Transcript Diabetes Mellitus

Diabetes Mellitus
Talya Wolak
Overview
• Diabetes mellitus is a chronic disorder
characterized by the impaired metabolism
of glucose
• Late development of vascular and
neuropathic complications
Classification
• Type 1 -A. Immune-mediated
B. Idiopathic
• Type 2
• Other specific types
• Gestasional diabetes mellitus
Other Specific Types Of Diabetes
• Endocrinopathies—acromegaly, cushing's
syndrome, glucagonoma, pheochromocytoma,
hyperthyroidism, somatostatinoma,
aldosteronoma
• Genetic defects of cell function –MODY
• Drug- or chemical-induced—Vacor,
pentamidine, nicotinic acid, glucocorticoids,
thyroid hormone, diazoxide, -adrenergic
agonists, thiazides, phenytoin, -interferon,
protease inhibitors, clozapine, beta blockers
How To Define Diabetes?
• The spectrum of fasting plasma glucose
and the response to an oral glucose load
varies among normal individuals
• DM is defined as the level of glycemia at
which diabetes-specific complications
occur
Terminology
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Diabetes Mellitus -DM
Fasting plasma glucose -FPG
Impaired fasting glucose –IFG
Impaired glucose tolerance –IGT
Diagnostic Criteria For DM
• FPG at or above 126 mg/dL
• A two-hour value in an OGTT (2-h PG) at
or above 200 mg/dL
• A random plasma glucose concentration
200 mg/dL in the presence of symptoms.
Normal
IGF&IGT
Diabetes
Mellitus
FPG<100
mg/dL
IGF- FPG :100- FPG>=126
126 mg/dL
mg/dL
2H-PG<140
mg/dL
IGT - 2H-PG:
140-200 mg/dL
2H-PG>=200
mg/dL
PG>200 +
SYMPTOMS
Impaired Glucose Tolerance -IGT
• Category between
normality and
diabetes
• Subjects with IGT are
at increased risk of
developing overt
diabetes and
atherosclerotic
vascular disease
Con…
• Abnormalities on screening tests for
diabetes should be repeated before
making a definitive diagnosis of DM
• Unless acute metabolic derangements or
a markedly elevated plasma glucose are
present
Type 2 DM Screening
• The FPG as a screening test for type 2
DM is recommended
Why ?
• Type 2 DM may be present for up to a
decade before diagnosis
• A large number of individuals who meet
the current criteria for DM are
asymptomatic.
• 50% of individuals with type 2 DM have
one or more diabetes-specific
complications at the time of their diagnosis
• Treatment of type 2 DM may favorably
alter the natural history of DM
Type I DM Screening
• Screening for type 1 DM is no
recommended
• In contrast to type 2 DM, a long
asymptomatic period of hyperglycemia is
rare prior to the diagnosis of type 1 DM
Prevalence of DM
• Has risen dramatically over the past two
decades
• The prevalence of both type 1 and type 2
DM is increasing worldwide
• The prevalence of type 2 DM is expected
to rise more - increasing obesity and
reduced activity levels
Type IA Pthogenesis
Decline
• Beta cell mass then begins to decline, and
insulin secretion becomes progressively
impaired, although normal glucose
tolerance is maintained .
• Residual functional beta cells still exist but
are insufficient in number to maintain
glucose tolerance.
• The events that trigger the transition from
glucose intolerance to frank diabetes:
associated with increased insulin
requirements, as infections or puberty.
• Features of diabetes do not become
evident until a majority of beta cells are
destroyed ( 80%).
"Honeymoon" Phase
• Time glycemic control is achieved with
modest doses of insulin or, rarely, insulin is
not needed.
• fleeting phase of endogenous insulin
production from residual beta cells
disappears as the autoimmune process
destroys the remaining beta cells
• The individual becomes completely insulin
deficient
Genetic Factor
• Genetic susceptibility to type 1A DM
involves multiple genes.
• The major susceptibility gene for type 1A
DM is located in the HLA region on
chromosome 6.
