
improved glucose tolerance and appeared to improve insulin action.455 In a study of 73
Type-2 DM subjects with cardiac autonomic neuropathy, a supplement of 800 mg of
lipoic acid had no significant effect on BP and HbA1c but did improve slightly some
measures of cardiac autonomic neuropathy compared to a placebo.456
In a study of 70 patients with Type-2 DM, taking a lipoic acid (800 mg/d) supplement for
4 months resulted in a small improvement in neuropathy compared to those who took a
placebo.457 Improvement in diabetic neuropathy symptoms was also reported in
multicenter placebo-controlled study with 260 Type-2 DM subjects with symptomatic
diabetic neuropathy who received 600 or 1200 mg of lipoic acid daily for 3 weeks.458
Supplements of lipoic acid from 600 to 1200 mg/d appear to be well-tolerated and appear
safe and at least modestly effective for treating most Type-2 DM patients with
neuropathy (peripheral or autonomic). More research is needed on its long-term safety
and efficacy. In animals, lipoic acid appears to be quite toxic in those that are thiamin
deficient. It may be prudent to avoid using lipoic acid supplements in patients who are
alcoholics. A thiamin supplement in conjunction with lipoic acid may reduce this risk in
patients who may be thiamin-deficient.
Folic Acid and Vitamins B-6 and B-12 Supplements
Vitamin B-12 deficiency is common in people 60+ years due to a reduced ability to
absorb this vitamin. In a study of 50 patients with diabetic neuropathy (39 with Type-2
DM and 11 Type-1 DM), researchers found that those assigned to receive 1500 mcg of
80
methylcobalamin for 4 weeks showed significant improvement in both peripheral and
autonomic symptoms. However, motor and sensory nerve conduction studies were unable
to show any improvement.459 In this study vitamin B-12 status was not measured.
However, it seems that many, if not most diabetic patients 50 years or older may benefit
from a supplement of 100 to 1000 mcg/d). This has no known risk and much potential
benefit.
Diabetes has been associated more cognitive impairment and with a more rapid decline in
mental function in older women.460 Multiple regression analysis of this data suggested
that this decline in mental function could not be explained by stroke, HTN, CVD or
depression. However, previous cross-sectional studies have related a decline in mental
function with hyperinsulinemia, hyperglycemia and IR.461 462 463 464 In addition, elevated
levels of Hcy appear to be related to the decline in mental function in the elderly.465 The
combination of diabetes and elevated Hcy may promote an even more rapid decline in
mental function.
While elevated Hcy levels, unlike many other CVD risk factors, do not appear to be
associated with IR, IGT or Type-2 DM, they probably should be measured in Type-2 DM
patients because they are already at high-risk for CVD and elevated Hcy are likely only
to add to this risk. Elevated Hcy levels can be reduced with supplements of folic acid
(800 mcg/d), vitamin B-6 (5 mg/d) and vitamin B-12 (250 mcg/d).466 While IR itself does
not appear to elevate plasma Hcy levels, even modest deterioration of kidney function,
particularly when the B-vitamin status is in the low to low-normal range can result in an
increased Hcy levels which probably further increases the risk of CVD in Type-2 DM
patients.467
L-Arginine Supplements and Insulin Resistance
L-Arginine (ARG) is an amino acid that is utilized as a precursor for nitric oxide (NO)
synthesis in the body. It is released from endothelial cells and causes the smooth muscle
cells surrounding arteries and arterioles to relax. In animals, a diet high in fat and sugar
was shown to impair to impair endothelial function that resulted in increased BP and
restricted blood flow. The impaired endothelial function in these animals was then
reversed after they were placed on a very-low-fat, high-complex-carbohydrate diet.468
In a group of apparently healthy human subjects, ARG supplements improved
endothelium-dependent dilation of small blood vessels.469 ARG supplements have also
been shown to improve endothelium-dependent dilation and also reduced monocyte
adhesion in men with CAD.470
NO and its precursor ARG appear to promote the release of insulin from the beta-cells
and improve insulin sensitivity.471 Several grams of ARG daily has been shown to
potentiate nutrient-stimulated insulin secretion.472 In a group of diabetics subjects ARG
supplements were shown to improve insulin sensitivity.473
81
ARG supplements of several grams daily are probably safe but more research is needed
to determine if supplemental ARG has any long-term beneficial effects in patients with
IR, IGT and Type-2 DM. Very high doses ARG supplements (20-30g/d) may cause
diarrhea and do not appear to be justified by current research.
Niacin, Blood Lipids and Diabetes
Patients with IR and Type-2 DM often have low HDL-Cholesterol and elevated TG and
may also have elevated LDL-Cholesterol and Lp(a) putting them at very high risk for
CVD. Pharmaceutical doses (1-3gm/d) of niacin (as nicotinic acid but not nicotinamide)
have been shown to reduce total cholesterol, LDL-Cholesterol and TG. Nicotinic acid is
also the most effective drug for increasing HDL-Cholesterol and reducing Lp(a). It has
also been shown to reduce CVD mortality and all-cause mortality in people at high-risk
for CVD. 474 475
In most ways, high doses of niacin appear to be the ideal pharmaceutical agent for
treating many people with IR, IGT and Type-2 DM. One concern with niacin therapy for
patients with Type-2 DM is that niacin at about 3000 mg/d has been reported to increase
plasma Hcy levels.476 It is likely that this rise in Hcy if confirmed could be controlled
with supplements of folate, Vitamin B-12 and B-6. Of greater concern for Type-2 DM
patients are the results of a study that while confirming the beneficial impact of high-dose
(1.5g 3X/d) niacin on blood lipids showed that it had unfavorable effects on BS control.
On average FBS increased 16% and HbA1c increased 21%. Uric acid levels also
increased significantly and some patients experienced increased glycosuria.477 Given the
deterioration in BS control and elevated uric acid levels, high-dose niacin therapy is of
questionable value for patients with IGT and Type-2 DM although it may be of value in
treating patients with Metabolic syndrome but normal BS levels. It is possible that highdose nicotinamide or perhaps some other B-vitamins given with nicotinic acid could
blunt the deterioration of glycemic control seen with high-dose nicotinic acid alone but
this remains to be tested.
Nicotinamide therapy has no effects on blood lipids but has shown promise in animal
models of Type-1 DM. In these animal studies, nicotinamide it has been shown to slow
the destruction of the beta-cells. A meta-analysis of 16 clinical trials with nicotinamide in
Type-1 DM subjects of recent onset found that there was no difference in the insulin dose
required to control BS levels or HbA1c levels compared to those who received the
placebo. However, after one year C-peptide levels were significantly higher in those who
received nicotinamide.478 In a placebo-controlled trial of 55 identical twins (whose
siblings had already developed Type-1 DM), 1.2 gm of nicotinamide per meter of body
surface area did not reduce the risk or slow the progression of beta-cell destruction in
these high-risk subjects. 479
The potential of nicotinamide to slow the loss of beta-cell function in Type-2 DM has
received much less attention from researchers. A small study of a group of 18 Type-2
DM patients of normal body weight who were followed for 6 months, demonstrated that
those who received insulin with 1.5 g nicotinamide had increased C-peptide release.480
82
Omega-3 Fatty Acids, Blood Lipids and Type-2 DM
Patients with poorly controlled Type-2 DM often have very high serum TG levels and
lower HDL-Cholesterol, an increased tendency for blood to clot and an increase in proinflammatory cytokines. Patients with Type-2 DM frequently have HTN, are at increased
risk for cardiac arrhythmia, and have a much higher risk for atherosclerotic artery disease
than those with normal BS levels and without IR. Many studies have shown that
supplements of omega-3 fatty acids (a.k.a. fish oil) lower serum TG in patients with
hypertriglceridemia by about 50%.481 While LDL-Cholesterol may increase as serum TG
levels fall in response to omega-3 supplements it seems unlikely that this results in
increased atherosclerosis because of the anti-thrombotic, anti-inflammatory and
antivasoconstrictive effects of these supplements.482 Omega-3 fatty acids also appear to
reduce the risk of arrhythmia.483
Omega-3 supplements have been consistently shown to have a small but consistent BP
lowering effect in those who have HTN. This antihypertensive effect appears to be
strongest in those who have hypercholesterolemia and clinical atherosclerosis. 484Fish oil
supplements were also shown to significantly increase HDL-Cholesterol levels in men.485
In short, omega-3 supplements (1 to 6 g/d) when tested in nondiabetic subjects have
favorable effects on most of the CVD risk factors, which tend to be elevated in patients
with IR, IGT and Type-2 DM.
Despite the favorable impact of fish oil supplements on many CVD risk factors
commonly found in patients with Type-2 DM, some studies have found a modest increase
in BS levels when several grams of omega-3 fatty acids supplements are given to Type-2
DM patients.486 487 The results of studies such as these has led to concern that the
beneficial impact of omega-3 fatty acid supplement in patients with Type-2 DM may be
offset by higher BS levels.
A meta-analysis of 26 trials testing the benefits of fish oil supplements in in patients with
Type-1 and Type-2 DM revealed an average drop in serum TG of about 23-30% and a
small but significant increase in LDL-Cholesterol. The impact of the omega-3
supplements on these blood lipids tended to be somewhat greater in the type-2 than the
Type-1 DM subjects. However, FBS was modestly increased on average in the Type-2
DM subjects. When the impact of DHA and EPA were analyzed separately, it was found
that the EPA was positively associated with HbA1c whereas DHA was positively
correlated with both FBS and HbA1c levels in Type-2 DM patients but neither omega-3
fatty acid had a significant effect on either FBS or HbA1c levels in Type-1 DM patients.
The authors concluded that overall: "The use of fish oil has no adverse effects on HbA1c
in diabetic subjects and lowers triglyceride levels effectively by almost 30 percent.
However, this may be accompanied by a slight increase in LDL cholesterol
concentration. Fish oil may be useful in treating dyslipidemia in diabetes."488
It should be noted that while omega-3 fatty acids may have a small tendency to increase
BS levels in short-term studies, population studies suggest that long-term consumption of
diets with a higher ratio of omega-3 to omega-6 fatty acids may reduce the risk
83
developing Type-2 DM and CVD.489 It is unlikely that the relatively high consumption of
saturated, trans and omega-6 fatty acids coupled with the very low intake of omega-3
fatty acids in the modern diets provides the biologically correct nutritional fuel mix for
human beings490 represents optimal nutrition for human beings. An increased ratio of
omega-6 to omega-3 fatty acids has been accompanied by a striking increase in the
prevalence of Type-2 DM and may be playing a role.491
Other researchers have suggested that the short-term adverse effects on BS regulation
observed when fish oil supplements are given to Type-2 DM patients may be
transitory.492 More research is needed on the long-term effects of increasing omega-3
fatty acids in the diet. However, it seems prudent to encourage people with IR, IGT and
Type-2 DM to increase their intake of omega-3 fatty acids and reduce their intake of
saturated, trans and omega-6 fatty acids. Indeed, women who followed a healthier diet
and lifestyle, which included a greater intake of marine omega-3 fatty acids were found
to have an 83% lower death rate from CAD.493
Conjugated Linoleic Acid (CLA) and Glycemic Control
CLA supplements are promoted as an aid for weight loss. These claims are based
primarily on studies in animals which have shown CLA supplemented to their diets
resulted in reduced body fat and increased lean mass.494 CLA has recently shown to
reduce both FBS level and insulin level in Zucker Diabetetic fa/fa rats about as well as
thiazolidinediones. Indeed, CLA binds to peroxisome proliferator-activated receptors,
which are the same biochemical target that allow thiazolidinediones to reduce insulin
resistance in muscle cells. An 8 week study of people with Type-2 DM reported at the
American Chemical Society meeting in August 2000 found that a supplement of 6 gm
daily of CLA lowered serum TG, insulin levels and body weight compared to controls.
However, another study of 13 Type-2 DM subjects who were not taking BS lowering
medications found that taking a 4.8 gm/d supplement of CLA for 8 weeks did not
produce any favorable effects on blood lipids or glycemic control even though plasma
CLA levels increased about 4-fold.495 It is clear that much more research is needed about
the impact of CLA supplements in people with IR, IGT and Type-2 DM before any firm
conclusions about their safety and efficacy can be reached.
Medicinal Herbs and Glycemic Control
There is growing interest in the use of herbal products in the regulation of blood sugar
levels among both researchers and the general public. An increasing number of patients
are utilizing herbal products in the hope of improving a wide variety of medical
conditions. They often do so without advice from their medical doctors.496 Most
American physicians remain skeptical about the safety and efficacy of medicinal herbs
and correctly believe that more randomized, placebo controlled studies are needed to
provide sound evidence of their likely impact on health.497 Nevertheless, because many
patients with DM may try a variety of herbal products in the hope of improving BS
control both physicians, dietitians and diabetes educators need to ask about the use of
84
these products. It is likely that some may have some medicinal effects, most will have
little impact and some may prove harmful.
One herbal product hat has shown some promise for reducing both fasting and
postprandial BS levels is American ginseng. The health benefits for ginseng, like most
other herbal products has been greatly exaggerated. It is certainly not a panacea or cure
all as some “herbalist” would have the public believe.498 Nevertheless, ginseng has been
shown to have a modest hypoglycemic effect in several animal studies.499 500 Researchers
have also identified a group of phytochemicals in ginseng that have a BS lowering
effect.501 A study of patients with Type-2 DM showed that 3 gm of American ginseng
taken either with or 40 minutes before an oral glucose challenge lowered postprandial BS
levels.502 A follow-up study demonstrated that doses above 3gm had little impact on the
hypoglycemic effect of ginseng nor did the time of administration up to 2 hours before
the glucose challenge impact ginseng’s hypoglycemic effect. Postprandial BS levels
which were reduced close to 50% at 2 hrs after the glucose challenge.503 It now seems
likely that American ginseng has what appears to be potentially clinically beneficial
hypoglycemic effects on postprandial BS levels in Type-2 DM patients. Nevertheless, the
long-term safety and efficacy of this herbal product as a hypoglycemic agent for treating
Type-2 DM requires much more research.
Summary
As we have seen, the ideal treatment plan for patients with IGT or Type-2 DM must both
improve insulin sensitivity and BS regulation and also reduce the other metabolic
problems associated with the IRS which often lead to CVD. For the majority of people
with IGT or Type-2 DM the overall treatment plan must lead to a permanent reduction in
excess body fat, particularly in the abdominal region. The loss of visceral fat will usually
improve BS regulation, reduce IR and may also reduce other CVD risk factors such as
dyslipidemia, enhanced inflammation and increased thrombogenesis. While HTN and
smoking may not be part of the IRS, it is clear that both greatly increase the risk of both
microvascular and macrovascular complications in people with IR, IGT and Type-2 DM
patients.
