Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
The Skinny on Low-Carbohydrate Diets Wendy Knapp Pogozelski SUNY Geneseo September, 2009 How I got interested in carbohydrate restriction 1. Invitation from hospital to speak: “all the doctors here are on Atkins”… 2. Information for my undergraduates led to a paper, involvement w/Nutrition and Metabolism Society Just SOME of what Biochem students have to learn… (…and what professors have to make sound interesting) Low-carb Diets Abound U.S. France Germany Australia U.K. Russia Why the Issue is Important 1. Type 2 Diabetes Epidemic http://www.sanger.ac.uk/Teams/Team35/gfx/graph.png 2. Obesity epidemic, esp. in children It’s not just America… – 37% American children – 20% European children – 10% Chinese children – ↑ in “developing world” http://www.ehponline.org/docs/2003/111-13/focushead.jpg (12th European Congress on Obesity, 2003) Type 2 Diabetes in Children • 25% of all obese children already have Type 2 Diabetes. http://www.iconocast.com/B000000000000162/L3/News1_0.jpg Diabetes in Animals • ~1/4 of cats have diabetes – Can be transient • Stress-induced (glucocortocoids) • Drug-induced (steroids) • Illness-induced • Also common in horses Type 2 Diabetes and Fat Cells • One Theory: cross-section of a blood vessel • You have all your fat cells by the end of adolescence; they just get bigger. • If they get too engorged, they stop responding to insulin. • The body responds by churning out MORE insulin, driving MORE fat synthesis. • Eventually beta cells (where insulin is produced) begin to wear out, are unable to lower blood sugar. http://www.proteinpower.com/drmike/wp-content/uploads/2008/05/human-adipose-tissue.jpg Type 2 Diabetes • Other Theories: – Dysregulation of liver enzymes (1-GP ↔6-GP) – Cytokines (chemicals secreted) by fat cells cause inflammation Early Low-Carb Diet Advocates William Banting 1862: -5’5” 202 lbs, 61 yrs old -tried Turkish baths, 2h exercise/d, fasting -couldn’t tie shoes, walk down stairs 1863: -advised by Dr. William Harvey -gave up beer, potatoes, bread -lost 46 lb/yr •Self-published pamphlet sold over 100,000 copies in England, America, France,Germany. •Medical establishment disapproved of the Banting-Harvey diet •Banting died at age 81, maintained wt loss 19 yrs “to bant” = to diet http://www.proteinpower.com/drmike/wp-content/uploads/ 2007/08/banting-cover-blog-size.jpg Dr. Robert Atkins http://rjr10036.typepad.com/.shared/image.html? /photos/uncategorized/dratkins_youngman_300x330.jpg • Studied low-carb diet used to control seizures patients lost weight. • Experimented on himself, published book in 1972. • Reissued, repopularized in ’80’s, ’90’s Warning: The Subject of LowCarb Diets is Very Polarizing Resistance to new ideas? Cultural implications? Ethical implications? Lack of distinction between dieting vs. long-term eating plans? Argument over what is “best”? Reluctance to examine the science? Reluctance to let go of notions of “balance”? Individual differences? Personal experience vs. double-blind studies? What is a Carbohydrate? – molecule made of glucose (sugar) units Glucose www.umanitoba.ca/.../lab2/biolab2_2.html Starch vs. Sugar • In plants, glucoses link together to form starch (a polysacchardide) starch • Table sugar (sucrose) is a disaccharide of glucose and fructose. • Both are broken down to Glucose pslc.ws/macrog/kidsmac/starch.htm Glycogen • In animals (in muscle and liver), glucose links together to form glycogen. http://www.emc.maricopa.edu/faculty/farabee/BIOBK/1glycogen.gif Glycogen is used for temporary energy storage of glucose. Carbs are Digested to Glucose • Glucose enters cells to be converted to ATP for energy. – Insulin required for entry! • Excess glucose is converted to glycogen + fat. http://www.sugar.ca/english/images/tradealliances/stomach.jpg Glucose Stimulates Insulin • Glucose doesn’t enter cells on its own. • Glucose enters via the glucose receptor protein embedded in cell membranes. • Insulin “unlocks the gate” (binds to and opens the receptor) to let glucose into the cell. glucose Insulin + Receptor cell Insulin unlocks the gate (GLUT) of cells to let glucose enter. www.answers.com/topic/insulin http://themedicalbiochemistrypage.org/insulin.html http://themedicalbiochemistrypage.org/insulin.html Insulin also promotes fat storage. • Insulin leads to activation of fatty acid synthase (makes fat) and glycogen synthase (makes glycogen for short-term storage of energy). • Insulin leads to inactivation of hormone-sensitive lipase (breaks down fat) and glycogen phosphorylase (breaks down glycogen). • Insulin also leads to production of cholesterol (activates HMG-CoA reductase). Insulin release is related to the rate at which glucose enters the bloodstream. Faster glucose release More insulin Fat storage activated Fat breakdown inhibited Thus, greater insulin release when: high carbs (amount) high concentration due to fast-release carbs (simple carbs or no protein/fat to slow the entry of glucose into the bloodstream What Foods Contain Carbohydrates? • Grains, root vegetables, fruits, beans are rich in starch (polysaccharides). • Milk contains disaccharide. http://www.replica.co.uk/images/specials/bread.jpg – Lactose: disaccharide of galactose and glucose. • Most other vegetables are low in carbs. • Meat, fat, cheese, cream ~none. http://rjr10036.typepad.com/.shared/image.html?/photos/uncategorized/vege.jpg Relationship of Metabolic Syndrome and Type 2 Diabetes • Metabolic Syndrome – Cluster of diseases characterized by 3 or more of the following • Insulin resistance – High fasting blood sugar – Can lead to type 2 diabetes • Abdominal obesity • High blood pressure • High triglycerides – Can lead to Cardiovascular disease Prevalence of Metabolic Syndrome • 47 million in U.S. (2000) • Among obese kids, 25% Abdominal Obesity • Men: waist > 40 in • Women: waist > 35 in • Visceral fat around the middle increase inflammation markers • > 50% of U.S. adults over 60 are abdominally obese. Waist size predictor • Recent study: waist size predicted death from stroke or heart attack better than any other indicator (including smoking + LDL cholesterol) • Every 2-in increase in waist circumference increased risk of dying from heart attack by as much as 17% http://blogs.mercola.com/ImageServer/public/2007/07--july/7.12triglycerides.jpg Triglycerides (fats) • 150 mg/dl or higher considered risky • Known to increase on low-fat, high-carb diets • YET a low-fat, high-carb diet is recommended by the ADA and AHA. • What the heck??????? HDL cholesterol • the “good cholesterol” – lipoprotein that carries cholesterol back to the liver for degradation or recycling. • Want HDL to be high – Men: HDL > 40 mg/dL – Women: HDL > 50 mg/dL • Government and agency-recommended low-fat, high-carb regimens LOWER HDL. • Low-carb regimens RAISE HDL (if not too low in fat) http://www.ks.uiuc.edu/Gallery/Science/Structure/discoidalHDL_st.jpg Metabolic Syndrome Can Be Improved by Weight Loss • Low-fat methods work • Low-carbohydrate methods work BUT, low-carb diets improve CVD profiles, improve glycemic control • Carb restriction – Less insulin produced less fat storage, less hunger, less LDL cholesterol – HDL increases – Less glucose release so less taxing an overtaxed pancreas glycemic control improves – Reverses Metabolic Syndrome!! • “Carbohydrate restriction is one of several strategies for reducing body mass but even in the absence of weight loss or in comparison with low fat alternatives, CHO restriction is effective at ameliorating high fasting glucose and insulin, high plasma triglycerides, low HDL and high blood pressure. In addition, low fat, high CHO diets have long been known to raise TAG, lower HDL and, in the absence of weight loss, may worse glycemic control.” Volek, J., Feinman, R. “Carbohydrate restriction improves the features of Metabolic Syndrome”, Nutrition and Metabolism, 2005. Why Restrict Carbohydrates? http://rjr10036.typepad.com/.shared/image.html?