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DIABETES
MELLITUS
MELLITUS
Dr
Dr Prakash
Prakash H
HMM
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
400 370
350
300
Millions with Diabetes
300
250 221
200 177
135
150
100
30
50
0
1985 1995 2000 2010 2025 2030
Sources: www.who.int
www.idf
Zimmet P. et al Nature: 414, 13 Dec 2001
PHYSIOLOGICAL IMPACT
6th 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
<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
Glycogen
Low blood sugar Glucagon 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 counter-
regulatory 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 Mellitus
1 Diabetes - 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
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 5-10 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 pro-
inflammatory 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 THE PRIMARY EVENT AND IS FOLLOWED BY
INCREASING DEGREES OF Β-CELL
DYSFUNCTION.
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, anti- No islet auto-antibodies
GAD, anti-ICA512)
Diabetic ketoacidosis in absence of insulin Nonketotic hyperosmolar coma more common
therapy
GENETICS
Major linkage to MHC class I and II genes; also No HLA linkage; linkage to candidate diabetogenic and
linked to polymorphisms in CTLA4 and PTPN22, obesity-related genes (TCF7L2, PPARG, FTO, etc.)
and insulin gene VNTRs
PATHOGENESIS
Dysfunction in regulatory T cells (Tregs) leading Insulin resistance in peripheral tissues, failure of
to breakdown in self-tolerance to islet auto- compensation by β-cells
antigens
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 No insulitis; amyloid deposition in islets
macrophages)
β-cell depletion, islet atrophy Mild β-cell depletion
Type II Diabetes
Diagnostic testing - when to do it:
– Microvascular
• Blindness (retinal proliferation, macular degeneration)
• Amputations
• Diabetic neuropathy (diffuse, generalized, or focal)
• Erectile dysfunction
The Laboratory Examination
http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm#types
MKSAP13 Endocrinology and Metabolism. American College of Physicians 2004.
Impaired Fasting Glucose
Diet
Medication
– Oral hypoglycemics
– Insulins
Exercise
Diabetes Mellitus
Prevention of effects: combination approach
– Increased exercise
• Decreases need for insulin
– Weight reduction
• Improves insulin action
Classification of Diabetes
Type I DM Type II DM