Controlling BS with insulin and sulfonylureas does not correct the underlying IR.
However metformin and the glitazones have shown some promise for reducing the
metabolic features of IR in the liver and muscles, respectively. Reducing BS does reduce
microvascular diseases and neuropathy that are caused primarily by high BS levels.
Neither intensive insulin therapy nor sulphonlyures, both of which improve BS control
and reduce microvascular disease, have been shown to be beneficial in reducing
morbididty and mortality from CVD in Type-2 DM patients. 504 505 To reduce the risk of
CVD, control of dyslipidemia, increased thrombogenesis, HTN, elevated Hcy and a
physically more active lifestyle, as well as control of hyperglycemia are needed in Type-2
DM patients.
In addition to improving BS levels, reducing IR and reducing risk factors for CVD, it is
also important to reduce visceral fat stores. Weight reduction by calorie restriction
85
without changing what people eat is usually unsuccessful in the long run because it leads
to increased hunger and a slower metabolic rate. By contrast, a diet with a high fiber
content and with a low ED has been shown to promote weight loss without conscious
calorie restriction in the short-term and shows more promise for long-term weight control
than diets based on reducing portion sizes and/or counting calories. Regular exercise like
walking should be strongly encouraged as it has been shown to not only aid weight loss
but also to improve insulin sensitivity and reduce many of the risk factors associated with
increased CVD risk seen in people with IR.
Focus should be placed on the diet's ED rather than its % fat, protein and carbohydrate. In
general, foods with a high fiber content and low ED will also have a low GI but there
would be no harm and likely some benefit in choosing foods which have a lower
glycemic response, provided they have a similar ED, nutrient content and macronutrient
content. In thin patients with Type-2 DM and severely impaired glucose tolerance, a diet
with more energy dense foods and foods with a higher unsaturated fat content may be
preferable to a very high-carbohydrate diet provided these foods are also very low in
SFA, TFA, salt and cholesterol content. This would include most unsalted nuts, seeds,
avocados and modest amounts of unsaturated oils and fatty fish. Foods with a lower GI
may also be helpful in controlling postprandial hyperglycemia in thin patients with Type2 DM who usually have a marked reduction in the capacity to produce insulin and
metabolize carbohydrate.
Claims that the key to good health and treating obesity, Type-2 DM, IRS and CVD is a
diet that is higher in fat and lower in carbohydrate is not supported by scientific evidence.
However, just as different dietary fats and oils can have markedly different effects on
blood lipids and the risk of heart disease, different types of dietary carbohydrate can have
very different metabolic effects. Studies that have shown adverse metabolic effects on
high-carbohydrates should be interpreted with caution and certainly not over generalized
to claims that all high-carbohydrate diets would produce the same or similar adverse
effects. This is because all of the studies that purport to show harmful effects from diets
higher in carbohydrate have controlled body weight and/or calorie intake. Most have used
high-carbohydrate diets consisting largely of sugar and refined grains (resulting in a
much higher glycemic load) and have also been low in fiber. In nearly all cases the
amount of SFA and cholesterol have been the same in the higher carbohydrate diets than
contained in the higher fat diets. Such an experimental design yields results that can
easily be over generalized by clinicians.
Results of short-term studies which claim to show that high-carbohydrate diets may cause
metabolic problems leading to CVD and Type-2 DM are at odds with most
epidemiological studies that have examined the prevalence of diabetes and CVD in
human populations that have followed high-carbohydrate diets throughout their lives.
These studies generally show low rates of CVD and both Type-1 and Type-2 DM in
human populations consuming very-high-carbohydrate diets. However, in these
populations the people are generally more active, have lower levels of body fat and
consume less processed and refined carbohydrate-rich foods. As a result, their diets have
much more fiber, a lower GI, lower ED and higher levels of other phytochemicals than
86
found in a more modern diet. These other differences besides the higher percentage of
energy from carbohydrate may play an important role in protecting the body from the
development of IR, Type-2 DM and atherosclerosis. The overall pattern of the diet is
likely far more important than the content of any single nutrient or chemical found in
foods.506 This is why food supplements should not be viewed as an acceptable substitute
for healthier eating habits.
While dietary supplements and prescription drugs should not be the first line of treatment
of patients with Type-2 DM they may become warranted on a case by case basis in
patients who fail to adhere to a healthy diet and lifestyle and/or do not attain adequate
control of their BS levels and/or CVD risk factors. The use of both pharmaceutical doses
of food supplements (a.k.a. nutraceuticals) and prescription drugs carry both benefit as
well as risk and health professionals who advocate their use should fully inform patients
about what current research has shown are the potential risks and benefits of these
therapeutic agents.
Overall dietary pattern of most Americans provides a diet that is energy dense and
marginally low in many nutrients and phytochemicals.507 Just such a dietary pattern
undoubtedly contributes to the development of IR, IGT and Type-2 DM. A diet high in
minimally processed whole grain foods like pasta, hot cereals, corn, and brown rice and
generous amounts of fruits, vegetables and starchy foods (eg. yams, potatoes, beans,
lentils and peas) and a modest amount of nonfat-dairy products and a little seafood
appears to be ideal. By preventing weight gain with increasing age, most research
suggests that IR, IGT and Type-2 DM will not develop in the vast majority of people.
Even in those with the strongest genetic predisposition to develop IR these people can
usually postpone the development of IGT and Type-2 DM into old age by eating a
healthy diet, exercising regularly and maintaining a low BMI. To prevent or treat HTN
the diet it is now clear that the diet should also be low in added salt (< 1500 mg
sodium/day). It is likely that such a dietary pattern combined with regular exercise will
prove most effective for both the prevention and treatment of both Type-2 DM and
CVD.
Updates and Further Discussion:
Muscles May Be Key To Dyslipidemia of High-CHO Diets
The National Cholesterol Education Program has suggested people with insulin resistance
(IR) and the Metabolic Syndrome (MetS ) avoid diets high in carbohydrates (CHO). This
recommendation is based on the many studies showing high-CHO diets tend to raise
serum triglyceride levels, increase the proportion of small dense LDL particles, and lower
HDL-C levels – known collectively as dyslipidemia. People with IR, the MetS, and Type
2 diabetes mellitus (DM) are more CHO sensitive than those without IR and so are more
prone to dyslipidemia and atherosclerosis when consuming a low-fiber, high-CHO diet
and are inactive and fail to lose weight.
87
By contrast, epidemiological studies of people living in places where high-fiber, highCHO diets are the norm, such as rural China, rarely develop type 2 DM and have far less
atherosclerosis than Americans. Indeed, as their diets Westernize and become lower in %
CHO and fiber and higher fat and animal products the prevalence of type 2 DM and
atherosclerotic diseases increase dramatically. No doubt the increasing body weight and
reduced activity levels often seen in human populations adopting a more Westernized diet
plays a role in promoting IR, the MetS, Type 2 DM, and the accompanying dyslipidemia.
However, Americans who come to the Pritikin Longevity Center and adopt a high-CHO
diet often experience marked drops in insulin levels and serum triglyceride levels in a
week or two and long before much body fat is lost. How can we explain what on the
surface appears conflicting data?
A recent article by Dr. Gerald Shulman508 sheds light on the important role of skeletal
muscle in the development of dyslipidemia seen in people with the MetS. Dr. Shulman
screened 400 young, healthy, normal weight but sedentary subjects. He selected half the
subjects who had normal glucose tolerance and insulin sensitivity and the other half had
reduced insulin sensitivity (or were IR). Despite differences in insulin sensitivity the two
groups had a similar amount of abdominal fat. Both groups of subjects were then fed a
standard liquid meal or the same meal enriched with added sucrose. Compared to the
insulin sensitive subjects those with IR in their skeletal muscle responded to the higher
CHO diet by increasing fat synthesis from CHO in their livers while the muscles of the
insulin sensitive subjects responded by synthesizing more muscle glycogen. The authors
state “These data demonstrate that IR in skeletal muscle, due to decreased muscle
glycogen synthesis, can promote atherogenic dyslidemia….”.
Research has shown that exercise reduces muscle glycogen stores. Until the muscle
glycogen is replenished the muscle cells remain far more sensitive to insulin. Last month
we discussed how diets high in fructose tend to raise serum triglyceride levels by
delaying the clearance of fat-rich lipoprotein particles from the blood stream. The authors
stated that “The similarity of fructose-induced hypertriglyceridemia to certain forms of
endogenous hypertriglyceridemia is also suggestive of potential cardiovascular risk.”509
Because fructose goes primarily to the liver for metabolism it is more likely to stimulate
fat synthesis in the liver.
Bottom Line: Those genetically prone to develop IR should remain active, thin, and limit
their intake of refined CHO and especially those containing fructose or they will likely
develop a more atherogenic blood lipid profile. By contrast, a diet high in unrefined CHO
and limited in fructose when combined with regular exercise can promote weight loss,
improve insulin sensitivity, and reverse the dyslipidemia associated with the MetS and
Type 2 DM.
References:
1
Mokdad AH, Ford ES, Bowman BA, et al. Diabetes trends in the U.S.: 1990-1998. Diabetes Care
2000;23:1278-83
88
2
Harris MI, Hadden WC, Knowler WO, Bennett PH. Prevalence of diabetes and impaired glucose
tolerance and plasma glucose levels in the U.S. population aged 20-74 yr. Diabetes 1987;36:523-34
3
Amos AF, McCarty DJ, Zimmet P. The rising global burden of diabetes and its complications: estimates
and projections to the year 2010. Diabet Med 1997;14(suppl):S7-S85
4
Finch CF, Zimmet PZ. Mortality from diabetes. In The Daibetes Annual/4. Alberti KGMM, Krall LP, eds.
Amesterdam, Elsvier, 1988, p. 1-16, Songer TJ, Zimmet PZ,. Epidemiology type 2 diabetes: an
international perspective. Pharmoceconomics 1995;8(suppl):1-11
5
Shaw JE, Zimmet PZ, McCarty D, de Courten M. Type 2 diabetes worldwide according to the new
classification and criteria. Diabetes Care 2000;23(suppl. 2):B5-B10
6
Shaw JE, Zimmet PZ, de Courten M, et al. Impaired fasting glucose or impaired glucose tolerance: what
best predicts future diabetes in Mauritius? Diabetes Care 1999;22:399-402
7
Tominga M, Eguchi H, Manaka H, et al. Impaired glucose tolerance is a risk factor for cardiovascular
disease, but not impaired fasting glucose: the Fungata Diabetes Study. Diabetes Care 1999;22:920-4
8
Hollenbeck CB, Reaven G. Variations in insulin-stimulated glucose uptake in healthy individuals with
normal glucose tolerance. J Clin Endocrinol Metab 1987;64:1169-73
9
Feskens EJM, Loeber JC, Kromhut D. Diet and physical activity as determinants of hyperinsulinemia. Am
J Epidemiol 1994;140:350-60
10
Tromileho J. Data presented at the annual American Diabetes Association meeting; San Antonio, TX;
6/11/2000
11
Meneilly GS, Elliott T. Metabolic alterations in middle-aged and elderly obese patients with Type-2
diabetes. Diabetes Care 1999; 22:112-8
12
DeFronzo RA. The triumvirate: beta-cell, muscle, liver: a collusion responsible for NIDDM. Diabetes
1988;37:667-87
13
Kelly DE. Overview:what is insulin resistance? Nutr Rev 2000;58 (suppl):S2-3
14
The DECODE Study Group on behalf of the European Diabetes Epidemiology Group: Is fasting glucose
sufficient to define diabetes? Epidemiological data from 20 European studies. Diabetologia 1999;42:647-54
15
Vaccaro O, Ruffa G, Imperatore G, et al. Risk of diabetes in the new diagnostic category of impaired
fasting glucose. Diabetes Care 1999;22:1490-3
16
Shaw JE, Zimmet PZ, De Couten M, et al. Impaired fasting glucose or impaired glucose tolerance?
Diabetes Care 1999;22:399-402
17
Matsuda M, DeFronzo R. Insulin sensitivity indices obtained from oral glucose tolerance testing:
comparison with the euglycemic clamp. Diabetes Care 1999;22:1462-70
18
Alberti KGM, McLarty DG, Swai ABM. The clinical implications of impaired glucose tolerance. Diabet
Med 1996;13:927-37
19
Edelstein SL, Knowler WC, Bain RP, et al. Predictors of progression from impaired glucose tolerance to
NIDDM: an analysis of six prospective studies. Diabetes 1997;46:710-10
20
Lemieux I, Pascot A, Coulliard C, et al. Hypertriglyceridemic waist: a marker of the atherogenic
metabolic triad (hyperinsulinemia; hyperapolipoprotein B; small, dense LDL) in men? Circulation
2000;102:179-84
21
Hanefeld M, Fischer S, Julius U, eta al. Risk factors for myocardial infarction and death in newly
detected NIDDM: the Diabetes Intervention Study, 11-year follow-up. Diabetologia 1996;39:1577-83
22
Sator G, Schersten B, Carlstrom S, et al. Ten-year follow-up of subjects with impaired glucose tolerance:
prevention of diabetes by tolbutamide and diet regulation. Diabetes 1980;29:41-9
23
Valmadrid CT, Klein R, Moss SE, Klein BEK. The risk of cardiovascular disease mortality associated
with microalbuminuria and gross proteinuria in persons with older-onset diabetes mellitus. Arch Intern
Med 2000;160:1093-1100
24
Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes
on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N
Engl J Med 1993;329:97725
U.K. Prospective Diabetes Study Group. Intensive blood-glucose control with sulfonlyureas or insulin
compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS
34). Lancet 1998;352:85426
Yamagishi S, Fujimori H, Yonekura H, et al Advanced glycation end products accelerate calcification in
microvascular pericytes. Biochem Biophys Res Commun 1999;258:353-7
89
27
Waltenberger J, Lange J, Kranz A. Vascular endothelial growth factor-A-induced chemotaxis of
monocytes is attenuated in patients with diabetes mellitus: a potential predictor for the individual capacity
to develop collaterals. Circulation 2000;102:185-90
28
Bierman EL. Atherogenesis in diabetes. Arterioscler Thromb 1992;12:647-56 and
29
Niskanen L, Penttila I, Turpeinen A, Uusitupa MIJ. Hyperglycemia and compositional lipoprotein
abnormalities as predictors of cardiovascular mortality in Type 2 diabetes. Diabetes Care 1998;21: 1861-9
30
Stamler J, Vaccaro O, Neaton JD, et al. Diabetes, other risk factors, and 12-yr cardiovascular mortality
for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993;16:434-44
31
Stamler J. Epidemiology, established major risk factors, and the primary prevention of coronary heart
disease. In Parmley WW, Chatterjee K (eds): Cardiology. Philadelphia, PA, JB Lippincott, 1987, pp1-41
32
Stern MP, Patterson JK, Haffner SM, et al. Lack of awareness and treatment of hyperlipidemia in type II
diabetes in a community survey. JAMA 1989;262:360-4
33
Lee WL, Cheung AM, Cape D, Zinman B. Impact of diabetes on coronary artery disease in women and
men: a met-analysis of prospective studies. Diabetes Care 2000;23:962-8
34
Reaven GM. The role of insulin resistance and hyperinsulinemia in coronary artery disease. Metabolism.