/photos/uncategorized/09_gallery_ornish.jpg • Rate of glucose release into bloodstream dictates release of insulin. • Insulin activates fat storage pathways. • Insulin inhibits fat breakdown pathways. – Hyperinsulinemias lead to obesity. • These pathways reversed by glucagon (secreted when glucose levels are low). Atkins Diet • Replace carbs with protein, fat. • No bread, pasta, fruit or starchy vegetables for 2 wks. (“induction”). • Include cream, butter, red meat. • Gradually reintroduce carbs as long as wt loss maintained. Where Low-carb Diets Differ • Ketogenic (Atkins) vs. Non-ketogenic (South Beach) • Ketogenic - < 20 g carbs/day on induction – (Most Americans ~ 300 g carbs/day) – Advantage : fats break down incompletely into “ketone bodies” • Loss of efficiency! • Some ketones used as fuel, others released via breath and urine • Fats metabolized faster than usual. •In ketosis, intermediates (oxaloacetate, etc.) of Krebs’/citric acid cycle are used for gluconeogenesis (making glucose for the brain). Insufficient oxaloacetate to condense with Acetyl CoA. •Acetyl CoA is diverted to ketone formation rather than going through CAC and being completely oxidized. Metabolic Changes in Ketosis • Metabolites normally used for energy are diverted to glucose-making pathway for the brain. • Fat stores break down more rapidly to meet energy needs. Calories in, calories out? • Law of Conservation of Energy still holds. • But ketosis is less efficient, so weight loss is faster. • The composition of the diet does matter. Advantages and Disadvantages of Ketosis/Carb Deprivation • • • • • Fat loss is faster, motivating Eventually, greater energy, improved sleep. Less hunger (no insulin-mediated swings). Some people enjoy eating protein, fat. Most see blood sugar improvements, HDL/LDL improvements, triglyceride improvements. • Requires adaptation (3 days – 2 wks). • Lack of fiber in diet, even for short term. • Effect of hormones if meat consumption increases? • Compliance? Ketone strips -Detect ketones in urine -- Fe(CN)3, turns pink/purple upon reaction with acetoacetate Low-fat vs. Low-carb • Both low-fat and low-carb diets lower LDLs, triglycerides, reduce weight. • However, low-carb diets show significantly more improvement in blood sugar, LDLs, HDLs, esp for diabetics. • Low-fat considered safe in long term, advocated by “establishment” (AMA, AHA). • Low-carb advocated by many physicians and researchers (Drs. Michael and Mary Eades, Dr. Richard Bernstein, Dr. Jeff Volek, Dr. Eric Westmann, Dr. Mary Vernon) • I don’t advocate one approach; eating/dieting decisions best made by individuals in consultation with physicians. Insulin and Diabetes • Type 1: Insufficient insulin secreted. -autoimmune attack on pancreatic cells • Type 2: Insulin resistance – Cell receptors don’t respond to insulin, more insulin gets churned out obesity – Insulin-producing cells may become exhausted. – Former aging disorder, now being seen in overweight children. Low-carb Diet Fallout • …should anything unfortunate happen to you--"even moles in [your] front lawn," as the New York physician Blake Donaldson, an early proponent of carbohydraterestricted diets, noted in his 1961 memoirs--everyone will blame it on your diet. • This past winter, I was anxious (as I will be next winter) that I would slip on an icy sidewalk, as Dr. Robert Atkins did, and crack my head open, thus prompting some chortling among critics and book reviewers that my fall was actually the result of a fat-induced coronary. -Gary Taubes in Prevention magazine http://www.prevention.com/cda/article/diary-of-a-carb-phobe /d69f12b73d8e8110VgnVCM10000013281eac____/news.voices/in.the.magazine/may.2008.issue/0/0/2 A “Healthy” Low-fat Lunch for Elementary School Children Columbia Public Schools, Missouri 789 calories, 23g protein, 21 g fat (24%) 127g carbohydrate, or the equivalent of 32 teaspoons of sugar. Thanks to Regina Wiltsire, http://weightoftheevidence.wordpress.com/ http://www.columbia.k12.mo.us/food/nutrinfo.php • Since the U.S. government began pushing low-fat diets in 1977, we have witnessed significant increases in consumption of grain products and sugars, significant increases in obesity and type 2 diabetes, and no decrease in heart disease. It questioned whether all this was coincidence or cause and effect. Two Studies from the Primary Literature about Carbohydrate Restriction 1. Effect of a Low–Glycemic Index or a High–Cereal Fiber Diet on Type 2 Diabetes A Randomized Trial David J. A. Jenkins, MD; Cyril W. C. Kendall, PhD; Gail McKeown-Eyssen, PhD; Robert G. Josse, MB, BS; Jay Silverberg, MD; Gillian L. Booth, MD; Edward Vidgen, BSc; Andrea R. Josse, MSc; Tri H. Nguyen, MSc; Sorcha Corrigan, BSc; Monica S. Banach, BSc; Sophie Ares, MA, RD, CDE; Sandy Mitchell, BASc, RD; Azadeh Emam, MSc; Livia S. A. Augustin, MSc; Tina L. Parker, BASc, RD; Lawrence A. Leiter, MD JAMA. 2008;300(23):2742-2753. 210 patients with type 2 diabeteswere randomly assigned to receive a high-fiber diet or a low-GI diet for 6 months. The low-GI group ate lower-GI carbs while keeping their overall carb intake the same as that of the high-fiber group. “Lowering the glycemic index of the diet improved glycemic control and risk factors for coronary heart disease (CHD). “ 2. The effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus Eric C Westman , William S Yancy Jr., John C Mavropoulos, Megan Marquart and Jennifer R McDuffie Nutrition & Metabolism 2008, 5:36 Dec 2008 doi:10.1186/1743-7075-5-36 84 subjects with with obesity and type 2 diabetes were randomized to either a low carbohydrate ketogenic diet (less than 20 g carbs/day) or a low-glycemic, reduced calorie diet (500 calories/day) for 6 months. Both groups attended group meetings, had nutritional supplementation and an exercise regimen. The volunteers in the low-carb diet group had greater improvements in hemoglobin A1C and diabetes medications were reduced or eliminated in 95 percent of the volunteers, compared to 62 percent in the low-glycemic group. The low carb diet also resulted in a greater reduction in weight. Comparison of the JAMA Results and the Nutrition & Metabolism Results Thanks to Michael Eades, M.D. for graphing the results from these two studi Thanks to Michael Eades, M.D. for graphing the results from these two studi Thanks to Michael Eades, M.D. for graphing the results from these two studi Thanks to Michael Eades, M.D. for graphing the results from these two studi Thanks to Michael Eades, M.D. for graphing the results from these two studi Thanks to Michael Eades, M.D. for graphing the results from these two studi Thanks to Michael Eades, M.D. for graphing the results from these two studi Reductions in Insulin use Lectins • Proteins that bind to cellular receptors • Lectins in food are sometimes not broken down into amino acids, can cause problems if they are absorbed into circulation. Wheat Germ Agglutinin (WGA) • • • • Can bind to insulin receptors Can STAY bound to insulin receptors Activates part of the insulin signaling chain Can block leptin receptors From Dr. Weill’s Website How Dr. Weil Eats Your diet, and dietary recommendations, have evolved over time, can you take us through that? When I was a child, I ate a fairly standard American diet, which is to say, a bad one. When I was out of the house and on my own, I became a vegetarian for many years. Then, based on my research, I decided to add fish to my diet in 1984. Now, I follow my anti-inflammatory diet quite closely. A common critique one hears among the public at large is that, "even the experts can't agree on what's healthy." Do you think that's true? No, I don't. Every year, in conjunction with the Columbia University College of Physicians and Surgeons, the Program in Integrative Medicine at the University of Arizona sponsors one of the leading conferences on science and nutrition. The top nutrition scientists from all over the world come to it. I am always heartened by the fact that there is now widespread consensus among them on what constitutes the most healthy diet. For example, there is universal agreement that high fructose corn syrup, white flour, white sugar and hydrogenated fats have no place in any diet. And there is near-universal agreement that a diet should be rich in vegetables and fruits and quality sources of protein, especially fish. I think there is also consensus that supplementation to cover nutritional gaps in the diet makes sense for most people. On the Larry King show, you recently defended Gary Taubes, the science writer who questions the value of low-fat diets, and who says saturated fats have gotten a bum rap. Is this a change in your views? No, I have said this in my books. I have never felt that saturated fat was as bad as it is made out to be, if it is eaten in the context of a diet that includes mostly monounsaturated fats, plenty of omega 3 fatty acids, and plenty of antioxidants. With regard to saturated fat, I tell people that you can have some saturated fat in your diet; just think about where you want to spend your saturated fat budget. I choose to spend mine on quality cheese. So what ideas have you changed? I think there is more of a change in my thinking about carbohydrates. In the past five or six years, there has been a real explosion of quality research into the glycemic load and its effect on weight gain and insulin sensitivity. And are you using this insight personally? You were on the Martha Stewart show recently, and she was quite effusive about how good you looked. Yes, I think I am quite sensitive to high-glycemic-load carbohydrates. Most of the processed, refined, manufactured foods are the ones that are quick digesting and problematical. Cutting