Download Type 2 Diabetes

DIABETES
MELLITUS
What is diabetes mellitus?
 The majority of intake of food is
converted into glucose.
 The pancreas produces the insulin
hormone, which help the organism to
take advantage of glucose.
 In persons with diabetes, the insulin does
not work. Therefore, the sugar and the
fat increase in the blood.
The World Wide Epidemic:
Prevalence of Diabetes
5%
8%
3%
14%
4%
The Worldwide Epidemic:
Diabetes Trends
Millions with Diabetes
400
370
350
300
300
250
221
177
200
135
150
100
50
30
0
1985
1995 2000
Sources: www.who.int
www.idf
Zimmet P. et al Nature: 414, 13 Dec 2001
2010
2025 2030
PHYSIOLOGICAL
IMPACT
th
 6 leading cause of death by disease
 Decreases life expectancy of middle-aged people
by 5-10 years
 2-4 x greater risk of death d/t heart disease
– Compounding factors include: duration of disease,
glycemic control, HTN, smoking, dyslipidemia,
decreased activity, and obesity
 Leading cause of blindness in 25-74 year olds
 Leading cause of non-traumatic amputations
 Responsible for 25-30% of all new dialysis
patients
DIABETES MELLITUS
Definition: a metabolic disorder in which
there is deficiency of insulin
production or resistance of organs to
the effect of insulin
DIABETES MELLITUS
 Diabetes is a disorder of metabolism--the way
our bodies use digested food for growth and
energy.
 Most of the food we eat is broken down into
glucose, the form of sugar in the blood.
 Glucose is the main source of fuel for the
body.

<http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm#what>
DIABETES MELLITUS
 After digestion, glucose passes into the
bloodstream, where it is used by cells for
growth and energy.
 For glucose to get into cells, insulin must be
present.
 Insulin is a hormone produced by the
pancreas, a large gland behind the stomach.

<http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm#what>
Regulation of Blood Sugar
Cori & Cori (1947)
Signal Transduction
Decreased
Tyrosine-kinase-linked receptor
High blood sugar Insulin
Liver
Blood Pancreas Hormone Glycogen
Low blood sugar Glucagon
Glycogen
synthase
Glucose
Glycogen
phosphorylase
GTP-protein-linked receptor
Increased
Juang RH (2004) BCbasics
Normal glucose homeostasis is tightly
regulated by three interrelated processes:
 (1) glucose production in the liver,
 (2) glucose uptake and utilization by
peripheral tissues, chiefly skeletal muscle,
 (3) actions of insulin and counterregulatory hormones (e.g., glucagon).
DIABETES MELLITUS
 NORMAL: When non-diabetic people eat, the
pancreas automatically produces the right
amount of insulin to move glucose from blood
into our cells.

<http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm#what>
DIABETES MELLITUS
 DIABETES: In people with diabetes, when
they eat, the pancreas either produces little
or no insulin, or the cells do not respond
appropriately to the insulin that is produced
(or both) => glucose builds up in the blood,
overflows into the urine, and passes out of
the body in urine => body loses its main
source of fuel even though blood contains
large amounts of glucose.

<http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm#what>
 Diabetes mellitus is not a single disease
entity but rather a group of metabolic
disorders sharing the common underlying
feature of hyperglycemia.
Hyperglycemia in diabetes
results from
 defects in insulin secretion,
 defects in insulin action,
 most commonly, both.
 The principal metabolic function of insulin
is to increase the rate of glucose transport
into certain cells in the body
 These are the striated muscle cells
(including myocardial cells) and, to a lesser
extent, adipocytes, representing collectively
about two-thirds of the entire body weight.
 Glucose uptake in other peripheral tissues,
most notably the brain, is insulin
independent.
 metabolic effects of insulin - anabolic, with
increased synthesis and reduced
degradation of glycogen, lipid, and protein.
 In addition - several mitogenic functions,
including initiation of DNA synthesis in
certain cells and stimulation of their growth
and differentiation.