1992;41:826-34
35
Stout RW. Overview of the association between insulin and atherosclerosis. Metabolism 1985:34 (suppl
1);7-12
36
Wagenknecht LE, Savage PJ, D'Agostino RB, et al. Impaired glucose tolerance, Type 2 diabetes, and
carotid wall thickness. Diabetes Care 1998;21:1812-8
37
Khaw K-T, Wareham N, Luben R, et al. Glycated hemoglobin, diabetes and mortality in men in Norfalk
cohort of European Prospective Investigation of Cancer and Nutrition (EPIC- Norfalk). BMJ 2001;322:1-6
38
Singer DE, Nathan DM, Anderson KM, et al. Association of HbA1c with the prevalent cardiovascular
disease in the original cohort of the Framingham Heart Study. Diabetes 1992;41:202-8
39
Moss SE, Klein R, Klein BEK, Meuer SM. The association of glycemia and cause-specific mortality in a
diabetic population. Arch Intern Med 1994;154:2473-9
40
Vitelli LL, Shahar E, Heiss G, et al. Glycosylated hemoglobin levels and carotid intimal-medial
thickening in non-diabetic individuals. Diabetes Care 1997;20:1454-8
41
Norhammer AM, Ryden L, Malmberg K. Admission plasma glucose: an independent risk factor for longterm prognosis after myocardial infarct even in nondiabetic patients. Diabetes Care 1999;22:1827-31
42
Reaven G, et al. Metabolism 1999;48:98943
Despres JP. The insulin-dyslipidemic syndrome of visceral obesity: effect on patients' risk. Obesity Res
1998;6(suppl):8S-17S
44
Reaven GM. Metabolic syndrome Clinical Diabetes 1994; March/April:32-6
45
Reaven GM. The role of insulin resistance in human disease. Diabetes 1988;37:1495-1507
46
Bjorntorp P. Abdominal fat distribution and the metabolic syndrome. J Cardiovasc Pharmacol
1993;20:S26-8
47
Mauiege P, Despres JP, Marcotte M, et al. Abdominal fat cell lipolysis, body fat distributions, and
metabolic variables in pre-menopausal women J Clin Endocrinol Metab 1990;71:1028-35
48
Pergola G, Ciccone M, Pannacciulli N, et al. Lower insulin sensitivity as an independent risk factor for
carotid wall thickening in normotensive, non-diabetic, non-smoking normal weight and obese
premenopausal women. Int J Obesity 2000;24:825-9
49
Lempiainen P, Mykkanen L, Pyorala K, et al. Insulin resistance syndrome predicts coronary heart disease
events in elderly nondiabetic men. Circulation 1999;100:123-8
50
Campos H, Genest JJ, Blijlenens E, et al. Low density lipoprotein particle size and coronary artery
disease. Arterioscler Thromb 1992;12:187-95
51
Austin MA. Plasma triglycerides and coronary artery disease. Arterioscler Thromb 1991;11:2-14
52
Allavee H, Aouizerat BE, Cantor RM, et al. Families with familial combined hyperlipidemia and families
enriched for coronary artery disease share genetic determinants for the atherogenic lipoprotein phenotype.
Am J Hum Genet 1998;63:577-85
53
Epstein M, Sowers JR. Diabetes mellitus and hypertension. Hypertension 1992;19:403-18
54
Cooper ME, Johnston CI. Optimizing treatment of hypertension in patients with diabetes. JAMA
2000;283:3177-9
90
55
Alder AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure with macrovascular and
microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. Br Med J
2000;321412-9
56
Johnson D, Prudihomme D, Despres JP, et al. Relation of abdominal obesity to hyperinsulinemia and
high blood pressure in men. Int J Obes 1992;16:881-90
57
Landsberg L. Pathophysiology of obesity-related hypertension: role of insulin and the sympathetic
nervous system. J Cardiovasc Pharacol 1994;23(suppl 1):S1-8
58
Modan M, Halkin H, Almay S, et al. Hyperinsulinemia: a link between hypertension, obesity and glucose
tolerance. J Clin Invest 1985;75:809-17
59
Gans ROB, Toorn L, Bilo HJG, et al. Renal and cardiovascular effects of exogenous insulin in healthy
volunteers. Clin Sci 1991;80:219-25
60
Hall JE. Mechanisms of abnormal renal sodium handling in obesity hypertension. Am J Hypertens
1997;10:S49-55
61
Brands MW, Hall JE, Van Vliet BN, et al. Obesity and hypertension: roles of hyperinsulinemia,
sympathetic nervous system and intrarenal mechanisms. J Nutr 1995;125:1725S-31S
62
Saad MF, Knowler WC, Pettitt DJ, et al. Insulin and hypertension, relationship to obesity and glucose
tolerance in Pima Indians. Diabetes 199039:1430-5
63
Hall JE, Brands MW, Zappe DH, Alsonso-Galicia M. Insulin resistance, hyperinsulinemia, and
hypertension: causes, consequences or merely correlations? Proc Soc Exp Biol Med 1995;208:317-29
64
Brieffwuil P, Huynh-Thu T, Kolanowski J. Reappraisal of the role of insulin on sodium handling by the
kidney: effect of intrarenal insulin infusion in the dog. Eur J Clin Invest 1992;22:523-8
65
Meigs JB. Invited commentary: insulin resistance syndrome? Metabolic syndrome? Multiple metabolic
syndrome? A syndrome at all? Factor analysis reveals patterns in the fabric of correlated metabolic risk
factors. Am J Epid 2000;152:908-11
66
Sugerman HJ, Windsor ACJ, Bessos MK, Wolfe L. Intra-abdominal pressure, sagital abdominal diameter
and obesity co-morbidity. J Int Med 1997;241:71-9
67
Bloomfield GL, Sugerman HJ, Blocher CR, et al. Chronically increased intra-abdominal pressure
produces systemic hypertension in dogs. Int J Obes 2000;24:819-24
68
Scaglione R, Ganguzza A, Corrao S, et al. Central obesity and hypertension: Pathophysioloc role of renal
hemodynamics and function. Int J Obes 1995;19:403-9
69
Scaglione R, Ganguzza A, Corrao S, et al. Central obesity and hypertension: Pathophysioloc role of renal
hemodynamics and function. Int J Obes 1995;19:403-9
70
Hall JE. Renal and cardiovascular mechanisms of hypertension in obesity. Hypertension 1994;23:381-94
71
Higashi Y, Oshima T, Sasaki N, et al. Relationship between insulin resistance and endotheliumdependent vascular relaxation in patients with essential hypertension. Hypertension 1997;29(part 2):280-5
72
Roberts CK, Vaziri D, Wang XQ, Barnard RJ. Enhanced NO inactivation and hypertension induced by a
high-fat, refined-carbohydrate diet. Hypertension. 2000;36 (in press)
73
Forte P, Copland M, Smith LM, et al. Basal nitric oxide synthesis in essential hypertension. Lancet
1998;31:1248-54
74
DASH-Sodium Trial personal communication from ?
75
Whelton PK, Appel LJ, Espeland MA, et al. for the TONE Collaborative Research Group. Sodium
reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled Trial
of Nonpharmocological Interventions in the Elderly (TONE). JAMA 1998;279:839-46
76
Gillum RF, Prineas RJ, Jefferey RW, et al. Nonpharmocological therapy of hypertension: the
independent effects of restriction in overweight borderline hypertensive subjects. Am Heart J
1983;105:128-33
77
Ashley FW, Kannel WB. Relation of weight change to changes in atherogenic status: the Framingham
study. J Chronic Dis 1974;27:103-14
78
Sjostrom CD, Lissner L, Sjostrom L. Reduction in the incidence of diabetes, hypertension and lipid
disturbances after intentional weight loss induced by bariatric surgery: the SOS Intervention Study. Obes
Res 1999;7:477-84
79
Sjoostrom CD, Peltonen M, Wedel H, Sjostrom L. Differentiated long-term effects of intentional weight
loss on diabetes and hypertension. Hypertension 2000;36:20-5
80
Sacks FM, Svetsky LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary sodium and the
Dietary Approaches to Stop Hypertension (DASH) Diet. N Engl J Med 2001;344:3-10
91
81
Izzo JL, Levy D, Black HR. Clinical Advisory Statement: importance of systolic blood pressure in older
Americans. http://www.nhlbi.nih.gov/hpb/resourses/systolic_statement.html]
82
Kenney JJ. Salt: has it been given a fair shake? Or is it a serial killer? http//:www.foodandhealth.com
83
Kenney JJ. Salt: Has it been given a fair shake? Or is it a cereal killer? @www.foodandhealth.com
84
Thorburn AW, Brand JC, Truswell AS. Salt and the glycaemic response. Br Med J 1986;292:1697-9
85
Feldman RD, Schmidt ND. Moderate dietary salt restriction increases vascular and systemic insulin
resistance. Am J Hypertens 1999;12:643-7
86
Iwoka T, Umeda T, Inoue J, et al. Dietary NaCl restriction deteriorates oral glucose tolerance in
hypertensive patients with impairment of glucose tolerance. Am J Hypertens 1994;7:460-3
87
Messerli FH, Schmeider RE, Weir MR. Salt: a perpetrator of hypertensive target organ disease? Arch
Intern Med 1997;157:2449-52
88
Kahn A, Bryden NA, Polansky MM, Anderson RA. Insulin potentiating factor and chromium content of
selected foods and spices. Biol Trace Elem Res 1990;24:183-8
89
Kenney JJ. Salt: Has it been given a fair shake? Or is it a serial killer? http//www.foodandhealth.com
90
Juhan-Vague I, Alessi MC, Vague P. Increased plasminogen activator inhibitor levels: a possible link
between insulin resistance and atherothrombosis. Diabetolgia 1991;34:457-62
91
Morange PE, Alessi MC, Verdier D, et al PAI-1 produced ex vivo by human adipose tissue is relevant to
PAI-1 blood level. Arterisclero Vasc Biol 1999;19:1361-5
92
Festa A, D'Agostino R, Howard G, et al. Chronic subclinical inflammation as part of the insulin
resistance syndrome: The Insulin Resistance Atherosclerosis Study (IRAS). Circulation 2000;102:42-7
93
Koenig W, Sund M, Frohlich M, et al. C-reactive protein, a sensitive marker of inflammation, predicts
future risk of of coronary heart disease in initially healthy middle-aged men. Circulation 1999;99:17:11217
94
Lindahl B, Asplund K, Eliasson M, Ervin PE. Insulin resistance syndrome and fibrinolytic activity: the
Sweden MONICA study. Int J Epidemiol 1996;25:291-9
95
Mohamed-Ali V, Gould MM, Gilles S, et al. Association of proinsulin-like molecules with lipids and
fibrinogen in non-diabetic subjects: evidence against a modulating role for insulin. Diabetologia
1995;38:1110-6
96
Hak AE, Stehouwer CDA, Bots ML, et al. Associations of C-reactive protein with measures of obesity,
insulin resistance, and subclinical atherosclerosis in healthy, middle-aged women. Arterioscler Thromb
Vasc Biol 1999;19:1986-91
97
Pickup JC, Crook MA. Is type II diabetes mellitus a disease of the innate immune system? Diabetologia
1998;41:1241-8
98
Kushner I. Regulation of the acute phase response by cytokines. Perspect Biol Med 1993;36:611-22
99
Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular
disease in apparently healthy men. N Engl J Med 1997;336:973-9
100
Guba SC, Fink LM, Fonesca VA. Hyperhomocysteinemia -An emerging important risk factor for
thromboembolic and cardiovascular disease. Am J Clin Pathol 1996;106:709-22
101
Munshi MN, Stone A, Fink LM, et al. Hyperhomocysteinemia following a L-methionine (precursor to
Hcy) load in patients with non-insulin-dependent diabetes mellitus and macrovascular disease. Metabolism
1996;45:133-5
102
Barnard RJ, Faria DJ, Menges JE, et al. Effects of a high-fat, sucrose diet on serum insulin and related
atherosclerotic risk factors in rats. Atherosclerosis 1993;103:229-36
103
Pagliassotti MJ, Shahrokhi KA, Moscarello M. Involvement of the liver and skeletal muscle in sucroseinduced insulin resistance: dose-response studies. Am J Physiol 1994;266:R1637-44
104
Thorbun AW, Storlien LH, Jenkins AB, et al. Fructose-induced in vivo insulin resistance and elevated
plasma triglyceride concentrations in rats. Am J Clin Nutr 1989;49:1155-63
105
Fonesca V, Dicker-Brown A, Ranganthan S, et al. Effects of a high-fat-sucrose diet on enzymes in
homocysteine metabolism in the rat. Metabolism 2000;49:736-49
106
Grubben MJ, Boers GH, Blom HJ, et al. Unfiltered coffee increases plasma homocysteine
concentrations in healthy volunteers: a randomized trial. Am J Clin Nutr 2000;71:480-4
107
Broekmans WMR, Klopping-Ketelaars IAA, Schuurman CRWC, et al. J Nutr 2000;130:1578-83
108
Appel LJ, Miller ER, Jee SH, et al. Effect of dietary patterns on serum homocysteine: results of a
randomized, controlled feeding study. Ciculation 2000;102:852-7
109
Mann J. Stemming the tide of diabetes mellitus. Lancet 2000;356:1454-5
92
110
Barnard RJ, Roberts CK, Varon SM, Berger JJ. Diet-induced insulin resistance precedes other aspects of
the metabolic syndrome. J Appl Physiol 1998;84:1311-5
111
Barnard JB, Youngren JF, Scheck SH. Reversibility of diet-induced skeletal muscle insulin resistance.