back on them has helped me get my weight down, because my metabolism is certainly carbohydrate sensitive. http://www.drweil.co m Insulin • Most potent anabolic hormone known – (stimulates anabolic processes such as protein, glycogen and fat synthesis) • Elicits multiple responses by binding to the insulin receptor • Stimulates pathways to regulate growth, differentiation and metabolism • Maintains glucose homeostasis by stimulating uptake, utilization and storage of glucose in muscle and adipose tissue • Also stimulates the uptake of amino acids GLUT-4 • One of a family of glucose-transporter proteins • The only one specifically to promote glucose uptake in insulin-sensitive cells (muscle, fat) • In response to insulin, translocates from intracellular vesicles to the plasma membrane How Insulin Stimulates GLUT-4 Translocation to the Membrane • Insulin binds to the tyrosine kinase receptor • Activated tyrosine kinase receptor undergoes autophosphorylation, catalyzes the phosphorylation of several substrates such as the insulin-receptor substrate (IRS-1) protein, which activates downstream components to result in translocation of GLUT4 Glucagon • • • • • Also a hormone Has opposite effect of glucose Causes release of glucose from glycogen Stimulates gluconeogenesis Stimulates fat mobilization Does a VLCarb Diet result in loss of muscle mass? • Protein needed for gluconeogenesis • BUT, liver makes ketones (which it can’t use), so ketones flow to extra-hepatic tissues (brain, muscle) for fuel • Ketones displace glucose utilization by the brain, thus sparing muscle mass. • The brain derives energy from stored fat via ketosis How to glycolytic tissues fare on a vlc diet? • Glycolytic tissues = red blood cells, renal medulla (lack mitochondria, rely on glucolysis) • They need some glucose, (can’t use ketones), but produce lactate that goes to the liver to be reconverted to glucose (the Cori Cycle) When carbs are restricted, glucose comes from protein (and glycerol) Why Ketosis in Low-Carb Diets ≠ Ketoacidosis in Diabetics Normally, hyperglycemia (high blood sugar) suppresses glucagon secretion. In most diabetics, there is excessive excretion of glucagon because it is NOT suppressed by hyperglycemia. Levels of ketone bodies differ. Confusion • • • • • • What is “bad” cholesterol? What is “good” cholesterol? Are triglycerides bad? What are LDLs? What are HDLs? What are vLDLs? Terminology • Lipids – Fat-soluble molecules like fat and cholesterol • Most fat is in the form of triacylglycerol (triglyceride/triacylglyceride) – 3 carboxylic acids with long hydrocarbon chains (fatty acids) + glycerol backbone Problem: Fats and cholesterol are not water-soluble • Won’t they clog your veins and arteries like grease in the sink? Lipids are carried in the blood by lipoproteins • Lipoproteins wrap the lipid in a protein coat – The protein is water-soluble problem solved – The protein allows the lipid to bind to specific receptors on the outside of cells, so they can perform different functions, depending on receptor binding Chylomicrons and vLDLs are the lipoproteins that carry most fats • Chylomicrons: made in intestine for packaging up fatty acids and cholesterol. • Transported through lymphatic system • Released to bloodstream via thoracic duct • Bind to cells that grab the fat or cholesterol • Fat used for energy • Rather short-lived – The liver vacuums up chylomicron remains and repackages them with any lipids left over as very-low-density lipoproteins (vLDLs) • vLDLs – protein + initially rejected fat – repackaged by the liver • vLDLs return to blood bind to receptors cells can again strip away the fat, use it for energy • vLDLs also carry fat created by the liver from excess glucose HDL vs. LDL • Differ in the protein • LDLs bind to cell receptors that allow the cells to extract cholesterol • HDLs bind to cell receptors that allow them to take away “used” cholesterol for recycling in the liver (when cells die, etc.) Fats carried by lipoproteins are released by lipoprotein lipase (LPL). • TAGs are too large to go across cell membrane • So lipoprotein lipase hydrolyzes the bond between the glycerol and the fatty acids, releasing free fatty acids that cross the cell membrane. • Lipoprotein lipases (LPL) regulated by insulin Fat Cells remake TAGs • Cells don’t store free FA, they store TAGs • Glycerol can’t cross the cell membrane though, so cells make alpha glycerol phosphate (precursor to glycerol backbone) from glucose. • NOTE: the higher the glucose availability, the greater the likelihood of TAGs being made. Review • Fat storage requires two things: – Lipoprotein lipase action on chylomicrons or vLDLs to free the fatty acids – Availability of glucose to make the glycerol backbone of storage TAGs How are these controlled? BY INSULIN Insulin is the primary control mechanism for LPL activity and glucose transport • More insulin more LPL activated • More insulin more glucose in fat cells • One more component: – Hormone-sensitive lipase (HSL) inside fat cells • Frees the fatty acids from TAGs so they can reenter the bloodstream (carried by albumin) • More insulin LESS active HSL • More insulin LESS stored fat is broken down Insulin favors fat storage • Increased availability of glucose for glycerol synthesis • Increased activity of Lipoprotein lipase (LPL) • Decreased activity of Hormone-sensitive lipase (HSL) Insulin is released in proportion to the rate at which glucose enters the bloodstream • Pure glucose greatest insulin response – (Refined carbs) • Starch + protein, fat, fiber less insulin response. – However, there is not THAT much difference between white bread and “wheat” bread – AND, total carbohydrate intake is important, not just whether the carbs are refined or not. Does Protein Increase Insulin? • Protein still raises insulin • Insulin needed to get cells to open up for amino acids, etc. • BUT, protein also causes glucagon to be released. • Glucagon action reduces glucose entry into cells, increases activity of fat-oxidation enzymes, inhibits fat-storage enzymes Overconsumption of carbohydrates drives most obesity A New Fat Storage Pathway • Acylation Stimulation Protein (ASP) ASP • Also secreted by fat cells • Can increase LPL activity, making fatty acids available for transport into fat cells • Increases the expression of glucose transporters in fat cells, allowing more glucose to enter cells • Stimulates production of triglycerides in the fat cells • Works like insulin but is generated by fat cells, not by carbohydrate ingestion • What stimulates ASP? Chylomicrons have a role in stimulating ASP • When fat cells are exposed to chylomicrons, they generate ASP – Concentration-dep, time-dep. • Fat cells DON’T generate ASP in response to anything else known (glucose, vLDLs, HDLs, etc.) Summary • Eat fat, generate chylomicrons • Chylomicrons result in ASP secretion • ASP increases LPL activity so more fatty acids enter cells • ASP increases glucose transporters so more glucose can enter cells • Even without carbohydrate, fat can be stored. • BUT, chylomicrons are short-lived, quickly turn into vLDL that don’t stimulate fat storage. Why a High-Fat, Low-Carbohydrate Diet is Not a Starvation Diet Why People Can Still be Fat on a Low-Carbohydrate, High-Fat Diet BUT, the body has other feedback control mechanisms Result: ASP can lead to fat storage, but it is limited. • Most energy from dietary fat (in the absence of carbs) leads to fat being USED for energy, not stored. • May explain why low-carb diets are sometimes known to “stall” • Perhaps may be alleviated with a “fat fast” (but VERY dangerous) lean protein “Rabbit starvation” conduct only under doctor’s supervision, short-term Leptin • Released when fat cells expand from storing fat • Sensitizes the hypothalamus to the effects of hormones affecting satiety and GI activity • When fat cells store fat, they release leptin that suppresses your appetite Leptin, cont. • Leptin probably regulated by insulin in fat cells • Gary Taubes: A “downstream effect”, less important than insulin – Same probably true for ghrelin, adiponectin, etc. • d Leptin Deficiency • Knockout mice have huge appetite, become obese • Treatment with leptin reverses the effect • Cushing’s Disease – – Pituitary tumor that raises hormone cortisol • Cortisol causes compensatory secretion of insulin • Cortisol from sympathetic endocrine system, insulin from opposing parasympathetic endocrine system. • Patients can eat very little, exercise much, still be obese. Insulin levels can override leptin signals • If glucose dramatically lowered, brain senses the depletion, overrides leptin, causes you to be hungry • If you respond by eating more carbs Vicious circle What about studies that contradict the success of low-carb diets? • Hirsch and Leibel (then at Rockefeller) Evidence that