Etiologic Classification of
Diabetes
 Type
1 Diabetes - Mellitus
β-cell destruction, leads to absolute









insulin deficiency
Type 2 Diabetes -Insulin resistance with relative insulin
deficiency
Genetic Defects of β-Cell Function
Genetic Defects in Insulin Processing or Insulin Action
Exocrine Pancreatic Defects
Endocrinopathies
Infections
Drugs
Genetic Syndromes Associated with Diabetes
Gestational Diabetes Mellitus
DM TYPE I
Auto-immune disease
Constitutes 5-10% of DM diagnosed in the
USA
Mostly appears in children and young adults
Develops as a result of auto-immune
destruction of beta-cells in the pancreas
Presents with polyuria, thirst, weight loss,
marked fatigue
Can be complicated by coma with ketoacidosis
•
<http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm#what>
DM TYPE II
 Most common form of diabetes
 Involves about 90-95% of people with DM
 Associated with:
–
–
–
–
–
–
older age
obesity
family history of DM
prior history of gestational diabetes
physical inactivity
ethnicity
•
<http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm#what>
DM TYPE II
 Patient with type II DM usually makes
enough insulin but the body cannot use it
effectively => insulin resistance
 Gradually insulin production decreases over
the following years
 Symptoms are similar to type I but develop
more gradually
•
<http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm#what>
Genetic defects of β-cell
function









Maturity-onset diabetes of the young (MODY),
caused by mutations in:
Hepatocyte nuclear factor 4α (HNF4A), MODY1
Glucokinase (GCK), MODY2
Hepatocyte nuclear factor 1α (HNF1A), MODY3
Pancreatic and duodenal homeobox 1 (PDX1), MODY4
Hepatocyte nuclear factor 1β (HNF1B), MODY5
Neurogenic differentiation factor 1 (NEUROD1), MODY6
Neonatal diabetes (activating mutations in KCNJ11 and ABCC8,
encoding Kir6.2 and SUR1, respectively) Maternally inherited
diabetes and deafness (MIDD) due to mitochondrial DNA mutations
(m.3243A➙G) Defects in proinsulin conversion Insulin gene
mutations
Maturity onset Diabetes of
Young
{MODY }
 Insulin secretory defect without beta cell
loss
 Autosomal dominant inheritance with high
penetrance
 Early onset before 25
 Impaired β - cell function , normal weight ,
lack of GAD antibodies ,
lack of INSULIN resistance syndrome
Genetic defects in insulin
action
 Type A insulin resistance
 Lipoatrophic diabetes, including mutations
in PPARG
Exocrine pancreatic defects
 Chronic pancreatitis
 Pancreatectomy/trauma
 Neoplasia
 Cystic fibrosis
 Hemachromatosis
 Fibrocalculous pancreatopathy
Endocrinopathies
 Acromegaly
 Cushing syndrome
 Hyperthyroidism
 Pheochromocytoma
 Glucagonoma
Infections
 Cytomegalovirus
 Coxsackie B virus
 Congenital rubella
Drugs
 Glucocorticoids
 Thyroid hormone
 Interferon-α
 Protease inhibitors
 β-adrenergic agonists
 Thiazides
 Nicotinic acid
 Phenytoin (Dilantin) Vacor
Genetic syndromes
associated with diabetes
 Down syndrome
 Kleinfelter syndrome
 Turner syndrome
 Prader-Willi syndrome
GESTATIONAL DIABETES
 Develops only during pregnancy
 More common in:
– African Americans
– American Indians
– Hispanic Americans
– women with a family history of diabetes
 Women with a history of gestational diabetes have
a 20-50% chance of getting type II DM within 510 years
<http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm#what>
Gestational Diabetes Mellitus
 Hyperglycemia diagnosed during pregnancy
 Occurs in 2-5% of pregnancies
 Occurs due to placental hormone changes that
effect insulin function (greater resistance)
 Screening usually occurs during the 24th-28th week
in high risk patients
 Criteria for diagnosis is different than for Type 1
and Type 2
 Dietary changes are initial treatment and insulin is
the only BG lowering agent used
 Concern is both for maternal and fetal well-being
 Postpartum BG levels usually return to normal
 Increased risk for Type 2 diabetes (30-50%)
Pathogenesis of Type 1
Diabetes Mellitus
 autoimmune disease in which islet destruction is caused
primarily by T lymphocytes reacting against as yet poorly
defined β-cell antigens, resulting in a reduction in β-cell
mass
 genetic susceptibility and environmental influences play
important roles in the pathogenesis.
 most commonly develops in childhood, becomes manifest
at puberty, and is progressive with age.
 Most individuals with type 1 diabetes depend on
exogenous insulin supplementation for survival, and
without insulin, they develop serious metabolic
complications such as acute ketoacidosis and coma.
 The classic manifestations of the disease
(hyperglycemia and ketosis) occur late in its
course, after more than 90% of the β cells
have been destroyed.