Diabetes Research 1997;32:213-21
112
Barnard RJ, Faria DJ, Menges JE, Martin DA. Effects of a high-fat, sucrose diet on serum insulin and
related atherosclerotic risk factors in rats. Atherosclerosis 1993;100:229-36
113
Abbott WGH, Boyce VL, Grundy SG, Howard BV. Effects of replacing saturated fat with complex
carbohydrate in diets of subjects with NIDDM. Diabetes Care 1989;12:102-7
114
Riccardi G, Rivellese A, Pacioni D, et al Separate influences of dietary carbohydrate and fiber on the
metabolic control of diabetes. Diabetolagia 1984;26:116-21
115
Recommendations for the nutritional management of patients with diabetes mellitus. Eur J Clin Nutr
2000;54:353-55
116
Eriksson J, Lindstrom J, Valle T, et al. Prevention of type II diabetes in subjects with impaired glucose
tolerance: the Diabetes Prevention Study (DPS) in Finland. Study design and 1 year interim report on the
feasibility of the lifestyle intervention programme. Diabetolgia 1999;42:793-801
117
The Diabetes Prevention Program. Design and methods for a clinical trial in the prevention of type 2
diabetes. Diabetes Care 1999;22:623-34
118
Ferrannini E, Insulin resistance is central to the burden of diabetes. Diabetes Metab Rev 1997;13:81-6
119
Garg A, Grundy SM, Unger RH.Comparison of effects of high and low carbohydrate diets on plasma
lipoproteins and insulin sensitivity in patients with mild NIDDM. Diabetes 1992;41:1278-85
120
Garg A, Bantle JP, Henry RR, et al. Effects of varying carbohydrate content of diet in patients with noninsulin-dependent diabetes mellitus. JAMA 1994;271:1421-8
121
Conner WE, Cerqueria MT, ConnoRW, et a. The plasma lipids, lipoproteins, and diet of the Tarahumara
Indians of Mexico. Am J Clin Nutr 1978;31:1131-42
122
Zhuang H, Han QQ, Chen HZ. Study of serum lipids and lipoproteins in healthy subjects in Shanghai.
Chin Med J 1986;99:657-9
123
Antonis A, Bersohn I. Serum triglyceride levels in South African Europeans and Bantu and in ischaemic
heart disease. Lancet 1960;1:998-1002
124
Kasim-Karakas SE, Lane E, Almario R, et al. Effects of dietary fat restriction on particle size of plasma
lipoproteins in postmenopausal women. Metabolism 1997;46:431-6
125
Abbasi F, McLaughlin T, Lamendola C, et al. High carbohydrate diets, triglyceride-rich lipoproteins,
and coronary heart disease risk. Am J Cardiol 2000;85:45-8
126
Gill JMR, Hardman AE. Postprandial lipemia: effects of exercise and restriction of energy intake
compared. Am J Clin Nutr 2000;71:465-71
127
Avins AL, Neuhaus JM. Triglyceride levels not independently predictive of coronary heart disease.
Arch Intern Med 2000;160: 1937-44
128
Rubens HB, Editorial. Arch Intern Med 2000;160:1903-4
129
Reaven GM, Chen Y-Di, Jeppensen J, et al. Insulin resistance and hyperinsulinemia in individuals with
small, dense, low density lipoprotein particles. J Clin Invest 1993;92:141-6
130
Parks EJ, Hellerstein MK. Carbohydrate-induced hypertriacylglcerolemia: historical perspective and
review of biological mechanisms. Am J Clin Nutr 2000;71:412-33
131
Jarvi AE, Karlstrom BE, Granfeldt AE, et al. Improved glycemic control and lipid profile and
normalized fibrinolytic activity on a low-glycemic index diet in Type 2 diabetic patients. Diabetes Care
1999;22:10-8
132
Dintenfass. Effect of a low-fat, low-protein diet on blood viscosity factors in patients with
cardiovascular disorders. Med J Australia 1982;1:543-7
133
Oakley FR, Sanders TAB, Miller GJ. Postprandial effects of an oleic acid-rich oil compared with butter
on clotting factor VII and fibrinolysis in healthy men. Am J Clin Nutr 1998;68: 1202-7
134
Marckmann P, Raben A, Astrup A. Ad libitum intake of low-fat diets rich in either starchy foods or
sucrose: effects on blood lipids, Factor VII coagulant activity, and fibrinogen. Metabolism: Clin &
Experim. 2000;49:731-5
135
Meade TW, Brozovic M, Chakrabarti R, et al. Haemostatic function and ischaemic heart disease:
Principal results of the Northwich Park Heart Study. Lancet 1986;2:533-7
136
Meade TW, Ruddock V, Sterling Y, et al. Fibrinolytic activity, clotting factors, and long-term incidence
of ischaemic heart disease in the Northwich Park Heart Study. Lancet 1993;342:1076-9
93
137
Heinrich J, Balleisen L, Schulte H, et al. Fibrinogen and factor VII in the prediction of coronary risk.
Results from the PROCAM study in healthy men. Arterioscler Thromb 1994;14:54-9
138
Stensvold I, Tverdal A, Urdal P, Graff-Iverson S. Non-fasting serum triglyceride concentration and
mortality from coronary artery disease and any cause in in middle-aged Norwegian women. Br Med J
1993;307:1318-22
139
Groot PHE, van Stiphout WAHJ, Krauss XH, et al. Postprandial lipoprotein metabolism in
normolipidemic men with and without coronary artery disease. Arterioscler Thromb 1991;11:653-62
140
Katan MB. Effect of low-fat diets on plasma high-density lipoprotein concentrations. Am J Clin Nutr
1998;67(suppl):573S-6S
141
Coulston AM. The role of dietary fats in plant-based diets. Am J Clin Nutr 1999;70(suppl):512S-5S
142
Thuesen L, Henriksen LB, Engby B. One-year experience with a low-fat, low-cholesterol diet in patients
with coronary heart disease. Am J Clin Nutr 1986;44:212-9
143
Frost G, Leeds AA, Dore CJ, et al. Glycaemic index as a determinant of serum HDL-cholesterol
concentrations. Lancet 1999;353: 1045-8
144
Ornish DM, Brown SE, Scherwitz LW, et al. Can Lifestyle changes reverse coronary atherosclerosis?
the Lifestyle Heart Trial. Lancet 1990;336:129-33
145
Connor WE, Connor SL. Should a low-fat, high-carbohydrate diet be recommended for everyone? The
case for a low-fat, high-carbohydrate diet. N Engl J Med 1997;337:562-3
146
Brinton EA, Eisenberg S, Breslow JL. A low-fat diet decreases high density lipoprotein(HDL)
cholesterol levels by decreasing HDL apoprotein transport rates. J Clin Nutr 1999;85:144-51
147
Woolett LA, Kearney DM, Spady DK. Diet modification alters plasma cholesterol concentrations but
not the transport of HDL cholesteryl esters to the liver in hamsters. J Lipid Res 1997;38:2289-302
148
Kasim-Karakas SE, Alario RU, Mueller WM, Peerson J. Changes in plasma lipoproteins during low-fat,
high-carbohydrate diet: effects of energy intake. Am J Clin Nutr 2000;71:1439-47
149
Poppitt SD, Swann DL, Murgatroyd PR, et al Effect of dietary manipulation on substrate flux and
energy balance in obese women taking the appetite suppressant dexfenfluramine. Am J Clin Nutr
1998;68:1012-21
150
Ornish D, Scherwitz LW, Billings JH, et al. Intensive lifestyle changes for reversal of coronary heart
disease. JAMA 1998;280: 2001-7
151
Lichtenstein AH, Van Horn L. AHA Science Advisory: very low fat diets. Circulation 1998;98: 935-9
152
Rutledge JC, Hyson DA, Garduno D, et al. Lifestyle modification program in management of patients
with coronary artery disease: the clinical experience in a tertiary care hospital. J Cardiopulm Rehabil
1999;19:226-34
153
Ornish D, Brown SE, Scherwitz LW, et al. Can lifestyle changes reverse coronary artery disease? Lancet
1990;336:129-33
154
Ornish D. Serum lipids after a low-fat diet. JAMA 1998;279:1345-6
155
Schueler G, Hambrecht R, Schrief G, et al. Regular physical exercise and a low-fat diet. effects on
progression of coronary artery disease. Circulation 1992;86:1-11
156
Morrison L. Diet and coronary atherosclerosis. JAMA 1960;173:884-8
157
Georgopoulos A, Bantle JP, Noutsou M, Hoover HA. A high carbohydrate versus a high
monounsaturated fatty acid diet lowers the atherogenic potential of big VLDL particles in patients with
Type 1 diabetes. J Nutr 2000;130:2503-7
158
Packard CJ, Shepard J. Lipoprotein heterogenity and apolipoprotein B metabolism. Arterioscler Thromb
Vasc Biol 1997;17:3542-6
159
Freedman DS, Otvos JD, Jeyarajah EJ, et al. Relation of lipoprotein subclasses as measured by proton
nuclear magnetic resonance spectroscopy to coronary artery disease. Arterioscler Thromb Vasc Biol
1998;18:1046-53
160
Otvos J. Measurement of triglyceride-rich lipoproteins by magnetic resonance spectroscopy. Clin
Cardiol 1999;22(suppl II):21-7
161
Mutoni S, Cocco P, Aru G, et al. Nutritional factors and worldwide incidence of childhood type 1
diabetes. Am J Clin Nutr 2000;71;1525-9
162
Elliott RB, Martin JM. Dietary protein: a trigger of insulin-dependent diabetes in the BB rat?
Diabetologia 1984;26:297-9
163
Donner G, Thoelke H, Mohinke A, Schneider H. High food supply in perinatal life appears to favour the
development of insulin-treated diabetes mellitus (ITDM) in later life. Exp Clin Endocrinol 1985;85:1-6
94
164
Johansson C, Samuelsson U, Ludvighsson J. A high weight gain early in life is associated with an
increased risk of type1 (insulin-dependent) diabetes mellitus. Diabetolologia 1994;37:91-4
165
Rowe JW, Minaker KL, Pallotta JA, Flier JS. Characterization of the insulin resistance of aging. J Clin
Invest 1983;71:1581-7
166
Harris MI, Flegal KM, Cowie CC, et al. Prevalence of diabetes, impaired glucose tolerance in U.S.
adults: the Third National Health and Nutrition Examination Survey, 1988-94. Diabetes Care 1998;21:51824
167
Barnard RJ, Youngren JF, Martin DA. Diet, not aging, causes skeletal muscle insulin resistance.
Gerontology 1995;41:205-11
168
Harris MI, Hadden WC, Knowler WC, Bennett PH. Prevalence of diabetes and impaired glucose
tolerance and plasma glucose levels in U.S. population aged 20-74 years. Diabetes 1987;36:523-34
169
Zavaroni I, Dall-Aglio E, Bruschi F, et al. Effect of age and environmental factors on glucose tolerance
and insulin secretion in a worker population. J Am Geriatr Soc 1986;34:271-5
170
Shimokata H, Muller DC, Fled JL, et al. Diabetes 1991;40:44-51; and Pacini G, Valerio A, Beccaro F, et
al Insulin sensitivity and beta-cell responsivity are not decreased in elderly subjects with normal OGTT. J
Am Geriatr Soc 1988;36:317-23
171
Kohrt WM, Kirwan JP, Staten MA, et al. Insulin resistance in aging is related to abdominal obesity.
Diabetes 1993;42:273- 81
172
Tessari P. Changes in protein, carbohydrate, and fat metabolism with aging: possible role of insulin.
Nutr Rev 2000;58:11-9
173
Kohrt WM. Effect of aging. Nutr Rev 2000;58(suppl):S19-21)
174
Dietary Guidelines Advisory Committee. Report of the Dietary Advisory Committee on the dietary
guidelines for Americans. Human Nutrition Information Service, U.S. Department of Agriculture, 1995
175
Kuczmarski RJ, Flegal KM, Campbell SM, Johnson CL. Increasing prevalence of overweight among US
adults. JAMA 1994;272:205-11
176
Seidell JC. Obesity in Europe: scaling an epidemic. Int J Obesity 1995;19(suppl. 3):S1-4
177
Meneilly GS, Elliott T. Metabolic alterations in middle-aged and elderly obese patients with Type 2
diabetes. Diabetes Care 1999;22:112-8
178
Porte D Jr. Beta-cells in type II diabetes mellitus. Diabetes 1991;37:667-87
179
Laakso M, Sarland H, Salonen R, et al. Asymptomatic atherosclerosis and insulin resistance.
Arterioscler Thromb 1991;11:1068-76
180
Howard G, O'Leary DH, Zaccaro D, et al. Insulin sensitivity and atherosclerosis. Circulation
1996;93:1809-17
181
Caro JF, Sinha MK, Raju SM, et al. Insulin receptor kinase in human skeletal muscle from obese
subjects with and without non-insulin dependent diabetes. J Clin Invest 1987;79:1330-7
182
Bennett AH. Diabetes and identical twins. Diabetologia 1981;70:87-93
183
Fujimoto WY, Bergstrom RW, Boyoko EJ, et al. Susceptibility to the development of central adiposity
among populations. Obesity Res 1995;3(suppl):179S-86S
184
Ravussin E, Valencia ME, Esparza J, et al. Effects of a traditional lifestyle on obesity in Pima Indians.
Diabetes Care 1994;17:1067-74
185
Olefsky JM, Nolan JJ. Insulin resistance and non-insulin-dependent diabetes mellitus: cellular and
molecular mechanisms. Am J Clin Nutr 1995;61(suppl):980S-6S
186
Dietz W. Critical periods in childhood for the development of obesity. Am J Clin Nutr 1994;59:955-9
187
Valdez RA, Athens MA, Thompson GH, et al. Birthweight and adult health outcomes in a biethnic
population in the USA. Diabetologia 1994;37:624-31
188
Moller DE, Flier JS. Insulin resistance - Mechanisms, syndromes, and implications. N Engl J Med
1991;325: 938-47
171a. Jensen MD. Genetic and environmental contributions. Nutr Rev 2000;58(suppl):S22-4
189
Beck-Nielsen H, Vaag A, Dambo P, et al. Insulin resistance in skeletal muscles in patients with
NIDDM. Diabetes Care 1992;15:418-29
190
Walford RL. The 120 Year Diet. 1986. Simon and Schuster, New York, New York.