Diet Alters Genes • Homma et al., 2008 • Mice: Group 1 – high-carb, low-fat diet 7 days Group 2 – low-carb, higher-fat • Researchers looked at Glucose Transport-1 gene (encodes the protein GT-1) – Giving carbs is like turning up the volume in this gene. The more glucose the mice ingest, the more GT-1 they need, so the more the gene gets a workout. – The GT-1 gene has histone proteins bound to it. – Under the high-carb conditions, these histones were more acetylated. • d Diet Can Change Your Genes • Diet composition isn’t likely to change sequence of DNA but can change structure. (epigenetic changes) • DNA or the proteins that bind to DNA can acquire or lose chemical tags (such as methyl groups or acetyl groups) • Changes can persist and can be passed on. • Why a mother’s diet during pregnancy can affect children. Negative Effects of Low-carb Diet • Wang et al. (Steven Lloyd’s lab in Birmingham) • Heart glycogen ↓ • ↑ heart injury with ischemia (O2 deprivation) – With ischemia, heart relies on glycolysis from glycogen • However, no ↑ risk of mycardial infarction or death in women (Halton et al., 2006) • Low-carb diet associated with many outcomes considered beneficial for ↓ risk of CVD (HDLs, TG, etc.) Positive Effects of Low-carb Diet • Weight loss • TAG ↓ (Foster et al., 2003; Samaha et al 2003) • HDL ↑ Genes associated with diabetes • Type 2 – Tenomodulin (TNMD) • Type 1 What is Diabetes? • Abnormally high blood sugar (The sugar is glucose – the primary building block that enters cells for energy) – Normal is 80-110 mg/dl (fasting) and up to 140 post-prandial (after meals) http://themedicalbiochemistrypage.org/diabetes.html http://www.fi.edu/learn/heart/healthy/images/large_glucose-insulinsupplies.jpg Why is High Blood Sugar a Problem? • Body tries to dilute the glucose – Cells become dehydrated, – increased thirst, urination • Glucose gums up proteins – causes mini-strokes in blood vessels – Links proteins in eyes cataracts, etc. – Hemoglobin (protein that carries oxygen to cells) hindered – HbA1c is glycosylated hemoglobin • Usually ~4-5% is normal http://knol.google.com/k/anne-peters/type-1diabetes/VxIOS9KU/QWqllQ# How Many People are Affected? • • • • 246 million worldwide India (40.9 million) China (39.8 million) U.S. (19.2 million) http://cdn.mapquest.com/mqatlasenglish/world – 18 million are type 2; 1 million are type 1 • Russia (9.6 million) • Germany (7.4 million). • Countries with highest prevalence in the adult population: – – – – – Nauru (30.7%) United Arab Emirates (19.5%) Saudi Arabia (16.7%), Bahrain(15.2%) Kuwait (14.4%). • Each year an additional 7 million people develop diabetes. Source: International Diabetes Foundation and Diabetes Statistics in the United States: NID http://www.idf.org/home/index.cfm?node=37 Statistics for Age Groups • In the U.S.: http://www.ehponline.org/docs/2003/111-13/focushead.jpg – Age 65+: 18.4 % of all people in this age group – Age 20-65 years or older: 8.2 % – Under age 20: 0.16% in 2007 but rising rapidly – 25% of obese kids are type 2 diabetics Source: Diabetes Statistics in the United States: NIDDK Classic Definitions of Diabetes • Type 1 – Pancreas makes insufficient insulin – Can result from autoimmune attack, genetic defect, trauma – Treated with insulin • Type 2 – Cells lose their insulin receptors, become “insulin-resistant” – Often due to constant oversecretion of insulin - Often mis-regulation by liver – Often related to obesity and high levels of carbohydrates in the diet – Pancreatic cells may become exhausted – Treated with insulin-sensitizers, beta cell stimulators, appetite suppressants, insulin http://www.insightempire.com/diabetes/diabetes1.jpg http://z.about.com/f/p/440/graphics/images/en/19818.jpg Type 1.5: Latent Autoimmune Diabetes in Adults (LADA) • Diagnosed later in life rather than in juveniles • Usually less severe • Antibodies to GAD65 protein, not islet cells http://www.phlaunt.com/diabetes/pics/ 183820531LADA.gif MODY: Mature-Onset Diabetes in the Young • Genetic form • Like LADA, usually diagnosed later in life • Like LADA, pancreas usually makes some insulin • Can be an insulin secretion problem Why is Insulin so Important? • Glucose doesn’t enter cells on its own. • Has to go through a “gate” – binds to a receptor protein that’s in cell membranes • Insulin “unlocks the gate” (binds to and opens the receptor) to let glucose into the cell. glucose Insulin + Receptor cell AND, Insulin also… • stimulates enzymes that lead to fat storage + cholesterol synthesis • Inhibits enzymes that lead to fat breakdown More insulin…..more energy storage (fat) Less insulin…less energy storage Insulin drives fat accumulation! From the following article: Metabolism: A higher power for insulin Fiona M. Gribble Nature 434, 965-966 (21 April 2005) doi: 10.1038/434965a Glucose absorbed from the intestine stimulates the release of insulin into the bloodstream, which in turn inhibits liver glucose production by both a classical direct pathway and a newly identified indirect pathway. The indirect pathway involves the opening of ATP-sensitive potassium ion channels (KATP channels) in the outer membranes of neurons in the hypothalamus, resulting in signal transmission to the liver through the vagus nerve. This contrasts with the concomitant inhibition of KATP channels in pancreatic cells that underlies the glucose-stimulated release of insulin. - Type 2 Diabetes Can Occur When Cells Lose Ability to “unlock the gate” • Inflammation may damage insulin receptors or fat cells may become too engorged. – Cells don’t respond to glucose as well • Pancreas may at first churn out more insulin – Hyperinsulinemia drives MORE fat storage. • Age/stress on pancreas take a toll. – (More refined carbs, more insulin needed) • Lack of exercise can contribute. – ↑ heart rate, ↑ muscle to help get glucose into cells http://www.wellnessalternativesstl.com/imagesnew/IR%20receptor%20site.JPG Human Adipose (Fat) Cells cross-section of a blood vessel • ~All fat cells made by end of adolescence • They can become so engorged that they no longer respond to insulin. http://www.proteinpower.com/drmike/wp-content/uploads/2008/05/human-adipose-tissue.jpg Stress and Diabetes • Stress causes: – ↓ insulin secretion. – release of glucocorticoids + hormones of the sympathetic nervous system. • epinephrine and norepinephrine, cortisol • These act on fat cells to make them more insulinresistant. – “Steroid diabetes” can be induced by glucocorticoid drugs. – “An exaggerated stress response is associated with less well-controlled diabetes.” (Robert Sapolsky, Why Zebras Don’t Get Ulcers) How is type 1 diabetes treated? • Insulin (pens or pumps) – Basal insulin (Lantus, Levemir) – Bolus insulin for meals (Humalog, Novolog, Regular) • Easy these days http://mhts.com.au/slides/insulin-pen.jpg http://assets.aarp.org/external_sites/adam/graphics/images/en/18035.jpg How is Type 2 Diabetes Treated? • Weight loss + exercise • Low-carb diet • Oral Drugs: insulin sensitizers and pancreas stimulators – Metformin/glucophage (biguanines) • Keep liver from dumping glucose – Sulfonylureas • Stimulate pancreas to produce insulin – Other insulin sensitizers • Insulin http://www.reinventioninc.com/images/email/exercise.gif Types of Insulins Humalog, Novolog Lantus Diabetes and Heart Disease: Low-density Lipoproteins (LDLs) • LDLs that damage arteries: – Small, dense LDL, (“type A”) – oxidized LDL – glycated LDL – All of these increase as blood sugar increases. Glucose Reacts with LDLs and LDL Receptors (Glycosylation) • Normally, LDL receptor proteins on liver cells remove LDL from the blood, tell the liver to stop making more LDL. • BUT, glucose can bind to the receptors AND to the LDL particle (glycosylation) so that LDL isn’t recognized by its receptors and LDLs aren’t cleared by the liver. Glycosylation can be Irreversible (Glycation) • Within ~24 hrs, glycosylation becomes irreversible . • (Glycolsylation becomes glycation). • Proteins become AGEs (Advanced Glycation End products) • Reaction can happen with lots of proteins, not just LDLs. Advanced Glycation End products (AGEs) Form Plaques • AGEs accumulate , can be incorporated into the walls of arteries, become sticky, form fatty deposits called atherotic plaques. • Other glycated proteins stick to the plaques clots, etc. Glycated Proteins Keep LDL High • Since liver LDL production cannot be turned off by the glycosylated/glycated LDL and LDL receptors, the liver continues to make MORE LDL. Other Contributions to Heart Disease • White blood cells called macrophages ingest glycated LDL + proteins – swell up with LDL become large “foam cells” – Foam cells bind to sticky artery walls, disrupt them • • • • Normally, smooth muscle in arteries prevents rupture of plaques. If nerve cells die (as in diabetic neuropathy), the muscles calcify and