 Several mechanisms contribute to β-cell
destruction, and it is likely that many of
these immune mechanisms work together to
produce progressive loss of β cells,
resulting in clinical diabetes:
Type 1 diabetes
 complex pattern of genetic association
 the principal susceptibility locus for type 1 diabetes resides
in the region that encodes the class II MHC molecules on
chromosome 6p21 (HLA-D).
 Between 90% and 95% - HLA-DR3, or DR4, or both,
 also evidence to suggest that environmental factors,
especially infections, - viruses may be an initiating trigger,
-molecular minicry
Pathogenesis of Type 2
Diabetes Mellitus
 pathogenesis of type 2 diabetes remains enigmatic.
Environmental influences, such as a sedentary life
style and dietary habits, clearly have a role,
 Nevertheless, genetic factors are even more
important than in type 1 diabetes,
 Among identical twins, the concordance rate is
50% to 90%, while among first-degree relatives
with type 2 diabetes (including fraternal twins) the
risk of developing the disease is 20% to 40%
 Insulin Resistance
 Insulin resistance is defined as the failure of
target tissues to respond normally to insulin.
 leads to decreased uptake of glucose in
muscle, reduced glycolysis and fatty acid
oxidation in the liver, and an inability to
suppress hepatic gluconeogenesis.
 Few factors play as important a role in the
development of insulin resistance as
obesity.
 Obesity and Insulin Resistance.
 epidemiologic association of obesity with type 2
diabetes - observed in greater than 80% of
patients.
 Insulin resistance is present even in simple obesity
unaccompanied by hyperglycemia, indicating a
fundamental abnormality of insulin signaling in
states of fatty excess (see metabolic syndrome,
below).
 The risk for diabetes increases as the body mass
index (a measure of body fat content) increases. It
is not only the absolute amount but also the
distribution of body fat that has an effect on
insulin sensitivity:
 central obesity (abdominal fat) is more likely to
be linked with insulin resistance than are
peripheral (gluteal/subcutaneous) fat depots.
Obesity can adversely impact insulin sensitivity in numerous ways
 Nonesterified fatty acids (NEFAs):
 Adipokines:Leptin and adiponectin improve insulin sensitivity by
directly enhancing the activity of the AMP-activated protein kinase
(AMPK), an enzyme that promotes fatty acid oxidation, in liver and
skeletal muscle. Adiponectin levels are reduced in obesity, thus
contributing to insulin resistance.
 Inflammation: Adipose tissue also secretes a variety of proinflammatory cytokines like tumor necrosis factor, interleukin-6, and
macrophage chemoattractant protein-1, the last attracting macrophages
to fat deposits. These cytokines induce insulin resistance by increasing
cellular “stress,” which in turn, activates multiple signaling cascades
that antagonize insulin action on peripheral tissues.
 Peroxisome proliferator-activated receptor γ (PPAR γ): PPARγ is a
nuclear receptor and transcription factor expressed in adipose tissue,
and plays a seminal role in adipocyte differentiation. Activation of
PPARγ promotes secretion of anti-hyperglycemic adipokines like
adiponectin, and shifts the deposition of NEFAs toward adipose tissue
and away from liver and skeletal muscle. AS DISCUSSED BELOW,
RARE MUTATIONS OF PPARG THAT CAUSE PROFOUND
LOSS OF PROTEIN FUNCTION CAN RESULT IN MONOGENIC
DIABETES.
 β-Cell Dysfunction
 In type 2 diabetes, β cells seemingly exhaust their
capacity to adapt to the long-term demands of
peripheral insulin resistance.
 In states of insulin resistance like obesity, insulin
secretion is initially higher for each level of
glucose than in controls. This hyperinsulinemic
state is a compensation for peripheral resistance
and can often maintain normal plasma glucose for
years. Eventually, however, β-cell compensation
becomes inadequate, and there is progression to
hyperglycemia.
 The two metabolic defects that characterize
type 2 diabetes are
 (1) a decreased ability of peripheral tissues
to respond to insulin (insulin resistance)
and
 (2) β-cell dysfunction that is manifested as
inadequate insulin secretion in the face of
insulin resistance and hyperglycemia. In
most cases, INSULIN RESISTANCE IS
 T2DM is a disorder characterized by a
Combination of reduced tissue sensitivity to
insulin and inadequate secretion of insulin
from the pancreas.