191
Lewis CE, Jacobs DR, McCreath H, et al. Weight gain continues in the 1990s: 10 year trends in weight
and overweight from CARDIA study. Am J Epidemiol 2000;151:1172-81
192
Bessensen DH. Obesity as a risk factor. Nutr Rev 2000;58(suppl):S12-5
95
193
Mayer EJ, Newman B, Austin MA, et al. Genetic and environmental influences on insulin levels and the
insulin resistance syndrome: an analysis of women twins. Am J Clin Epidemiol 1996;143:323-32
194
Bagdade JD, Bierman EL, Porte D Jr: The significance of basal insulin levels in the evaluation of the
insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest 1967;46:1549-57
195
Corditz GA, Willett WC, Rotnitzky A, Manson JE. Weight gain as a risk factor for clinical diabetes
mellitus in women. Ann Intern Med 1995:122;481-6
196
Saad MF, Knowler WC, Pettit DJ, et al. The natural history of impaired glucose tolerance in the Pima
Indians. N Engl J Med 1988;319: 1500-6
197
Lissner L, Sjostrom L, Bengtsson C, et al. The natural history of obesity in an obese population and
associations with metabolic aberrations. Int J Obesity 1994;18:441-7
198
Vinik AI, Wing RR. The good, the bad, and the ugly in diabetes diets. Endocrin and Metabol Clinics N
America 1992;21:237-79
199
Zimmerman BR (ed.). Medical Management of Type 2 Diabetes, 4th ed. Alexandria, VA: American
Diabetes Association, 1998
200
Heilbronn LK, Noakes M, Clifton PM. Effect of energy restriction, weight loss, and diet composition on
plasma lipids and glucose in patients with type 2 diabetes. Diabetes Care 1999;889-95
201
Karan JH: Reversible insulin resistance in non-insulin dependent diabetes mellitus. Horm Metab Rev
1994;28:440-4
202
Prando R, Cheli A, Melga P, et al. Is type 2 diabetes a different disease in obese and nonobese patients.
Diabetes Care 1998;21:1680-5
203
Sjorostrom CD, Peltonen M, Wedel H, Sjostrom L. Differentiated long-term effects of intentional
weight loss on diabetes and hypertension. Hypertension 2000;36:20-5
204
Tanaka Y, Aisumi Y, Maisuoka K, et al. Interesting insulin response to oral glucose load in young
Japanese subjects with impaired glucose tolerance. Diabetes Care 2000;23:710-2
205
Swinburn BA, Boyce VL, Bergman RN, et al. Deterioration in carbohydrate metabolism and lipoprotein
changes induced by modern, high fat diet in Pima Indians and Caucasians. J Clin Endocrinol 1991;73:15665
206
Fields M. Nutritional factors adversely influencing the glucose/insulin system. J Am Cll Nutr
1996;17:317-21
207
Ravussin E, Gautier JF. Metabolic predictors of weight gain. Int J Obesity 1999;23(suppl 1):37-41
208
Fraze E, Donner CC, Swislocki ALM, et al. Ambient plasma free fatty acid concentrations in noninsulin dependent diabetes mellitus: evidence for insulin resistance. J Clin Endocrinol Metab 1985;61:8-711
209
Eckel RH. Insulin resistance: an adaption for weight maintenance. Lancet 1992;340:1452-3
210
Schick SM, Wing RR, Klem ML, et al. Persons successful at long-term weight loss and maintenance
continue to consume a low-energy, low-fat diet. J Am Diet Assoc 1998;98:408-13
211
Phillips CV. Complex systems model of dietary choice with implications for improving diets and
promoting vegetarianism. Am J Clin Nutr 1999;70(suppl): 608S-14S
212
Shepherd PR, Kahn BB. Glucose transporters and insulin action: Implications for insulin resistance and
diabetes mellitus. N Engl J Med 1999;341:248-57
213
Peters A, Davidson M. Protein and fat effects on glucose responses and insulin requirements in subjects
with insulin dependent diabetes mellitus. Am J Clin Nutr 1993;58:555-60
214
Holt SA, Brand Miller JC, Petocz P. An insulin index of foods: insulin demand generated by 1000 kJ
portions of common foods. Am J Clin Nutr 1997;66:1264-76
215
Holt SHA, Brand Miller JC, Petocz P. An insulin index of foods: the insulin demand generated by 1000
kj-portions of common foods. Am J Clin Nutr 1997;66:1264-76
216
Storlein LH, Tapsell LC, Calvert GD. Role of dietary factors: macronutrients. Nutr Rev
2000;58(suppl):S7-9
217
Hrdlicka A, Physiological and medical observations among the Indians of Southwestern United States
and Northern Mexico. Smithsonian Institution. Bureau of Indian Ethnology; 1908;Bulletin 34
218
Knowler WC, Bennett PH, Hamman RH, Miller M. Diabetes incidence sand prevalence in Pima
Indians: a 19-fold greater incidence than in Rochester, Minnesota. Am J Epidemiol 1978;108:497-505
219
Marshall JA, Shetterly S, Hoag S, Hamman RF. Dietary fat predicts conversion from impaired glucose
tolerance to NIDDM: the San Louis Valley Diabetes Study. Diabetes Care 1994;17:50-5
96
220
Swinburn BA, Boyce VL, Bergman RN, et al. Deterioration in carbohydrate metabolism and lipoprotein
changes induced by modern, high fat diet in Pima Indians and Caucasians. J Clin Endocrinol Metab
1991;73:156-65
221
Grundy SM. The optimal ratio of fat-to-carbohydrate in the diet. Ann Rev Nutr 1999;19:325-41
222
Nutrition recommendations and principles for people with diabetes mellitus. Diabetes Care
2000;23:S43-6
223
Skolnik EY, Marcusohn J. Inhibition of insulin receptor signaling by TNF: a potential role of obesity
and non-insulin-dependent diabetes mellitus. Cyokine Growth Factor Rev 1996;7:161-73
224
Zaorska-Markiewicz B, Janowski J, Olszanecka-Glinianowicz M, Zurakowski A. Serum concentrations
of TNF-alpha and soluble TNF-alpha receptors in obesity. Int J Obesity 2000;24:1392-5
225
Hotamisligil GS, Budavari A, Murray D, Spiegelman BM. Reduced tyrosine kinase activity of the
insulin receptor in obesity – diabetes. Central role of tumor necrosis factor-alpha. J Clin Invest
1994;94:1543-9
226
Kern PA, Saghizadeh M, Ong JM, et al. The expression of tumor necrosis factor in human adipose
tissue. Regulation by obesity, weight loss, and the relationship to lipoprotein lipase. J Clin Invest
1995;95:2111-9
227
Abel EP, Shepherd PR, Kahn BB. Glucose transporters and pathophysiologic states. In LeRoth D,
Taylor SI, Olefsky JM, eds. Diabetes mellitus: a fundamental and clinical text. Philadelphia: LippincottRaven, 1996:530-43
228
Zierath JR, Horenecht KL, Gnudi L, Kahn BB. High-fat feeding impairs insulin-stimulated GLUT-4
recruitment via an early insulin-signaling defect. Diabetes 1997;46:215-23
229
Hawkins M, Barzilai N, Liu R, et al. Role of glucosamine pathway in fat-induced insulin resistance. J
Clin Invest 1997;99:2173-82
230
Prentice AM. Manipulation of dietary fat and energy density and subsequent effects on substrate flux
and food intake. Am J Clin Nutr 1998;67(suppl.):S535-41
231
Himsworth HP. The dietetic factor determining the glucose tolerance and sensitivity to insulin in healthy
men. Clin Sci 1935;2:67-94
232
Tremblay A. Nutritional determinants of insulin resistant syndrome. Int J Obes 1995;19 (suppl 1):S60-8
233
Wilkenson HLI, Hyman H, Kaufman MS, et al. Diagnostic evaluation of oral glucose tolerance tests in
non-diabetic subjects after various levels of carbohydrate intake. N Engl J Med 1960;262:1047-53
234
Unger RH. Lipotoxicity in the pathogenesis of obesity-dependent NIDDM: genetic and clinical
implications. Diabetes 1995;44:863-70
235
Mayer-Davis EJ, Monaco JH, Hoen HM, et al. Dietary fat and insulin sensitivity in a triethnic
population: the role of obesity. The Insulin Resistant Atherosclerosis Study (IRAS). Am J Clin Nutr
1997;65:79-87
236
Lovejoy JC, Windhauser MM, Rood JC et al Effect of a controlled high-fat versus low-fat diet on
insulin sensitivity and leptin levels in African American and Caucasian women. Metabolism:Clin and
Exper 1998;47:1520-4
237
Garg A, Bantle JP, Henry RR, et al. Effects of varying carbohydrate content of the diet in patients with
non-insulin-dependent diabetes mellitus. JAMA 1994;271:1421-8
238
Coulston AM, Hollenbeck CB, Swislocki ALM, Reaven GM. Persistence of the hypertriglyceridemic
effect of a low-fat, high-carbohydrate diet in NIDDM patients. Diabetes Care 1989;12:94-101
239
Morgan SA, O'Dea K, Sinclair AJ. A low-fat diet supplemented with monounsaturated fat results in less
HDL-C lowering than a very-low fat diet. J Am Diet Assoc 1997;97:151-6
240
Schaefer EJ, Lichtenstein AH, Lamon-Fava S, et al.Body weight and low-density lipoprotein cholesterol
changes after consumption of a low-fat ad libitum diet. JAMA 1995;274:1450-5
241
Lichtenstein AH, Ausman LM, Carrasco W, et al. Short-term consumption of a low-fat diet beneficially
affects plasma lipid concentrations only when accompanied by weight loss. Arterioscler Thromb
1994;14:1751-60
242
Berdamier CD. Role of membrane lipids in metabolic regulation. Nutr Rev 1988;46:145-9
243
Storlien LH, Baur LA, Kriketos AD, et al. Dietary fats and insulin action. Diabetolgia 1996;39:621-31
244
Storlien LH, Hulbert AJ, Else PL. Polyunsaturated fatty acids, membrane function and diseases such as
diabetes and obesity. Curr Opin Clin Nutr Metab Care 1998;1:559-63
245
Klimes I, Haffner SM, Sebokova E, et al, eds. Lipids and syndromes on insulin resistance: from
molecular biology to clinical medicine. Ann NY Acad Sci 1997;51:417-23
97
246
Glauber H, Wallace P, Griver K, Brechtel G, Adverse metabolic effect of omega-3 fatty acids in noninsulin dependent diabetes mellitus. Ann Intern Med 1988;108:663-8
247
Friday KE , Childs MT, Tsunehara C, et al. Elevated plasma glucose and lowered triglyceride levels
from omega-3 fatty acid supplementation in type II diabetes. Diabetes Care 1989;12:276-81
248
Hendra TJ, Britton ME, Roper DR, et al. Effects of fish oil supplements in NIDDM subjects. Diabetes
Care 1990;13:821-9
249
Torjessen PA, Birkland KI, Anderssen SA, et al. Lifestyle changes may reverse development of the
insulin resistance syndrome. The Oslo Diet and Exercise Study: a randomized trial. Diabetes Care
1997;20:26-31
250
Montori VM, Farmer A, Wollan PC, Dinneen SF. Fish oil supplementation in Type 2 diabetes. Diabetes
Care 2000;23:1407-15
251
Eaton SB, Eaton III SB, Konner MJ. Palaeolithic nutrition revisited: a twelve year retrospective on its
nature and implications. Eur J Clin Nutr 1997;51:207-16
252
Lissner L, Levitsky DA, Strupp BJ, et al. Dietary fat and the regulation of energy intake in human
subjects. Am J Clin Nutr 1987;46:886-92
253
Bray GA, Popkin BM. Dietary fat intake does affect obesity. Am J Clin Nutr 1998;68:1157-73
254
Willett WC. Is dietary fat a major determinant of body fat? Am J Clin Nutr 1998;67(suppl):556S-62S
255
Burkitt DP, Trowell HC. Refined carbohydrate foods and disease: some implications of dietary fiber.
London. Academic Press, 1975, Burkitt DP, Walker ARP, Painter NS. Dietary fiber and disease. JAMA
1974;229:1068-72
256
Nestle M. Mediterranean diets: historical and research overview. Am J Clin Nutr 1995;61(suppl):
1313S-20S
257
Nutrition recommendations and principles for individuals with diabetes mellitus. Diabetes Care
2000;23:S43-6
258
Chandalia M, Garg A, Lutjohann D, et al. Beneficial effects of high dietary fiber intake in patients with
Type 2 diabetes mellitus. N Engl J Med 2000;342:1392-8
259
Anderson JW, Smith BM, Gustafson NJ. Health benefits and practical aspects of high-fiber diets. Am J
Clin Nutr 1994;59:1242S-7S
260
Jarvi AE, Karlstrom BE, Granfeldt YE, et al. The influence of food structure on postprandial
metabolism in patients with non insulin dependent diabetes mellitus. Am J Clin Nutr 1995;61:837-42
261
Holt SHA, Brand Miller JC, Petocz P. An insulin index of foods: insulin demand generated by 1000 kj
portions of common foods. Am J Clin Nutr 1997;66:1264-76
262
Haber GB, Heaton KW, Murphey D, et al. Depletion and disruption of dietary fiber. Effects on satiety,
plasma glucose and serum insulin. Lancet 1977;2:679-82
263
Daly ME, Vale C, Walker M, et al. Dietary carbohydrate and insulin sensitivity: a review of the
evidence and clinical implications. Am J Clin Nutr 1997;66:1072-85
264
Swanson JE, Laine DC, Thomas W, Bantle JP. Metabolic effects of dietary fructose in healthy subjects.
Am J Clin Nutr 1992;55:851-6
265
Bantle JP, Raatz SK, Thomas W, Georgopoulos A. Effects of dietary fructose on plasma lipids in
healthy subjects. Am J Clin Nutr 2000;72:1128-34
266
Marckmann P, Raben A, Astrup A. Ad libitum intake of low-fat diets rich in either starchy foods or
sucrose: effects on blood lipids, Factor VII coagulant activity, and fibrinogen. Metabolism: Clin &
Experim. 2000;49:731-5
267
Hollenbeck CB. Dietary fructose effects on lipoprotein metabolism and risk of coronary artery disease.