can’t prevent rupture of plaques. Ruptured or loose plaques can block blood vessels and cause heart attacks. Heart attacks are also caused by individual tendency of blood to clot (form a thrombus) . – Factors that enhance clotting include fibrinogen and factor VII – Lipoprotein(a), inhibits the destruction of small thrombi before they become large enough to cause a heart attack. • All of these factors have been found to increase in people with chronically high blood sugars but they tend to normalize when blood sugars become normal. Facts About Heart Disease • 50% heart attacks in people with normal cholesterol • Best drug to reduce heart attacks is aspirin doesn’t affect cholesterol • Most dangerous plaques aren’t large but are the most prone to rupture. Russell Ross’s Hypothesis: Inflammation Causes Heart Disease • 1970’s theory • Shown in 1990’s when marker for “silent” inflammation found: C-reactive protein (CRP) • CRP produced by liver in response to inflammation Fat Cells and Inflammation • Pro-inflammatory cytokines produced by fat cells make them resistant to inuslin Lessons I’ve Learned • • • • • • • • • I attribute my success to God, my spouse, my family and my friends. Having diabetes is mostly okay. Sometimes it’s very hard. Exercise ROCKS! It is SO helpful to go for a walk or exercise after a meal (makes insulin work better). Carbohydrate restriction helps with control. Record-keeping is essential for identifying what works/doesn’t work. On-line forums are super helpful for emotional support, wisdom from successful diabetics. SOME books are helpful. (see next slides) I’m thankful for SOME health care professionals who respect my reading/research/knowledge. Some dieticians are helpful, some are COMPLETELY NOT. – Find dieticians who keep up with research, not ones who rely on old out-of-date guidelines. To be a good friend to diabetics: • Ask what they can eat. • For a sure-bet treat, give a diabetic an 85% Lindt dark chocolate bar, nuts, cheese, sugarfree jello, or Cheesecake Factory 6-carb cheesecake, NOT “sugar-free” (almost never is) or fat-free (high in carbs) garbage. • The ADA does a mediocre job of helping diabetics be successful and does not contribute much to research. • Lee Iacocca is DA MAN! He DOES contribute to much to research. Contributions should go to his foundation!!!!!! Recommended Reading • For type 2 diabetes treatment and prevention • For the biochemistry behind carbohydrate control – Atkins’ Diabetes Revolution by Dr. Mary Vernon • For type 1 and/or type 2 treatment – Dr. Bernstein’s Diabetes Solution by Dr. Richard Bernstein – Diabetes 101 by Jenny Ruhl – Protein Power by Drs. Michael and Mary Eades – Good Calories, Bad Calories by Gary Taubes World Sugar Consumption in Millions of To Year 1800 1850 1880 1890 1900 1950 1970 1990 2000 Medscape J Med. 2008; 10(7): 159. Published online 2008 July 9. Copyright ©2008 Medscape Sucrose 0.25 1.5 3.8 5.2 11.0 35.0 70.0 110.0 128.0 Fructose 0.125 0.75 1.9 2.6 5.5 17.5 35.0 55.0 64.0 One Wrong Statement • 1988, Surgeon General C.Everett Koop: – The American diet is too high in fat, and fat causes coronary disease – “The depth of the science base underlying its findings is even more impressive than that [Surgeon General’s report] for tobacco and health in 1964.” • d How did the Medical Community Get it Wrong? • Information cascade – starts as a guess then is repeated so often it becomes fact • Imagery coupled with misunderstanding – fat clogging pipes • History Ancel Keyes • 1950s, thought that heart disease was increasing because Americans were eating more fat than their ancestors had. • True? • 1. Antibiotics, etc – people living longer, contracting heart disease • 2. 19th century Americans ate a LOT of fat and meat • 3. Hunter-gatherers at as much or more fat than today’s Americans • Comparied diets and heart disease in Japan, the U.S., + 4 countries, found correlation with fat and heart disease in this group of 6 • Subsequent studies of 22 countries show no correlation – (“French paradox” , etc) • 1957: American Heart Association: the correlation “does not stand up to critical examination.” • 1960, changed mind, (Dr. Keyes on the committee) History of the Low-Fat Food Pyramid • Keyes’ proclamation taken up by Senate Committee led by George McGovern • Report written by non-scientist relying on advice from one nutritionist, Mark Hegsted • Assistant Agriculture Secretary Carol Tucker Foreman hired Dr. Hegsted to write dietary guidelines for the Dept of Agriculture food pyramid Clinical Trials • No correlation between low-fat diets and a lack of coronary disease Result • Americans replaced fat with carbohydrates. USDA 2010 Dietary Recommendations Thanks to Dr. Richard Feinman, Nutrition & Metabolism Society The Key Enzyme in Cholesterol Synthesis is Regulated by INSULIN What textbooks say… • Gropper and Smith, Advanced Nutrition and Human Metabolism – “Despite years of investigation, the mechanism by which hypercholesterolemic fatty acids exert their effects has not been conclusively defined.” – “Contrary to widespread belief, changing the amount of cholesterol in the diet has only a minor influence on blood cholesterol concentration in most people. This is because compensatory mechanisms are engaged, such as HDL activity in scavenging excess cholesterol and the down-regulation of cholesterol synthesis by dietary cholesterol.” • Gurr, Harwood, Frayn, Lipid Biochemistry: – “The mechanism for the effects of different dietary fatty acids on serum cholesterol concentration is not clearly understood.” Why I think Normal Blood Sugar is Crucial to Weight Loss Malonyl-CoA, a Fat-Storage Metabolite, Responds to Blood Glucose Levels • Malonyl-CoA ↑ when blood glucose ↑ • High levels shift fat toward storage – Stimulates fatty acid synthase • Converts carbohydrates to fat – Inhibits CPT-1 that transports fat into mitochondria • When blood glucose is low…shift toward fat burning. – CPT-1 is uninhibited, moves fat into mitochondria Normal Blood Sugar • ~ 4 g or ~1 teaspoon (according to M. Eades) • ~85-110 mg/dl Sugar Content of Foods Mountain Dew 20 oz (590 ml) Bottle Sugars, total: 77g ; 290 calories Apple Juice 8 oz (240 ml) Serving Sugars, total: Calories, total: 26g 120 1 L (34 oz) Bottle Sugars, 124g Calories: 440 16 oz Bottle Sugars, total: Calories, total: www.sugarstacks.com 52g 240 Note that “sugar” means total carbohydrate. World Sugar Consumption in Millions of To Year 1800 1850 1880 1890 1900 1950 1970 1990 2000 Medscape J Med. 2008; 10(7): 159. Published online 2008 July 9. Copyright ©2008 Medscape Sucrose 0.25 1.5 3.8 5.2 11.0 35.0 70.0 110.0 128.0 Fructose 0.125 0.75 1.9 2.6 5.5 17.5 35.0 55.0 64.0 Hemoglobin http://rjr10036.typepad.com/.shared/image.html?/photos/uncategorized/hemoglobin.jpg http://rjr10036.typepad.com/.shared/image.html?/photos/uncategorized/leafy.jpg http://rjr10036.typepad.com/.shared/image.html?/photos/uncategorized/09_gallery_ornish.jpg http://rjr10036.typepad.com/.shared/image.html?/photos/uncategorized/proteinspread.jpg The Duke Study confirms that the Atkins Diet is likely the best solution to Type 2 Diabetes. The majority of study subjects in the Duke study were able to eliminate or reduce medications. Contrary to the common myth, most subjects were able to remain compliant beyond six months. Overall for people with Type 2 Diabetes following Atkins in this new Duke study, cholesterol levels stabilized, dangerous triglycerides were reduced and good cholesterol increased. http://rjr10036.typepad.com/.shared/image.html?/photos/uncategorized/295111 332_59f8553b86_o.jpg http://rjr10036.typepad.com/.shared/image.html?/photos/uncategorized/arnie_1.jpg Studies of the Inuit http://rjr10036.typepad.com/.shared/image.html?/photos/uncategorized/inuit.jpg http://www.proteinpower.com/drmike/wp-content/uploads/2007/10/ancel-keys.jpg Exercise will extend your life by the same number of hours you spent exercising." http://themedicalbiochemistrypage.org/diabetes.html As heart-disease rates were skyrocketing in the mid-1900s, consumption of animal fat was going down, not up. Consumption of vegetable oils, however, was going up dramatically. Half of all heart-attack victims have normal or low cholesterol. Autopsies performed on heart-attack victims routinely reveal plaquefilled arteries in people whose cholesterol was low (as low as 115 in one case). Asian Indians - half of whom are vegetarians - have one of the highest rates of heart disease in the entire world. Kids who were diagnosed as suffering from ADD have been successfully treated by re-introducing natural saturated fats into their diets. Your brain is made largely of fat. http://www.fathead-movie.com/NoBolognaFacts.htm High protein diets (30% of total energy intake) vs. low-fat, low-protein diet (10% protein) 6 month duration increased diet-induced thermogenesis (DIT) increased satiety higher sleeping metabolic rate average 7.6 pounds more weight lost decreased insulin more mobilization of fatty acids Current Opinion in Endocrinology, Diabetes & Obesity.