 Hyperglycemia in T2DM is a failure of theβ
cells to meet an increased demand for
insulin in the body
MORPHOLOGY PANCREAS
 TYPE - 1
- reduction in number & size of islets
- leukocytic infilteration of islets
 TYPE - 2
- subtle reduction in islet cell mass
- amyloid replacement of islets
Diabetes Mellitus
 Absence (or ineffectiveness of ) insulin
 Cellular resistance
 Cells can’t use glucose for energy
– Starvation mode
• Compensatory breakdown of body fat/protein
• Ketone bodies from faulty fat breakdown
• Metabolic acidosis, compensatory breathing
(Kussmal’s breathing)
DM TYPE II
 Symptoms of type II DM include:
–
–
–
–
–
–
–
–
–
Fatigue
Nausea
Frequent urination/polyuria
Thirst
Unusual weight loss
Blurred vision
Frequent infections
Slow healing of wounds or sores
Sometimes no specific symptoms
•
<http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm#what>
Diabetes Mellitus
 HYPERGLYCEMIA: fluid/electrolyte
imbalance.
– Polyuria
• Sodium, chloride, potassium excreted
– Polydipsia from dehydration
– Polyphagia: cells are starving, so person feels
hungry despite eating huge amounts of food.
Starvation state remains until insulin is
available.
CLINICAL
Onset: usually childhood and adolescence
Onset: usually adult; increasing incidence in childhood and
adolescence
Normal weight or weight loss preceding diagnosis
Vast majority are obese (80%)
Progressive decrease in insulin levels
Increased blood insulin (early); normal or moderate
decrease in insulin (late)
Circulating islet autoantibodies (anti-insulin, antiGAD, anti-ICA512)
No islet auto-antibodies
Diabetic ketoacidosis in absence of insulin
therapy
Nonketotic hyperosmolar coma more common
GENETICS
Major linkage to MHC class I and II genes; also
linked to polymorphisms in CTLA4 and PTPN22,
and insulin gene VNTRs
No HLA linkage; linkage to candidate diabetogenic and
obesity-related genes (TCF7L2, PPARG, FTO, etc.)
PATHOGENESIS
Dysfunction in regulatory T cells (Tregs) leading
to breakdown in self-tolerance to islet autoantigens
Insulin resistance in peripheral tissues, failure of
compensation by β-cells
Multiple obesity-associated factors (circulating
nonesterified fatty acids, inflammatory mediators,
adipocytokines) linked to pathogenesis of insulin resistance
PATHOLOGY
Insulitis (inflammatory infiltrate of T cells and
macrophages)
No insulitis; amyloid deposition in islets
β-cell depletion, islet atrophy
Mild β-cell depletion
Type II Diabetes
Diagnostic testing - when to do it:
People  45 years old => if normal then every
3 years
MKSAP13 Endocrinology and Metabolism. American College of Physicians 2004.
Type II Diabetes: diagnostic testing
Younger than 45 yr or more often than every 3 years if:
overweight
first degree relative with diabetes
member of high risk ethnic group (Afro-American, Hispanic
American, Native American, Asian American, Pacific Islander)
delivered a baby  9 lbs.
gestational diabetes
hypertensive (BP  140/90mmHg)
High Density Lipoprotein cholesterol 35mg/dl or less
TriGlyceride level 250mg/dl or more
pre-diabetes
MKSAP13 Endocrinology and Metabolism. American College of Physicians 2004.
Who’s at risk of Type II?
Diabetes Mellitus
The good news:
– Blood glucose control reduces complications of
Diabetes!
Diabetes Mellitus
 Complications of chronic hyperglycemia
– Macrovascular complications
• Cardiovascular disease (heart attack)
• Cerebrovascular disease (strokes)
– Microvascular
•
•
•
•
Blindness (retinal proliferation, macular degeneration)
Amputations
Diabetic neuropathy (diffuse, generalized, or focal)
Erectile dysfunction
The Laboratory Examination
Laboratory plays an important
part in the diagnosis and care of
diabetic patients
Diagnosis
 Blood glucose levels - 70 to 120 mg/dL.
 Diagnosis - By Elevation Of Blood Glucose By
Any One Of Three Criteria:
 A random blood glucose concentration of 200
mg/dL or higher, with classical signs and
symptoms
 A fasting glucose concentration of 126 mg/dL or
higher on more than one occasion,
 An abnormal oral glucose tolerance test (OGTT),
in which the glucose concentration is 200 mg/dL
or higher 2 hours after a standard carbohydrate
load (75 gm of glucose).