Am J Clin Nutr 1993;58(suppl):800S-9S
268
Hallfrisch J, Reiser S, Prather ES, et al. Blood lipid distribution of hyperinsulinemic men consuming
three levels of fructose. Am J Clin Nutr 1983;37:740-8
269
Reiser S, Hallfrisch J, Michaelis OE, et al. Isocaloric exchange of dietary starch and sucrose in humans:
effects on levels of fasting blood lipids. Am J Clin Nutr 1978;32:1659-69
270
Reiser S, Hallfrisch J, Fields M, et al. Effects of sugars on indices of glucose tolerance in humans. Am J
Clin Nutr 1986;43:151-9
271
Bray GA, Popkin BM. Dietary fat intake does affect obesity. Am J Clin Nutr 1998;68:1157-73
272
Yu-Poth S, Zhoa G, Etherton T, et al. Effects of the National Cholesterol Education Program’s Step I
and Step II dietary intervention programs on cardiovascular disease risk factors: a meta-analysis. Am J Clin
Nutr 1998;69:632-46
98
273
Astrup A, Ryan L, Grunwald GK, et al. The role of dietary fat in body fatness: Evidence from a
preliiminary meta-analysis. Br J Nutr 2000;83(suppl 1):S25-32
274
Willett WC. Is dietary fat a major determinant of body fat? Am J Clin Nutr 1998;67:556S-62S
275
Bell EA, Castellanos VH, Pelkman CL, et al. Energy density of foods affects energy intake in normal
weight women. Am J Clin Nutr 1998; 67:1332-9
276
Stubbs RJ, Johnstone AM, Harbonon CG, Reid C. Covert manipulation of energy density of high
carbohydrate diets in "pseudo free-living" humans. Intl J Obesity 1998;22:885-92
277
Stubbs RJ,Jonstone AM, O'Reilly J, et al. The effect of covertly manipulating the energy density of
mixed diets on ad libitum food intake in "pseudo free-living" humans. Intl J Obesity 1998;22:980-7
278
Mayer-Davis EJ, Monaco JH, Hoen HM, et al. Dietary fat and insulin sensitivity in a triethnic
population: the role of obesity. The Insulin Resistance Atherosclerosis Study (IRAS). Am J Clin Nutr
1997;65:79-87
279
Lovejoy, DiGirolamo M. Habitual dietary intake and insulin sensitivity in lean and obese adults. Am J
Clin Nutr 1992;55:1174-9
280
Collier GR, Wolever TMS, Jenkins JA. Concurrent ingestion of fat and reduction in starch content
impairs carbohydrate tolerance to subsequent meals. Am J Clin Nutr 1987;45:963-9
281
Lijeberg H, Bjorck I. Effects of a low-glycaemic index spaghetti meal on glucose tolerance and lipemia
at a subsequent meal in healthy subjects. Eur J Clin Nutr 2000;54:24-8
282
DiMiglio DP, Mattes RD. Liquid versus solid carbohydrate: effects on food intake and body weight. Int
J Obes 2000;24:794-800
283
Rolls BJ, Bell EA, Thorwart ML. Water incorporated into a food but not served with a food decreases
energy intake in lean women. Am J Clin Nutr 1999;70:448-55
284
Torsdottir I, Andersson H. Effect on the postprandial glycaemic level of the addition of water to a meal
ingested by healthy subjects and type 2 (non-insulin dependent) diabetic patients. Diabetologia
1986;29:784-91
285
Kabir M, Rizkalla SW, Champ M, et al. Dietary amylose-amylopectin starch content affects glucose and
lipid metabolism in adipocytes of normal and diabeteic rats. J Nutr 1998;128:35-43
286
http://www.sciencenews.org /20000408/bob2.asp
287
Foster-Powell K, Brand Miller J. International tables of glycemic index. Am J Clin Nutr 1995;62:871S93S
288
Franz MJ. Evaluating the Glycemic Response to Carbohydrates. Clinical Diabetes 1986;4:129-41 and
Jenkin DJA, Wolever TMS, Jenkins LJ, et al. Low glycemic response to traditionally processed wheat and
rye products: bulgur and pumpernickel bread. Am J Clin Nutr 1986;43:516-20
289
Hu FB, Stampher MJ, Manson JE, et al. Trends in the incidence of coronary heart disease and changes
in diet and lifestyle in women. N Engl J Med 2000;343:530-7
290
American Diabetes Association. Nutritional recommendations and principles for people with diabetes
mellitus. Diabetes Care 1994;17:519-22
291
Wolever TMS, Nuttall FQ, Lee R. et al. Prediction of the relative blood glucose response of mixed
meals using the white bread glycemic index. Diabetes Care 1985;8:418-28
292
Wolever TMS. The glycemic index: Flogging a dead horse? Diabetes Care 1997;20:452-6
293
Roberts SB. High-glycemic index foods, hunger, and obesity: Is there a connection? Nutr Rev
2000;58:163-9
294
Campfield LA, Smith FJ, Roenbaum M, Hirsch J. Human eating: evidence for a physiological basis
using a modified paradigm. Neurosci Biobehav Rev 1996;20:133-7
295
Ludwig DS, Majzoub JA, Al-Zahrani A, et al. High glycemic index foods, overeating, and obesity.
Pediatrics 1999;103:E261-6
296
Holt SHA,Brand-Miller JC, Petocz P. An insulin index of foods: insulin demand generated by 1000 kj
portions of common foods. Am J Clin Nutr 1997;66:1264-76
297
Liljeberg HGM, Akerberg AKE, Bjorck IME. Effect of the glycemic index and content of indigestible
carbohydrates of cereal based breakfast meals on glucose tolerance at lunch in healthy subjects. Am J Clin
Nutr 1999;69:647-55
298
Liljeberg and Bjorck I. Effect of a low-glycaemic index spaghetti meal on glucose tolerance and
lipaemia at a subsequent meal in healthy subjects. Eur J Clin Nutr 2000;54:24-8
99
299
Fraze E, Donner CC, Swislocki ALM, et al. Ambient plasma free fatty acids concentrations in
noninsulin-dependent diabetes mellitus: evidence for insulin resistance. J Clin Endocrinol Metab
1985;61:807-11
300
Havel RJ, Kane JP, Balesse O, et al. Splanchnic metabolism of free fatty acids and the production of
triglycerides of very low density lipoproteins in normotriglyceridemic and hypertriglceridemic humans. J
Clin Invest 1970;49:2017-35
301
Ellis A. Increased carbohydrate tolerance in diabetes following hourly administration of glucose and
insulin over long periods. Q J Med 1934;27:137-53
302
Jenkins DJA, Wolever TMS, Ocana AM, et al. Metabolic effects of reducing rate of glucose ingestion
by single bolus continuous sipping. Diabetes 1990; 39:1339-46
303
Bjorklund A, Yaney G, McGarry J, Weir G. Fatty acis and beta cell function. Diabetologia
1997;40:B21-6
304
Paolisso G, Tagliamonte M, Rizzo M, et al. Lowering fatty acid potentiates acute insulin response in
first degree relatives of people with type II diabetes. Diabetologia 1998;41:1127-32
305
Axelsen M, Lonnroth P, Lenner RA, et al. Suppression of nocturnal fatty acid concentrations by bedtime
carbohydrate supplement in type 2 diabetes: effects on insulin sensitivity, lipids, and glycemic control. Am
J Clin Nutr 2000;71:1108-14
306
Bornet FRJ, Billaux MS, Messing B. Glycaemic index concept and metabolic diseases. Int J Biol
Macromol 1997;21:207-19
307
Giacco R, Parillo M, Rivellese AA, et al. Long-term dietary treatment with increased amounts of fiberrich low-glycemic index natural foods improves blood glucose control and reduces the number of
hypoglycemic events in Type 1 diabetic patients. Diabetes Care 2000;23:1461-6
308
Wolever T, Jenkins DJ, Vuksan V et al. Beneficial effect of low-glycemic index diet in overweight
NIDDM subjects. Diabetes Care 1992;15:562-4
309
Storlein LH, Tapsell LC, Calvert DG. Role of dietary factors: macronutrients. Nutr Rev 2000;58
(suppl):S7-9
310
Sievenpiper JL, Mendelson RA, Vuksan V, et al. Effect of meal dilution on the postprandial glycemic
response: implications for glycemic testing. Diabetes Care 1998;21:711-6
311
Milne RM, Mann JI, Chisholm AW, Williams SM. Long-term comparison of three dietary prescriptions
in the treatment of NIDDM. Diabetes Care 1994;17:74-80
312
Frost G, Wilding J, Beechem J. Dietary advice based on glycaemic index improves dietary profile and
metabolic control in type 2 diabetic patients. Diabetic Med 1994;11:397-401
313
Wolever TMS, Jenkins DJA, Jenkins AL, Josse RG. The glycemic index: methodology and clinical
implications. Am J Clin Nutr 1991;54:846-54
314
Meneilly GS, Ryan EA, Radziuk J, et al. Effect of acarbose on insulin sensitivity in elderly patients with
diabetes. Diabetes Care 2000;23:1162-7
315
Wolever T, Hamad S, Chiasson JL et al. day-to-day consistency in the amount and source of
carbohydrate intake associated with improved blood glucose control in type 1 diabetes. J Am Coll Nutr
1999;18:242-7
316
Salomen J, Ascherio A, Rimm EB, et al. Dietary fiber, glycemic load, and risk of NIDDM in men.
Diabetes Care 1997;20:545-50
317
Wolever TMS, Jenkins DJA, Vuksan V, et al. Beneficial effect of low-glycemic index diet diet in
overweight NIDDM subjects. Diabetes Care 1992;15:562-4
318
Nestel PJ, Carroll KF, Havenstein N. Plasma triglyceride response to carbohydrates, fats and caloric
intake. Metabolism 1970;19:1-18
319
Hokansen J, Austin M. Plasma triglyceride level is a risk factor for cardiovascular disease independent
of high-density lipoprotein cholesteol level: a meta-analysis of population-based studies. J Cardiovasc Risk
1996;3:213-9
320
Jeppensen J, Schaaf P, Jones C, et al. Effects of low-fat, high-carbohydrate diets on risk factors for
ischemic heart disease in postmenopausal women. Am J Clin Nutr 1997;65:1027-33
321
Katan MB, Grundy SM, Willett WC. Should a low-fat, high-carbohydrate diet be recommended for
everyone? Beyond low-fat diets. N Engl J Med 1997;337:563-7
322
Liu S, Willett WC, Stampher MJ, et al. A prospective study of dietary glycemic load, carbohydrate
intake, and risk of coronary heart disease. Am J Clin Nutr 2000;71:14;55-61
100
323
Edelstein SL,Barrett-Connor EL, Wingard DL, Cohn BA. Increased meal frequency associated with
decreased cholesterol concentrations: Rancho Bernardo, CA 1984 -1987. Am J Clin Nutr 1992;55:664-9
324
Jenkins DJA, Wolever TMS, Vuksan V, et al. Nibbling versus gorging: metabolic advantages of
increased meal frequency. N Engl J Med 1989;321:929-34
325
Jenkins DJA, Jenkins AL, Wolever TMS, et al. Low glycemic index: lente carbohydrates and
physiological effects of altered food frequency. Am J Clin Nutr 1994;59(suppl):706S-9S
326
Jones PJH, Leitch CA, Pederson RA. Meal-frequency effects plasma hormone concentrations and
cholesterol synthesis in humans. Am J Clin Nutr 1993;57:868-74
327
Arnold LM, Ball MJ, Duncan AW, Mann J. Effect of isoenergetic intake of three or nine meals on
plasma lipoproteins and glucose metabolism. Am J Clin Nutr 1993;57:446-51
328
Metabolic effects of alterations in meal frequency in hypercholesterolemic individuals. Atherosclerosis
1994;108:167-74
329
Booth DA. Mechanisms from models - actual effects from real life: the zero-calorie drink-break option.
Appetite 1988;11(suppl):94-102
330
Basdevant A, Craplet C, Guy-Grand B. Snacking patterns in obese French women. Appetite 1993;21:1723
331
Drummond SE, Crombie NE, Cursiter MC, Kirk IR. Evidence that eating frequency is inversely related
to body weight status in male, but not female, nonobese adults reporting valid dietary intakes. Int J Obesity
1998;22:105-12
332
Fabry P, Tepperman J. Meal frequency - a possible factor in human pathology. Am J Clin Nutr
1970;23:1059-68
333
Marmonier C, Chapelot D, Louis-Sylvestre J. Metabolic and behavioral consequences of a snack
consumed in a satiety state. Am J Clin Nutr 1999;70:854-66
334
Tuomistro T, Tuomistro MT, Hetherington M, Lappalainen R, Reasons for the initiation and cessation
of eating in obese men and women and the affective consequences of eating in everyday situations.
Appetite 1998;30:211-22
335
Garrow J. Christmas factor and snacking. Lancet 2000;355:8
336
Speechly DP, Rogers GG, Buffenstein R. Acute appetite reduction associated with an increased
frequency of eating in obese males. Int J Obesity 1999;23:1151-9
337
Geliebter A, Schachter S, Lohmann-Walter C, et al. Reduced stomach capacity in obese subjects after
dieting. Am J Clin Nutr 1996;63:170-3
338
Jenkins DJA, Wolever TMS, Vuksan V, et al. Nibbling versus gorging: metabolic advantages of
increased meal frequency. N Engl J Med 1989;321:929-34
339
Patsch JR, Miesenbock G, Hopferweiser T, et al. Relation of triglyceride metabolism and coronary
artery disease. Studies in the postprandial state. Arterioscler Thromb 1992;12:1336-45
340
O'Dea K, Traianedes K, Ireland P et al. The effects of diet differing in fat, carbohydrate, and fiber on
carbohydrate and lipid metabolism in Type II diabetes. J Am Diet Assoc 1989;89:1076-86
341
Smith SR, de Jonge L, Zachwieja JJ, et al. Fat and carbohydrate balances during adaption to a high-fat
diet. Am J Clin Nutr 2000;71:450-7
342
Schwartz R, Woodcock NA, Blakely JD, MacKellar I. Metabolic responses of adolescent boys to two
levels of dietary magnesium and protein effect of magnesium and protein level on calcium balance. Am J
Clin Nutr 1973;26:519-23
343
Robertson WG, Peacock M. The pattern of urinary stone disease in Leeds and in the United Kingdom in
relation to animal protein intake during the period 1960-1980. Urol Int 1982;37:394-9
344
Martini LA, Wood RJ. Should dietary calcium and protein be restricted in patients with nephrolithiasis?