� Brehm, Bonnie J; D'Alessio, David A.� Benefits of high-protein weight loss diets:� enough evidence for practice? Current Opinion in Endocrinology, Diabetes & Obesity. 15(5):416-421, October 2008. A 12 month trial reports that high protein diets account for the largest beneficial effects on HDL, triglycerides and blood pressure compared to lower protein diets, however, the results of total cholesterol and LDL were �less favorable.�� The effects on LDL and total cholesterol may be attributed to lower fiber consumption in the high protein group.� Two recent studies show that after one year, patients on higher protein diets had a significantly sustained reduction in cardiovascular risk factors, specifically fasting glucose levels, lipids, and CRP. Current Opinion in Endocrinology, Diabetes & Obesity.� Brehm, Bonnie J; D'Alessio, David A.� Benefits of high-protein weight loss diets:� enough evidence for practice? Current Opinion in Endocrinology, Diabetes & Obesity. 15(5):416-421, October 2008. The effects of high protein intake on glycemic control.�� Benefits shown in several major studies include �improved insulin sensitivity or lower fasting insulin concentrations following dietary intervention.�� While these results are promising, it is still not clear if these benefits are specifically from the high protein diet, weight loss, or a combination of the two.� This study also notes that increased glucose metabolism and insulin sensitivity resulting in weight loss may counteract the harmful effects that amino acids may have on insulin sensitivity, however, this concept requires further investigation. Gary Taubes: • “My NYT article noted that copious evidence exists in contradiction to the lowfat-is-good-health hypothesis, while the alternative hypothesis may fit the data better but has never been adequately tested. “ • Squires apparently believes that learned expert committees and government agencies are incapable of arriving at biased and incorrect conclusions on subjects of national importance, or at least on this particular subject. I believe they can and, in this case, that they probably did. • Squires faults me for ignoring "high-quality," "significant and well-known peer reviewed research," including the 2000 Report of the Dietary Guidelines Advisory Committee (DGAC). The report cites "many years of epidemiological research" supporting the dangers of saturated fats, although the one relevant article both it and Squires discuss in detail was not published in a peer-reviewed journal, begging the question of whether it constitutes "high-quality research." This in turn raises the question: If there is so much significant high-quality research out there, why do the DGAC and Squires rely on non-peer-reviewed literature to make their case? • lard, for instance, has more "good fats" -monounsaturated and polyunsaturated -than "bad fats" -- saturated. Thus, the overall effect on cholesterol profiles of eating lard rather than refined carbohydrates or starches would be at worst harmless. • Squires says I reject the findings of The 1998 Clinical Guidelines on the Identification, Evaluation and Treatment of Overweight and Obesity in Adults, due to my "negative personal assessment of the panel's chair." This is incorrect. Nor do I reject the findings. The report actually concludes that low-fat diets do not work. It says reducing calories is crucial to successful weight loss, something we both agree on, then says on page 95 in English "Reducing dietary fat alone without reducing calories is not sufficient for weight loss. However, reducing dietary fat, along with reducing dietary carbohydrates can facilitate caloric reduction." • Squires says I disagree with the findings of the Diabetes Prevention Study. This is incorrect. I disagree with Squires's interpretation of the findings: that the DPP data are compelling evidence for the efficacy of low-fat diets. The DPP reported that low-fat low-calorie diets and 150 minutes of weekly exercise produced a 5 percent to 7 percent weight-loss (15 to 21 pounds for a 300-pounder) over six years. Because the study included no control group for the dietary arm, for all we know exercise and a low-carbohydrate low-calorie diet might have produced much greater weight loss. • Even small dietary trials can easily cost several hundred thousand dollars and require entire research teams. The DPP estimated a cost of $1,075 just to recruit each participant. • Fleming reports on a one-year trial of 100 participants and four diets with extensive follow-up. His paper, however, has no co-authors; it acknowledges no source of funding, nor any nurses, dietitians or technicians who might have helped. Fleming identifies himself as Medical Director of Preventive Cardiology, the Camelot Foundation at the Fleming Heart & Health Institute, but if his Web site or receptionist are any indication, he is the sole member of each of those. • Me:” Very unlikely in my opinion (and in that of many of my colleagues) for one person to have accomplished this study” – Angiology. 2000 Oct;51(10):817-26. Links – The effect of high-protein diets on coronary blood flow. – Fleming RM. – The Fleming Heart and Health Institute and the Camelot Foundation, Omaha, Nebraska 68114, USA. [email protected] – Prev Cardiol. 2002 Summer;5(3):110-8. Links – Erratum in: • Prev Cardiol 2002 Fall;5(4):203. – The effect of high-, moderate-, and low-fat diets on weight loss and cardiovascular disease risk factors. – Fleming RM. – Section of Preventive Cardiology, The Camelot Foundation at The Fleming Heart & Health Institute, and the Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE 68114, USA. rfmd1@... • I am sure Feinman enjoyed the following statement: • "Regardless of the dietary program used, the key is the same; one must reduce caloric intake to lose weight. The second law of thermodynamics still applies!" Second? That Fleming guy is even more clueless than I assumed ealier. • AM Eric Westman’s comments • Re: Fleming RM. Prev Card 2002;5:110-118 Comments This paper is so seriously flawed that no conclusions can be made about any of the recommended diets. There are several violations of standard clinical research practice methods: 1) Discrepancy of addition in the abstract: 28+16+38+38 = 120 not 100 as stated. 2) It makes no sense to mention "non-significant" results in the abstract, or highlight them in the text of the manuscript. The abstract reads: "There were nonsignificant reductions in HDL-C in those on MF (-1.5%) and HF (-5.8%)." A nonsignificant finding means that the findings were likely to be there based on chance alone. Stating the percentage changes when the statistic is nonsignificant is very misleading, and definitely not common practice. Trends are sometimes mentioned (p<0.10). I have never seen so many nonsignificant findings mentioned in an abstract or in the text. Is this a peer-reviewed journal? 3) Randomization: This statement makes no sense: "Patients had to commit to staying on the dietary program for a minimum of 1 year and were randomly assigned to one of the four dietary regimens based upon dietary preferences." I do not understand how you can randomize based on dietary preference. The whole concept of randomization is based upon making the allocation of subject unbiased. 4) Treatment: While the author lists the dietary regimens, there is no documentation AT ALL of what the patients actually consumed. There is no measure of adherence to the regimens to give confidence about use of any of the dietary regimens. Monthly return visits are generally too infrequent to ensure adherence: most investigators have patients return every week or every two weeks. 5) As to the question of whether the High Fat diet represents the Atkins Diet: there is no food record documentation or urinary ketone measurement to support the claim that the High Fat diet was the Atkins Diet. Because there was very little weight loss, and no change in triglycerides, these people were probably not following the Atkins Diet. 6) Analysis: It is standard practice to list the sample size in tables; there are no sample sizes listed. Table II lists percentage changes without any statistical tests to assist the reader in knowing which changes were likely to be present beyond chance. Were there any drop-outs? How were the drop-outs handled in the analysis? 