Method: Glucose Oxidase
 GLU+2H2O+O2
GOD
Gluconic acid
+2H2O2
 2H2O2 +4-aminoantipyrine +1,7-dihy-
droxynaphthalene
POD
red dye
Reference Interval
Fasting glucose : 3.9 - 6.11mmol/l
(fasting
is defined as no calorie
intake for at least 8 hours)
Urine Tests
 URINE "GLUCOSE"
– lacks sensitivity = positivity in disease
– poor specificity = negativity in health
 Problems
– renal threshold variable 6 to 15 mmol/L
– interferences : Clinitest / Glucose oxidase strips
IF URINE TEST POSITIVE
A CONFIRMATORY BLOOD TEST
IS NEEDED
Blood Tests
Glucose
– whole blood 10-15% lower than plasma
– venous 10% lower than capillary
– Venous blood - loss of 0.33 mmol/L per
hour
– There is no decrease within 24 h in the
presence of sodium fluoride
Oral Glucose Tolerance Test
(OGTT)
 A venous blood sample will be collected for
the determination of fasting glucose
 Load of 75g of glucose is ingested within 5
min
 Blood samples will be collected at timed
intervals (30min, 60min, 120min) for the
determination of glucose
OGTT Criteria
Plasma glucose (mmol/L)
0 min
Non diabetic
< 6.1
Impaired glucose tolerance 6.1 - 6.9
11.1
Diabetic
> 7.0
120 min
< 7.8
>7.8 -
> 11.1
Glycosylated proteins
Caused by non-enzymatic glycosylation
– Glycosylated hemoglobin
• HbA1c - LGI ref range 4.6-6.5 %
• indicates previous 2-3 months glycaemic exposure
• n.b. affetced by altered red cell survival
– Fructosamine
• mirrors glycosylation of all serum proteins
• indicates previous 2-3 weeks glycaemic exposure
• used pregnancy/children in some sites
– Glycosylated albumin
• indicates previous several days glycaemic exposure
• not commonly used
Hemoglobin A1c
 HbA1c is stable glycosylated
hemoglobin
 Its percentage concentration indicates
cumulative glucose exposure
Hemoglobin A1c
 A good indicator of blood glucose control.
 Gives a % that indicates control over the
preceding 2-3 months.
 Performed 2 times a year.
 A hemoglobin of 6% indicates good control
and level >8% indicates action is needed.
Lowering HbA1C Reduces Risk of Complications
Secondary Diabetes Mellitus
 DM occurs as a result of another problem
(primary)
– Diseases
– Conditions
– Medications
•
•
•
•
Thiazides
Diuretics
Beta blockers
Steroids
 Hyperglycemia is diagnostic for DM
 Treatment of the primary cause may resolve the
DM but lifestyle modifications and medications
may be needed as well
Pre-Diabetes
 Pre-diabetes refers to a state between
“normal” and “diabetes” = fasting
plasma glucose 100-125mg/dL (higher
than normal but not high enough for
diagnosis of diabetes)
Affects about 41 million people in
USA
(previously referred to as either impaired
fasting glucose or impaired glucose tolerance)
Impaired Fasting Glucose
 Defined as a fasting plasma blood glucose
of >/= to 110 but < 126
 Increased risk for DM
 Must educate regarding risks and need for
lifestyle modifications
Impaired
Glucose
Tolerance
 Defined as a plasma blood glucose of >/= to 140
but < 200 after a 2 hour 75 gram glucose tolerance
test
 8-10% of US population have this problem with a
25 % risk of developing DM 2
 Compounding risk factors effect risk of
developing Type 2 DM
–
–
–
–
Age
Activity
Comorbidities
Weight
 Increased risk for macrovascular diseases
 Must educate regarding risks and need for lifestyle
modifications
Diabetes is preventable by life style
modification
 Maintain a healthy body weight
 Half an hour of exercise daily
 Eat a healthy diet
(fruits, vegetables, bread, milk)
Triad of Treatment
 Diet
 Medication
– Oral hypoglycemics
– Insulins
 Exercise
Diabetes Mellitus
 Prevention of effects: combination approach
– Increased exercise
• Decreases need for insulin
– Reduce calorie intake
• Improves insulin sensitivity
– Weight reduction
• Improves insulin action
Classification of Diabetes
Type I DM
Type II DM
Aetiology
Autoimmune
(- cell destruction)
Insulin resistance and -cell
dysfunction
Peak age
12 years
60 years
Prevalence
0.3%
6% (>10% above 60 years)
Presentation
Osmotic symptoms,
weight loss (days to
weeks), DKA
Patient usually slim
Osmotic symptoms, diabetic
complications (months to
years).
Patient usually obese
Treatment
Diet and insulin
Diet, exercise (weight loss),
oral hypoglycemics, Insulin
later
In Conclusion :
Diabetes is a very complicated disease. It is
easy to diagnosis and it is difficult to treat
Laboratory plays an important part in the
diagnosis and care of diabetic patients