Nutr Rev 2000;58:111-7
345
Licata A, Bou E, Bartter FC, Cox J. Effects of dietary protein on urinary calcium in normal subjects and
in patients with nephrolithiasis. Metabolism 1979;28:895-900
346
Kenney JJ. Are high-protein ketogenic diets the key to weight control? www.foodandhealth.com
347
Mudugno B. Insulin resistance: a new paradigm for medical nutrition therapy and nutrition education.
SCAN's Pulse 1995;14(4):1-4
348
Ravussin E, Gautier JF. Metabolic predictors of weight gain. Int J Obesity 1999;23(suppl 1):37-41
349
Kenney J. Insulin Resistance: sorting out the research for a sound clinical approach. SCAN's Pulse
1996;15(2):13-5
101
350
Fraze E, Donner CC, Swislocki ALM, et al. Ambient plasma free fatty acids concentration in insulindependent diabetes mellitus: evidence for insulin resistance. J Clin Endocrinol Metab 1985;61:807-11
351
Eckel RH. Insulin resistance: an adaption for weight maintenance. Lancet 1992;340:1452-3
352
.Kenney JJ. Do high glycemic index foods cause obesity? A look at the false claims made in Sugar
Busters and The Zone diet books.www.foodandhealth.com
353
Garg A, Bonanome A, Grundy SM, et al. Comparison of a high-carbohydrate diet with a high
monounsaturated fat-diet in patients with non-insulin-dependent diabetes mellitus. N Engl J Med.
1988;319:829-34
354
Kenney JJ, Roenthal M, Inkeles S, et al. Letter to the editor. N Engl J Med 1989;320:526
355
Garg A. Letter to the editor. N Engl J Med.1989;320: 537
356
Dreon DM, Frey-Hewitt B, Ellsworth N, et al. Dietary fat to carbohydrate ratio and obesity in middleaged men. Am J Clin Nutr 1988;47:995-1000
357
Siedell JC. Dietary fat and obesity: an epidemiological perspective. Am J Clin Nutr
1998;67(suppl):546S-50S
358
Saltzman E, Dallal G, Roberts SB. Effect of high-fat and low-fat diets on voluntary energy intake and
substrate oxidation: Studies in identical twins consuming diets matched for energy density, fiber and
palatability. Am J Clin Nutr 1997;66:1332-9
359
Blundell JE, Stubbs RJ High and low carbohydrate and fat intakes: limits imposed by appetite and
palatability and their implication for energy balance. Eur J Clin Nutr. 1999;53 (suppl):S148-65
360
Blundell JE, Macdiarmid JI. Fat as a risk factor for over consumption: Satiation, satiety and patterns of
eating. J Am Diet Assoc 1997:97(suppl):S63-9
361
Kenney JJ. Research points to a more effective strategy for long-term weight control without chronic
hunger. http://www.foodandhealth.com
362
Tsihlias EB, Gibbs AL, McBurney MI, Wolever TMS. Comparison of high- and low-glycemic breakfast
cereals with monounsaturated fat in the long-term dietary management of type 2 diabetes. Am J Clin Nutr
2000;72:439-49
363
Boden G, Chen X, Ruiz J, et al. Mechanisms of fatty acid induced inhibition of glucose uptake. J Clin
Invest 1994;37:2438-46
364
Zhou Y-P. Grill VE. Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced
insulin secretion and biosynthesis through a glucose fatty acid cycle. J Clin Invest 1994;93:870-6
365
Wilson G. Relation of diet and voluntary weight loss to psychological functioning and binge eating. Ann
Intern Med 1993;119:727-30
366
Schwartz M, Brunzell J. Regulation of body adiposity and the problem of obesity. Arterioscler Thromb
Vasc Biol 1997;17:233-8
367
Morgan SA, O'Dea K, Sinclair AJ. A low-fat diet supplemented with monounsaturated fat results in less
HDL-C lowering than a very-low fat diet. J Am Diet Assoc 1997;97:151-6
368
Kenney JJ.Clinical research on weight loss must also have practical applications. J Am Diet Assoc
1997;97:840
369
Sinclair A. Author's reply. J Am Diet Assoc 1997;97:840
370
Lissner L, Hetmann BL. Dietary Fat and obesity:evidence from epidemiology. Eur J Clin Nutr
1995;49:79-90
371
Bennett PH. Type 2 diabetes among the Pima Indians of Arizona: An epidemic attributable to
environmental change? Nutr Rev 1999;57 (Suppl):S41-4
372
Thorburn AW, Brand JC, Truswell AS. Slowly digested and absorbed carbohydrate in traditional bush
foods: a protective factor against diabetes? Am J Clin Nutr 1987;45:98-106
373
Zimmet P, Guinea A, Guthrie W, et al. The high prevalence of diabetes mellitus on a central Pacific
island. Diabetologia 1977;13:111-5
374
Taylor RJ, Zimmet PZ. Obesity and diabetes in Western Somoa. Int J Obesity 1981;5:367-79
375
Shintani TT, Hughes CK, Beckham S, O'Conner HK. Obesity and cardiovascular risk intervention
through ad libitum feeding of traditional Hawaiian diet. Am J Clin Nutr 1991;53 (suppl):1674S-51S
376
Fields M. Nutritional factors adversely influencing the glucose/insulin system. J Am Coll Nutr
1996;17:317-21
377
Soman VR, Koivislo VA, Dielbert D, et al. Increased insulin sensitivity and insulin binding to
monocytes after physical training. N Engl J Med 1979;301:1200-4
102
378
Duncan KH, Bacon JA, Weinsier RL, et al. The effect of high and low energy density diets on satiety,
energy intake, and eating time of obese and nonobese subjects. Am J Clin Nutr 1983;37:763-7
379
see June 1998 issue of CFFH on Calorie Density vs % Fat article or for a more detailed explanation see
"Research points to a more effective strategy for losing weight without hunger" www.foodandhealth.com.
380
Drewnowski A. Energy density, palatability, satiety: Implication for weight control. Nutrition Reviews
1998;56:347-53
381
Eaton SB, Eaton SB III, Konner MJ, et al. Palaeolithic nutrition revisited: a twelve year retrospective on
its nature and implications. Europ J Clin Nutr 1997;51:207-16
382
Barnard RJ, Lattimore L, Holly RG, et al. Response of non-insulin-dependent diabetic patients to an
intensive program of diet and exercise. Diabetes Care 1982;5:370-4
383
Saleron J, Manson JE, Stampfer MJ, et al. Dietary fiber, glycemic load, and risk of non-insulindependent diabetes mellitus in women. JAMA 1997;277:472-77
384
The Diabetes and Nutrition Study Group (DSNG) of the European Association for the Study of Diabetes
(EASD). Recommendation for the nutritional management of patients with diabetes mellitus. Int J Obesity
2000;24:352-4
385
Klatsky AL, Armstrong MA, Friedman GD. Risks of cardiovascular mortality in alcohol drinkers, exdrinkers and nondrinkers. Am J Cardiol 1990;66:1237-42
386
Boffetta P, Garfinkel L. Alcohol drinking and mortality among men enrolled an American Cancer
Society prospective study. Epidemiology. 1990;1:342-8
387
Dallongeville J, Marecaux N, Ducimetiere P, et al. Influence of alcohol consumption and various
beverages on waist girth and waist-to-hip ratio in a sample of French men and women. Int J Obes
1998;22:1178-83
388
Manson JE, Colditz GA, Stampfer MJ, et al. A prospective study of maturity onset diabetes and risk for
coronary heart disease and stroke in women. Arch Intern Med 1991;151:1141-47
389
Gu K, Cowie CC, Harris MI. Mortality in adults with and without diabetes in a national cohort of the US
population, 1971-1993. Diabetes Care 1998;1138-45
390
Ajani UA, Gaziano M, Lotufo PA. Alcohol consumption and risk of coronary heart disease by diabetes
status. Circulation 2000;102:500-5
391
Solomon CG, Hu FB, Stampfer MJ, et al. Moderate alcohol consumption and risk of coronary heart
disease among women with Type 2 diabetes mellitus. Circulation;102:494-9
392
Regan TJ. Moderate alcohol consumption and risk of coronary heart disease among women with Type 2
diabetes mellitus: editorial. Circulation 2000;102:487-8
393
Horiskooshi H, Hashimoto T, Fujiwara T. Troglitazone and emerging glitazones: new avenues for
potential therapeutic benefits beyond glycemic control. Progress Drug Res 2000;54:191-212
394
Henrikkson J. Effect of training and nutrition on the development of skeletal muscle. J Sports Sci
1995(suppl):S25-30
395
van Baak MA, Borghouts LB. Relationship with physical activity. Nutr Rev 2000;58(suppl II):S16-8
396
Buse JB. Progressive use of medical therapies in Type 2 diabetes. Diabetes Spectrum 2000;13:211-20
397
Funnell MM, Anderson RM. The problem with compliance in diabetes. JAMA 2000;284:1709
398
Williams G. Obesity and type 2 diabetes: a conflict of interests? Int J Obesity 1999;23(suppl 7):S2-4
399
Piche T, Raimondi, Schneider S, et al. Acarbose and lymphocytic colitis. Lancet 2000;356:1246
400
Stern MP, Mitchell BD, Haffner SM, Hazuda HP. Does glycemic control of Type II diabetes suffice to
control dyslipidemia
401
Kaplan NM. Cardiovascular risk reduction: the role of antihypertensive treatment. Am J Med
1991;90(suppl 2A):19S-20S
402
Turner RC, Cull GA, Frighi V, Holman RR. Glycemic control with diet, sufonylurea, metformin, or
insulin in patients with Type 2 diabetes mellitus: Progressive requirement for multiple therapies (UKPDS
49). JAMA 1999;281:2005-12
403
UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with
metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet
1998;352:854-65
404
Glueck CJ, Tracy T, Weber K, et al. Metformin reduces weight, centripetal obesity, and LDL cholesterol
in non-diabetic, morbidly obese subjects with BMI > 30. FASEB Journal 2000;14 (abstr):A431
405
Williamson DF, Thompson TJ, Thun M, et al. Intentional weight loss and mortality among overweight
individuals with diabetes. Diabetes Care 2000;23:1499-1504
103
406
Bauman WA, Shaw S, Jayatilleke E, et al. Increased intake of calcium reverses vitamin B-12
malabsorption induced by metformin. Diabetes Care 2000;23:1227-31
407
Choi S-W. Vitamin B-12 deficiency: a new risk factor for breast cancer? Nutr Rev 1999;57:250-60
408
Schwartz S, Raskin P, Fonseca V, Graveline JF. Effects of troglitazone in insulin-treated patients with
type 2 diabetes mellitus. N Engl J Med 1998;338:861-6
409
Mauerholl T, Ketelslegers JM, Lambert AE. Effect of glibenclamide in insulin-treated diabetic patients
with residual insulin secretion. Diabetes Metab 1986;12:34-8
410
Garber AJ, Duncan TG, Goodman AM, et al. Efficacy of metformin in type II diabetes: results of a
double-blind, placebo-controlled, dose-response trial. Am J Med 1997;103:491-7
411
Schwartz K, Mertz W. Chromium (III) and the glucose tolerance factor. Arch Biochem Biophys
1959;85:292-5
412
International Agency for Research on Cancer. Monographs on the evaluation of carcinogenic risks in
humans. Chromium, nickel and welding. World Health Organization 1990;49:19-527
413
Vincent JB. Quest for the molecular mechanism of chromium action and its relationship to diabetes.
Nutr Rev 2000;58:67-72
414
Hathcock JN. Safety limits for nutrients. J Nutr 1996;126(suppl):2386-9
415
Anderson RA. Chromium as an essential nutrient for humans. Regul Toxicol Pharmacol
1997;26(suppl):35-41
416
Stoecker BJ. Chromium. In: Shils ME, Olsen JA, Shike M, Ross AC, eds. Modern Nutrition in Health
and Disease. 9th ed. Baltimore, MD: Williams & Wilkins; 1999:277-82, Nielsen FH. Controversial
chromium. Nutr Today. 1996;31:226-33
417
Offenbacher EG, Pi-Sunyer FX. Beneficial effects of chromium-rich yeast on glucose tolerance and
blood lipids in elderly subjects. Diabetes 1980;29:919-25
418
Lee NA, Reasner CA. Beneficial effect of chromium supplementation on serum triglyceride levels in
NIDDM. Diabetes Care 1994;17:1449-52
419
Mertz W, Chromium in human nutrition: a review. J Nutr 1993;123:626-33
420
Trent LK, Thielding-Cancel D. Effects of chromium picolinate on body composition. J Sports Med
1995;35:273-80
421
Sugden KD, Geer RD, Rogers SJ. Oxygen radical-mediated DNA damage by redox active Cr(III)
complexes. Biochemistry 1992;31:11626-31
422
Lukaski HC. Chromium as a supplement. Ann Rev Nutr 1999;19:279-301
423
Anderson RA, Cheng N, Bryden NA, et al. Elevated intakes of supplemental chromium improve glucose
and insulin variables in individuals with type 2 diabetes. Diabetes 1997;46:1786-91
424
Morris BW, MacNeil S, Hardisty CA, et al. Chromium homeostasis in patients with typeII (NIDDM)
diabetes. J Trace Elem Med Biol 1999;13:57-61
425
Jeejeebhoy KN. The role of chromium in nutrition and therapeutic and as a potential toxin. Nutr Rev
1999;57:329-35
426
Sun Y, Mallya K, Ramirez J, Vincent JB. The biomimetic (chromium compound) decreases plasma
cholesterol and triglycerides in rats: towards chromium-containing therapeutics. J Biol Inorg Chem
1999;6:838-45
427
Goldfine AB, Simonson DC, Foli F, et al. Metabolic effects of sodium metavandate in humans with
insulin-dependent and non-insulin dependent diabetes mellitus in vivo and in vitro studies. J Clin
Endocrinol Metab 1995;80:3311-32
428
Cohen N, Halberstam M, Shlimovich P, et al. Oral vanadyl sulfate improves hepatic and peripheral
insulin sensitivity in patients with non-insulin-dependent diabetes mellitus. J Clin Invest 1995;95:2501-9
429
Boden G, Chen X, Ruiz J, et al. Effects of vanadyl sulfate on carbohydrate and and lipid metabolism in
patients with non-insulin-dependent diabetes mellitus. Metabolism 1996:45:1130-5
430
Vema S, Cam MC, McNeill. Nutritional factors that can favorably influence the glucose/insulin system:
vanadium. J Am Coll Nutr 1998;17:11-8
431
Nielson F. Requirements for vanadium and impact on human health. Food and Nutrition Board Forum
presented at the annual meeting of the Federation of American Societies for Experimental Biology,
Washington, DC, April 17-21, 1999
432
Anderson RA. Role of dietary factors: micronutrients. Nutr Rev 2000;58(suppl): S10-1
433
Baldi S, Natali A, Buzzigoli G, et al. In vivo effect of insulin on intracellular calcium concentrations:
relation to insulin resistance. Metabolism 1996;45:1402-7
104
434
Barbagallo M, Resnick LM, Domingues LJ, Licata G. Diabetes mellitus, hypertension and aging: the
ionic hypothesis of ageing and cardiovascular-metabolic diseases. Diabetes Metab 1997;23:281-94
435
Kawano Y, Matsuoka H, Takishita S, Omae T, Effects of magnesium supplementation in hypertensive
patients: assessment by office, home, and ambulatory blood pressures. Hypertension 1998;32:260-5
436
Meyer KA, Kushi LH, Jacobs DR, et al. Carbohydrates, dietary fiber, and incident type 2 diabetes in
older women. Am J Clin Nutr 2000;71:921-30
437
Rosolva H, Mayer O, Reaven G. Effect of variations in plasma magnesium concentrations on resistance
to insulin-mediated glucose disposal in nondiabetic subjects. J Clin Endocrinol Metab 1997;82:3783-5
438
Balon TW, Jasman A, Scott S, et al. Dietary magnesium prevents fructose-induced insulin insensitivity
in rats. Hypertension 1994 ;23:1036-9
439
Bierman EL. Atherogenesis in diabetes. Arterioscler Thromb 1992;12:647-56
440
Semenkovich CF, Heinecke JW. The mystery of diabetes and atherosclerosis: time for a new plot.