7) Data interpretation: I've never seen such a discrepancy in a published paper before. The abstract reads, "Patients on HF [high fat] had a 6.0% (NS) increase in LDL-C." and then concludes "Only patients following HF diets showed a worsening of each cardiovascular disease risk factor (LDL-C, TG, TC, HDL-C, TC/HDL ratio, Ho, Lp(a), and fibrinogen)." The first statement DIRECTLY CONTRADICTS the second statement. The author clearly does not understand why statistics are used. This makes me question now how the statistics were generated. Was a statistician involved in the study? In my opinion, this paper provides no relevant information. “More science and less zealotry” -Dr. Mary Vernon World Sugar Consumption in Millions of Tons Year Sucrose Fructose 1800 0.25 0.125 1850 1.5 0.75 1880 3.8 1.9 1890 5.2 2.6 1900 11.0 5.5 1950 35.0 17.5 1970 70.0 35.0 1990 110.0 55.0 2000 128.0 64.0 Medscape J Med. 2008; 10(7): 159. Published online 2008 July 9. Copyright ©2008 Medscape • • Vos et al.. obtained information from the Health and Nutrition Examination Survey, conducted from 1988 to 1994. It is clear from the analysis that Americans are getting a lot of fructose in their diet. – – – – – Mean daily consumption of fructose was 54.7 g/d Range 38.4 to 72.8 g/d 0.2% of total daily caloric intake. Consumption was highest among adolescents (12- to 18-year-olds), who consumed 72.8 g/d, or more than 12% of their total calories from fructose. The largest source of fructose was sugar-sweetened beverages (30%), followed by grains (22%) and fruit/fruit juice (19%). Vos MB, Kimmons JE, Gillespie C, Welsh J, Blanck HM. Dietary fructose consumption among US children and adults: The Third National Health and Nutrition Examination Survey. Medscape J Med. 2008 • Dietary fructose was found to predict an increased level of low-density lipoprotein cholesterol in children.[6] Aeberli I, Zimmermann MB, Molinari L, et al. Fructose intake is a predictor of LDL particle size in overweight schoolchildren. Am J Clin Nutr. 2007;86:1174–1178. • • Fructose, unlike other sugars, increases serum uric acid levels. Nakagawa and colleagues [7] proposed that this happens when fructose is metabolized in the liver, its major organ for metabolism. Adenosine triphosphate (ATP) is used by the enzyme phosphofructokinase to phosphorylate fructose to fructose-1-phosphate. The adenosine-5′-diphosphate that is thus formed can be further broken down to adenosine-5′-monophosphate, then to inosine 5′-phosphate, and finally to uric acid. Thus, the metabolism of fructose in the liver leads to the production of uric acid. • These authors proposed that the high levels of uric acid could set the stage for advancing cardiovascular disease by reducing the availability of nitric oxide, which is crucial for maintaining normal blood pressure and for maintaining normal function of blood vessel walls (endothelium).[7] Nakagawa T, Hu H, Zharikov S, et al. A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol. 2006;290:F625–F631. Framingham Study: Individuals consuming at least 1 soft drink/d had a higher prevalence of Metabolic Syndrome (odds ratio, 1.48; 95% CI, 1.30–1.69) and an increased risk for Metabolic Syndrome over 4 years of follow-up. Dhingra R, Sullivan L, Jacques RF, et al. Soft drink consumption and risk of developing cardiometabolic risk factors and the metabolic syndrome in middle-aged adults in the community. Circulation. 2007;116:480–488. The most recent relationship shows that fructose intake is directly related to risk for gout in men. Choi HK, Curran G. Soft drinks, fructose consumption and the risk of gout in men: prospective cohort study. BMJ. 2008;336:309– 312 Low-carb diets lead to larger LDL particles • Higher HDLs and lower TGs correlate with larger LDL particles • Larger LDL particles are less likely to cause heart disease How is Type 2 Diabetes Treated? • Weight loss + exercise • Low-carb diet • Oral Drugs: insulin sensitizers and pancreas stimulators – Metformin/glucophage (biguanines) • Keep liver from dumping glucose – Sulfonylureas • Stimulate pancreas to produce insulin – Other insulin sensitizers • Insulin http://www.reinventioninc.com/images/email/exercise.gif Thiazolidinediones (Glitazones) • Bind to PPARs (peroxisome proliferator- activated receptors) – Normal receptors for PPARs are fatty acids and eicosanoids – Upregulate a host of genes resulting in: • Decreased insulin resistance • Inhibition of VEGF-induced angiogenesis • Decreased leptin (leads to increased appetite) • Decreased IL-6 and other cytokines, interleukins • Increased adiponectin *withdrawn due to hepatitis Rosiglitazone (Avandia) Pioglitazone (Actos) Troglitazone* (Rezulin), How do these drugs increase insulin sensitivity? • Mechanism to be determined… • May depend on reducing levels of circulating nonesterified fatty acids (NEFA), reducing lipolysis, increasing glyceroneogenesis and increasing reesterification of NEFA in TAGs in adipose tissue PPARs www.wikipedia.org Side effects • Fluid retention in 5% of patients heart failure risk for some Types of Insulins Humalog, Novolog Lantus Fat Metabolism Fat Breakdown Lipases (3 of them) hydrolyze triglycerides to glycerol + 3 FA – Glycerol Glyceraldehyde-3-phosphate (G3P) • Then G3P goes to glycolysis or gluconeogenesis – Fatty acids oxidized to acetyl CoA • Acetyl CoA then enters citric acid cycle or ketosis Lipolysis • Three lipases break down TAGs: 1. Triacylglycerol lipase - (hormone-sensitive; activated by epinephrine [adrenaline] and glucagon) 2. Diacylglycerol lipase 3. Monoacylglycerol lipase • Hormonal Control: – Lipolysis activated by glucagon and epinephrine (low blood sugar/immediate energy needs. – Lipolysis inhibited by insulin. Fatty Acid Activation and Transport • Liver cells take fatty acids from the bloodstream. • FA are activated to form acyl-CoA – If short-chain FA, activated in mt – If longer-chain FA, activated in ER – Longer-chain FA can’t diffuse across mt membrane, require carrier CARNITINE Carnitine • Derivative of Lysine • Found in red meats, dairy products, also synthesized by body • People w/low carnitine levels are weak, irritable, also have lipid deposits in muscles. Fatty Acid Oxidation • In mt, even # FA broken down by βoxidation. – (The β-C is attacked) • Broken down to acetyl CoA 1. 2. 3. 4. Dehydrogenation Hydration Oxidation Thiolysis • Req NAD+ and FAD+ Fats: New Nutritional Paradigms http://www.tcd.ie/Communications/assets/img/omega3 .jpg http://media.photobucket.com/image/lard/SmileyMags/Humor/Signs/l ard.jpg From Dr. Michael Eades’ Blog As we were eating breakfast on the last morning, a man was eating alone while reading the paper at the table next to us. He looked to be about 70 or so and was fairly thin with a pot belly. He had on two pressure stockings on his lower legs and bruising in the crook of one of his arms from where, obviously, blood had recently been taken. Watching him eat, I created an entire story about him that I’ll bet is not too far from the mark. Even if it is not accurate in this man’s case, it is totally (and sadly) accurate in many thousands of others. The man was eating a bowl of oatmeal. He had a glass of skim milk so fat free it was almost blue that he poured little bits of into his cereal from time to time. Along with his oatmeal, he was eating one of the giant pieces of toast the restaurant serves. He took one pat of butter (I assume there was no margarine available) and cut it in half. He carefully spread one half pat on one half of his toast then loaded it with an entire individual serving of jelly. After eating the first half piece of toast, he prepared the second half the same way and ate it. The only fat he got from his entire meal was that that came from that one pat of butter. Based on the size of the bowl of oatmeal and the size of the toast (and the skim milk), I calculated that this guy consumed about 100 grams of carbohydrate. (Thirty grams in the oatmeal; at least 30 in the toast; 15 in each container of jelly; and about 10 in the skim milk.) I imagine (here is where I’m speculating) that he has elevated cholesterol and has been told by his doctor to watch his fat. And he is complying. He got a whopping 4 grams of fat in his one pat of butter (36 calories-worth) while getting 100 grams of carb in the rest of his meal (400 calories-worth). The tiny bit of fat he got contained short-chain fatty acids that are immune enhancing whereas the 100 grams of carb he got provided really no health benefit. Since the 100 grams represents 20 times the amount of sugar circulating in his blood, his pancreas had to release a large amount of insulin to deal with it. His pot belly indicates that he is already insulin resistant with an abdomen full of visceral fat, so he no doubt secreted a lot more insulin than a person without insulin resistance. This excess insulin help him store fat in his liver, increase his level of visceral fat, ratchet up the inflammatory process, injure his blood vessels even more and increase his risk for heart disease, the very thing his doctor was trying to prevent by putting him on a low-fat diet. How much better off this guy would have been had he joined me in the Mike’s Special. But, his cardiologist, I’m sure, would have been apoplectic. A sad state of affairs indeed. Vegetable Oils • In the past: vegetable seed oils expensive to produce – Most fats were from butter, lard, olive oil (low amts omega-6 FA) • 1920s industrial processing of vegetable seeds (soybeans, corn) made these oils cheap. – Subsidized from ‘20’s on most calories per acre • 2007: $20 billion/yr in subsidies – Comparitively : $0 subsidies for fruits, vegetables • Vegetables oils are rich in omega-6 FA Sears, B. Toxic Fat, 2008 Soybean: http://vinniey.files.wordpress.com/2006/10/4216246844.jpg Rapeseed: (Canola oil) http://i.treehugger.com/images/2007/10/24/rapeseed%20 oil.jpg Omega-6 vs. Omega-3 Fats (ω-6 vs. ω-3) • Until ~1920s, ratio of omega-6-to omega-3 fats ~2:1. – Pre-1920’s diet: more fish, more cod liver oil, ~no vegetable oils – Post-1920’s diet: more margarine, Crisco, soybean oil, corn oil, vegetable shortening • Current typical American ratio: 20:1 Sears, B. The Anti-Inflammation Zone, http://www.nutritionexpress.com/images/Articles/americanconsume2 much.gif What’s Wrong with Omega6’s? • Building blocks for arachidonic acid • Increase inflammation What’s wrong with inflammation? • Acute (after injury good) • Silent/Chronic (bad) – destabilizes cholesterol deposits on arteries of heart CVDisease – attacks brain cells, nerve cells Alzheimer’s – triggers cell division cancer Dr. Paul Dudley White • Eminent cardiologist, pioneer in electrocardiograms • Wrote twelve books and more than 700 scientific articles. • Author of the famous text Heart Disease (1931) -classic in the field • Cardiologist to President Eisenhower "See here, I began my practice as a cardiologist in 1921 and never saw a myocardial infarction patient until 1928. Back in the MI-free days before 1920, the fats were butter, whole milk and lard, and I think we would all benefit from the kind of diet that we had when no one had ever heard of corn oil." http://www.spacedoc.net/heart_disease_carbohydr ate.htm Three Pro-inflammatory Hormones 1. Insulin 2. Cortisol 3. Pro-inflammatory eicosanoids What are Eicosanoids? • Hormones that control inflammation – Work with inflammation cells (neutrophils, macrophages) – Cause release of cytokines – Involved in cell repair – Can be pro-inflammatory or anti-inflammatory – Made by every cell in the body • Made from Arachidonic Acid (a 20-Carbon fatty acid) Eicosanoids Why Omega-6 Fatty Acids Should be Limited • Vegetable oils largely contain: – Omega-6-Linoleic Acid converts to Gamma-Linolenic Acid (can make good or bad eicosanoids) – GLA Dihomo-gamma-linolenic acid (DGLA) – still good, starting point for good eicosanoids DGLA (Dihomo-gamma-linolenic acid) Delta-5-Desaturase (D5D) Activated by insulin Inhibited by EPA (in fish oil) Inhibited by lignans (in sesame oil) Arachidonic AcidInhibited by tumeric Good Eicosanoids Bad Eicosanoids Insulin • Allows nutrients (glucose, amino acids) to enter cells • Drives fat storage, inhibits fat breakdown – Activates fatty acid synthase, glycogen synthase – Inhibits hormone-sensitive lipase, glycogen phosphorylase • Increases levels of Interleukin-6 (IL-6), a proinflammatory cytokine that leads to formation of C-reactive protein (CRP) Cortisol: The “Stress Hormone” • Hormone produced during stress - to lower levels of pro-inflammatory cytokines • Increases conversion of amino acids to glucose (gluconeogenesis) • Body has to churn our more insulin drives fat storage drives inflammation • Higher levels associated with more abdominal fat http://fastweightloss85.files.wordpress.com/2009/06/cortisol_i mage.jpg Sears, B. The Anti-Inflammation Zone, 2005 Fat Cells are a Source of Inflammation • Fat cells sequester Arachidonic Acid (AA) – (May be a protective mechanism to keep AA out of other cells) • If AA levels high enough, ↑ production of pro-inflammatory eicosanoids – These can lead to release of more proinflammatory cytokines • Interleukin-6 (IL-6), tumor necrosis factor (TNF) • More fat more inflammation Sears, B. The Anti-Inflammation Zone, 2005 Interleukin-6 (IL-6) • A cytokine • Chronically elevated in obesity-related pathologies • Partly derived from adipose tissue • Regulated by proinflammatory prostaglandins (also produced by adipose tissue) • *low-dose aspirin lowered IL-6 in humans and in mice. Ogston, N.C. et al., Int. J. Obes. 2008, 32, 1807-1815 Russell Ross’s Hypothesis: Inflammation Causes Heart Disease • 1970’s theory • Shown in 1990’s when marker for “silent” inflammation found: C-reactive protein (CRP) • CRP produced by liver in response to inflammation • CRP levels don’t singly correlate with heart disease but do provide marker of general inflammation • Levels should be under 1-2 mg/L Sears, B. The Anti-Inflammation Zone, 2005 Inflammation and Cancer • Macrophages and other inflammatory cells create free radicals that can damage DNA • Pro-inflammatory cytokines are associated with tumor formation and metastasis. Dietary Sources of AA • Egg yolks • Animal protein Fish Oil • Health benefits supported by multiple, robust, well-designed studies – Negative correlation with cancer, heart disease, immune disorders, brain disorders… • Yes, fish have mercury, PCBs, dioxins • Larger fish have more contamination • Japanese (high-fish diet) have high levels of these toxins (approaching upper limits) Sears, B. The Anti-Inflammation Zone, 2005 Refined Fish Oil/Fish Oil Substitutes • The major omega-3 FAs found in fish are EPA (eicosapentanoic acid) and DHA (docosahexanoic acid) • International Fish Oil Standards (IFOS) program www.ifosprogram.com – IFOS Standards: Hg < 10 ppb; PCBs <45 ppt; dioxins < 1 ppt Sears, B. The Anti-Inflammation Zone, 2005 Poor Man’s Test for SufficientlyRefined Fish Oil • Few teaspoons of liquid into a cup • Crack open a few capsules, put them in liquid • Put mix in freezer for a few hours • Mix should NOT freeze rock-solid if relatively pure. Sears, B. The Anti-Inflammation Zone, 2005 How Much Fish Oil? • Dr. Barry Sears: 2.5-10+ g/d of EPA/DHA – No chronic disease: 2.5 g/d – Obesity, CVD, type 2 diabetes: 5 g/d – Chronic pain: 7.5 g/d – Neurological disease: > 10 g day • Very high doses may increase risk of stroke Sears, B. The Anti-Inflammation Zone, 2005 Monounsaturated Fats are Inflammation-Neutral • Can’t be made into pro-inflammatory eicosanoids • In nuts, olive oil, avocados Sears, B. The Anti-Inflammation Zone, 2005 Diacylglycerol Consumption • Fat oxidation and resting metabolic rate significantly greater compared with TAG oil. Hibi et al., Int. J. Obesity, 2008, 32, 1841-1847 Two months later, the JAMA published an editorial in response to Kuo’s article suggesting that the “almost embarrassingly high number of researchers who boarded the ‘cholesterol bandwagon’ had done a disservice to the field. This fervent embrace of cholesterol to the exclusion of other biochemical alterations resulted in a narrow scope of study. Fortunately, other fruitful approaches have been made possible in the past few years by identification of the fundamental role of such factors as triglycerides and carbohydrate metabolism in atherogensis.” References – a sampling Babcock, T. et al. “Eicosapentaenoic acid: an anti-inflammatory omega-3 fat wit Clinical applications”, Nutrition, 2000, 16, 1116-1118. Barham, J.B. et al., “Addition of EPA to GLA supplemented diets prevents serum Arachidonic Acid accumulation in humans, J. Nutr. 2000, 130, 1925-1931. Cho, H.P. et al., “Cloning, expression, and fatty acid regulation of human delta 5 Desaturase, J. Biol. Chem. 1999, 274, 37335-37399. Clarke, S.D., “Polyunsaturated fatty acid regulation of gene transcription: a Mechanism to improve energy balance and insulin resistance.” Br. J. Nutr. 2000, 83, S59-S66. El Boustani, S., et al., “Direct in vivo characterization of the delta-5-desaturase Activity in humans by deuterium labeling: effect of insulin. Metabolism, 1989, 38, 315-3321. Phinney, S. “Potential risk of prolonged gamma-linolenic acid use”, Ann. Intern Med. 1994, 120, 692. References, - cont. Robertson, R. et al., “Inhibition of in vivo insulin secretion by prostaglandin E1” J. Clin. Invest. 1974, 54, 310-315. Serhan, C.N. “Lipoxins and aspirin-triggered 15-epi-lipoxin biosynthesis: an update and role in anti-inflammation and proresolution.” Prostaglandins and Other Lipid Mediations 2002, 69, 433-455. Shimizu, S. et al. “Sesamin is a potent and specific inhibitor of delta 5 desaturase in polyunsaturated fatty acid biosynthesis.” Lipids, 1991, 26, 512-516. Yam, D.B. et al., “Diet and disease: the Israeli paradox: possible dangers of a high omega-6 polyunsaturated fatty acid diet.” Isr. J. Med. Sci. 1996, 32, 1134-1143. USDA 2010 Dietary Recommendations Thanks to Dr. Richard Feinman, Nutrition & Metabolism Society