Diabetes 1997;46:327-34
441
Chan AC. Vitamin E and atherosclerosis. J Nutr 1998;128:1593-6
442
Jialal I, Devaraj S, Low-density lipoprotein postsecretory modification, monocyte function, circulating
adhesion molecules in Type 2 diabetic patients with and without macrovascular complications: the effect of
alpha-tocopherol supplementation. Circulation 2000;102:191-6
443
Costagliola C, Iuliano G, Menzione A, et al. Systemic human diseases as oxidative risk factor in
caterogenesis. Opthalmic Res 1988;20:308-16
444
Simonelli F, Nesti A, Pensa M, et al. Lipid peroxidation and human cataractogenesis and severe myopia.
Exp Eye Res 1989;49:181-7
445
Ceriello A, Giugliano D, Quatraro A, et al. Vitamin E reduction of protein glycosylation in diabetics:
new prospect for prevention of diabetic complications. Diabetes Care 1991;14:68-72
446
Paolisso G, Di Maro G, Galzerano D, et al. Pharmacological doses of vitamin E and insulin action in
elderly subjects. Am J Clin Nutr 1994;59:1291-6
447
Paolisso G, D'Amore A, Giugliano D, et al. Pharmacological doses of vitamin E improve insulin action
in healthy subjects and non-insulin-dependent diabetic patients. Am J CLin Nutr 1993;57:650-6
448
Tutunca NB, Bayraktar M, Varli K. Reversal of defective nerve conduction with vitamin E
supplementation in type 2 diabetes: a preliminary study. Diabetes Care 1998;21: 1915-8
449
Paolisso G, D'Amore A, Galzerano D, et al. Daily vitamin E supplements improve metabolic control but
not insulin action in elderly subjects. Am J Clin Nutr 1993;16: 1433-7
450
Duo C, Xu DP, Wells WW. Studies on the essential role of ascorbic acid in the energy dependent release
of insulin from the pancreatic islets. Biochem Biophys Res Commun 1997;231:820-22
451
Cunningham JJ. The glucose/insulin system and vitamin C: implication in insulin-dependent diabetes
mellitus. J Am Coll Nutr 1998;17:105-8
452
Johnston CS, Yen MF. Megadose of vitamin C delays insulin response to a glucose challenge in
normoglycemic adults. Am J Clin Nutr 1994;60:735-8
453
Upritchard JE, Sutherland WHF, Mann JI. Effect of supplementation with tomato juice, vitamin E, and
vitamin C on LDL oxidation and products of inflammatory activity in Type 2 diabtes. Diabetes Care
2000;23:733-8
454
Hu FB, Rimm EB, Stampher MJ, et al. Prospective study of major dietary patterns and risk of coronary
heart disease. Am J Clin Nutr 2000;72:912-21
455
Konrad T, Vicini P, Kusterer K, et al. Alpha-lipoic acid treatment decreases serum lactate and pyruvate
concentrations and improves glucose effectiveness in lean and obese patients with type 2 diabetes. Diabetes
Care 1999;22:280-7
456
Ziegler D, Schatz H, Conrad F, et al. Effects of treatment with the anti-oxidant alpha-lipoic acid on
cardiac autonomic neuropathy in NIDDM patients: A 4-monthrandomized controlled multicenter trial
(DEKAN Study). Diabetes Care 1997;20:369-73
457
Jacob S, Henriksen EJ, Scheimann AL, et al. Enhancement of glucose disposal in in patients with type 2
diabetes by alpha-lipoic acid. Arzeimttelforschung 1996;45:872-4
458
Ziegler D, Hanefeld M, Ruhnau KJ, et al. Treatment of symptomatic diabetic peripheral neuropathy with
anti-oxidant lipoic acid: a 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia
1995;38:1425-33
459
Yaqub BA, Siddique A, Sulimani R. Effects of methylcobalamin on diabetic neuropathy. Clin Neurol
Neurosurg 1992;94:105-11
105
460
Gregg EW, Yaffe K, Cauley JA, et. al. Is diabetes associated with cognitive impairment and cognitive
decline among older women? Arch Intern Med 2000;160:174-80
461
Reaven GM, Thompson LW, Nahum D, Haskins E. Relationship between hyperglycemia and cognitive
function in older NIDDM patients. Diabetes Care 1990;13:16-21
462
Vanhanen M, Koivisto K, Kuusisto J, et al. Cognitive function in an elderly population with persistent
impaired glucose tolerance. Diabetes Care 1990;14:385-8
463
Starchan MWJ., Deary IJ, Ewing FME, Friere BM. Is type II diabetes associated with an increased risk
of cognitive dysfunction? Diabetes Care 1997;20:438-45
464
Stolk RP, Breteler MM, Ott A, et al. Insulin and cognitive function in an elderly population: the
Rotterdam Study. Diabetes Care 1997;20:792-5
465
Weir DG, Molloy AM. Microvascular disease and dementia in the elderly: are they related to
hyperhomocysteinemia? Am J Clin Nutr 2000;71:859-60
466
Berg MV, Boers GHJ. Homocystinuria: what about mild hyperhomocysteinuria? Postgrad Med
1996;72:513-8
467
Smudlers YM, Rakic M, Slaats EH, et al. Fasting and post-methionine homocysteine levels in NIDDM.
Diabetes Care 1999;22:125-32
468
Reil TD, Barnard RJ, Kashyap VS, et al. Diet-induced changes in endothelial-dependent relaxation of
the rat aorta. J Surgical Res 1999;85:96-100
469
Leman A, Burnett JC Jr, Higano ST, et al. Long-term L-arginine supplementation improves small-vessel
coronary endothelial function in humans. Circulation 1998;97:2123-8
470
Adams MR, McCredie R, Jessup W, et al. Oral L-arginine improves endothelium-dependent dilation and
reduces monocyte adhesion to endothelial cells in young men with coronary artery disease. Atherosclerosis
1997;129:261-9
471
Wascher TC, Graier WF, Dittrich P, et al. Effects of low-dose L-arginine on insulin-mediated
vasodilation and insulin sensitivity. Eur J Clin Invest 1997;27:690-5
472
Schmidt H, Warner T, Ishii K, et al. Insulin secretion from pancreatic beta-cells caused by L-argininederived nitrogen oxides. Science 1992;255:721-3
473
Fochesato E, Piatti PM, Monti LD, et. al. Chronic L-arginine therapy improves insulin sensitivity in
NIDDM patients. Eur J Clin Invest 1999; 29 (abstr):31
474
Guyton JR. Effect of niacin on atherosclerotic cardiovascular disease. Am J Cardiol. 1998;82:
(12A):18U-23U
475
Cervantes-Laurean D, McElvaney NG, Moss J. Niacin. In: Shils ME, Olsen JA, Shike M, eds. Modern
Nurition in Health and Disease. 9th ed. Baltimore, MD: Williams & Wilkins;1999:401-11
476
Malinow MR, Boston AG, Krauss RM. Homocyst(e)ine, diet, and cardiovascular diseases: a statement
for the healthcare professionals from the Nutrition Committee, American Heart Association. Circulation
1999;99:178-82
477
Garg A, Grundy SM. Nicotinic acid as therapy for dyslipidemia in no-insulin-dependent diabetes
mellitus. JAMA 1990;264: 723-6
478
Pozzelli P, Browne PD, Kolb H. Meta-analysis of nicotinamide treatment in patients with recent onset
IDDM. The nicotinamide Trialists. Diabetes Care 1996;19:1357-63
479
Lampeter EF, Klinghammer A, Scherbaum WA, et al. The Deutsche Nicotinamide Intervention Study:
An attempt to prevent type 1 diabetes. Denis Group. Diabetes 1998;19:47:980-4
480
Polo V, Saibene A, Pontril AE. Nicotinamide improves insulin secretion and metabolic control in lean
type 2 diabetic patients with secondary failure to sulphonylureas. Acta Diabetol. 1998;35:61-4
481
Harris WS. N-3 fatty acids and serum lipoproteins in human studies. Am J Clin Nutr 1997;65:1645S54S
482
Simpoulous AP. Omega-3 fatty acids in health and disease and growth and development. Am J Clin
Nutr 1991;54:438-63
483
Nair SSD, Leitch JW, Falconer J, Garg ML. Prevention of cardiac arrhythmia by dietary (n-3_
polyunsaturated fatty acids and their mechanism of action. J Nutr 1997;127:383-93
484
Morris MC, Saks F, Rosner B. Does fish oil lower blood pressure? A meta-analysis of controlled trials.
Circulation 1993;88:523-33
485
Saks FM, Herbert P, Appel LJ, et al. The effect of fish oil on blood pressure and high-density
lipoprotein-cholesterol levels in phase I of the Trials of Hypertension Prevention. Trials of Hypertension
Prevention Collaborative Research Group. J Hypertens 1994;12(suppl): S23-31
106
486
Glauber H, Wallace P, Griver K, Brechtel G. Adverse metabolic effect of omega-3 fatty acids in noninsulin dependent diabetes mellitus. An Intern Med 1988; 108:663-8
487
Hendra TJ, Britton ME, Roper DR, et, al. Effects of fish oil supplements on NIDDM subjects. Diabetes
Care 1990;13:821-9
488
Friedberg CE, Janssen MJ, Heine RJ, et al. Fish oil and glycemic control in diabetes. A meta-analysis.
Diabetes Care 1998;21:494-500
489
Simopoulos AP. Essential fatty acids in health and chronic disease. Am J Clin Nutr
1999;70(suppl):560S-9S
490
Eaton SB, Konner M. Palaeolithic nutrition. A consideration of its nature and current implications. N
Engl J Med 1985;312:283-9
491
Raheja BS, Sadikot SM, Phatak RB, Rao MB. Significance of the n-6/n-3 ratio for insulin action in
diabetes. Ann NY Acad Sci 1993;258-71
492
Hendra TJ, Britton ME, Roper DR, et al. Effects of fish oil supplements in NIDDM subjects. Diabetes
Care 1990;13:821-9
493
Stampfer MJ. Healthy lifestyle linked to a very low risk of coronary heart disease in women. N Engl J
Med 2000;343:16-22
494
Pariza M, Park Y, Cook M. Conjugated linoleic acid (CLA) reduces body fat. FASEB J. 1996;53:49-58
495
Young TA, Peck L. Modulation of Type 2 diabetes mellitus with conjugated linoleic acid. J Am Diet
Assoc 2000;100(suppl):A-78 (abstr)
496
Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States,
1990-1997: results of a follow-up survey. JAMA 1998;280:1569-75
497
Angell M, Kassirer JP. Alternative medicine: the risk of untested and unregulated remedies. N Engl J
Med 1998; 339:839-41, Bent S, Avins AL. An herb for every illness? Am J Med 1999;106:259-60
498
Vogler BK, Pittler MH, Ernst E. The efficacy of ginseng: a systematic revie of randomized clinical
trials. Eur J Clin Pharmacol 1999;567-575
499
Liu CX, Xiao PG. Recent advances on ginseng research in China. J Ethnopharmacol 1992;36:27-38
500
Ohnishi Y, Takagi S, Miura T, et al. Effect of ginseng radix on GLUT2 protein content of mouse liver in
normal and epinephrine-induced hyperglycemic mice. Biol Pharm Bull 1996;19:1238-40
501
Oshima Y, Sato K, Hikino H. Isolation and hypoglycemic activity of quinquefolans A, B, and C glycans
of Panax quinquefolius roots. J Nat Prod 1987;50:188-90
502
Viksan V, Sieenpiper JL, Koo VYY, et al. Arch Intern Med 2000;160:1009-13
503
Vuksan V Stavro MP, Sievenpipier JL, et al. Similar postprandial glycemic reductions with escalation of
dose and administration time of American ginsen in Type 2 diabetes 2000;23:1221-6
504
Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of
microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a
randomized prospective 6-year study. Diabetes Res Clin Pract 1995;28:103-17
505
UK Prospective Diabetes Group. Intensive blood-glucose control with sulfonylureas or insulin
compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS
33). Lancet 1998;352:837-53
506
Jacobs DR, Murtaugh MA. It’s more than an apple a day: an appropriately processed plant-centered
dietary pattern may be good for your health. Am J Clin Nutr 2000;72:899-900
507
Kant AK. Consumption of energy-dense, nutrient poor foods by adult Americans: nutritional and health
implications. The third National Health and Nutrition Examination Survey, 1988-1994. Am J Clin Nutr
2000;72:929-36
508
The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome.
www.pnas.org/cgi/doi/10.1073.0705408104
509
Chong MF-F, Fielding BA, Frayn KN. Mechanism for the acute effect of fructose on postprandial
lipemia. Am J Clin Nutr 2007;85:1511-20
107