• The risk of developing type 1A DM is
increased tenfold in relatives of individuals
with the disease
Autoimmune Factors
• The pancreatic islets are infiltrated with
lymphocytes - Insulitis
• Pancreatic islet molecules targeted by the
autoimmune process include insulin,
glutamic acid decarboxylase
Immunologic Markers -ICAs
• Islet cell autoantibodies (ICAs) - different
antibodies directed at pancreatic islet
molecules: GAD, insulin, IA-2/ICA-512,
and an islet ganglioside
• Serve as a marker of the autoimmune
process of type 1A DM.
• Assays for autoantibodies to GAD-65 are
available.
Testing for ICAs
• Classifying the type of DM as type IA
• Identifying nondiabetic individuals at risk
for developing type 1A DM
ICAs Are Present :
• In individuals diagnosed with new-onset
type 1A DM (>75%)
• In individuals with newly diagnosed type 2
DM (5 to 10%)
• Individuals with GDM (<5%)
• 3 to 4% of first-degree relatives of
individuals with type 1A DM
Markers
• Genetic markers -present from birth
• Immune markers - after the onset of the
autoimmune process
• Metabolic markers can be detected with
sensitive tests once enough beta-cell
damage, but before the onset of
symptomatic hyperglycemia
Prediction Of Type 1A DM
• ICAs In combination with impaired insulin
secretion after intravenous glucose
tolerance testing, they predict a >50% risk
of developing type 1A DM within 5 years
Environmental Factors
• Trigger the autoimmune process in
genetically susceptible individuals
• Viruses (coxsackie and rubella most
prominently), bovine milk proteins
• None have been conclusively linked to
diabetes
Prevention of Type 1A DM
• Though results in animal models are
promising
• have not been successful in preventing
type 1A DM in humans.
• The Diabetes Prevention Trial—type 1
recently concluded that administering
insulin to individuals at high risk did not
prevent type 1A DM
Type II Pthogenesis
Type 2 DM
1. Insulin resistance
2. Abnormal insulin secretion
• Insulin resistance precedes insulin
secretory defects
• Diabetes develops only if insulin
secretion becomes inadequate
Genetic Considerations
• Type 2 DM has a strong genetic component.
• Major genes that predispose to this disorder
have yet to be identified
• The disease is polygenic and multifactorial
• Insulin resistance is present in many
nondiabetic, first-degree relatives of
individuals with type 2 DM
Some Numbers
• The concordance of type 2 DM in
identical twins is between 70 and
90%
• If both parents have type 2 DM, the
risk approaches 40%
Pathophysiology -Type 2 DM
• Peripheral insulin resistance
• Impaired insulin secretion
• Excessive hepatic glucose
production
Insulin Resistance
• Insulin resistance is a state in which a
given concentration of insulin is associated
with a subnormal glucose response
Early Stages
• Insulin resistance
• Pancreatic beta cells compensate by
increasing insulin output hyperinsulinisim
• Glucose tolerance remains normal
Impaired Glucose Tolerance
• As insulin resistance and compensatory
hyperinsulinemia progress
• Pancreatic islets are unable to sustain
the hyperinsulinemic state - Impaired
insulin secretion
• IGT- elevations in postprandial glucose
develops
Diabetes Mellitus
• A further decline in insulin
secretion
• An increase in hepatic glucose
production
• Fasting hyperglycemia
• Overt diabetes mellitus
In The End…
• Ultimately, beta cell failure may ensue.
Markers of inflammation such as IL-6 and
C-reactive protein are often elevated in
type 2 diabetes
• May become insulin deficient
Insulin Resistance
• The decreased ability of insulin to act
effectively on peripheral target tissues muscle and liver
• Prominent feature of type 2 DM
• Results from a combination of genetic
susceptibility and obesity
• Supernormal levels of circulating insulin
will normalize the plasma glucose
• Reduced sensitivity, and a reduced
maximal response, indicating an overall
decrease in maximum glucose utilization
(30 to 60% lower than normal individuals).
Insulin Resistancehyperglycemia
1. Impairs glucose utilization by insulinsensitive tissues
2. Increases hepatic glucose output
• Both effects contribute to the
hyperglycemia.
FPG Versus IGT
• Increased hepatic glucose output
predominantly accounts for increased FPG
levels
• Decreased peripheral glucose usage
results in postprandial hyperglycemia IGT
Molecular Mechanism Of Insulin
Resistance
• Insulin receptor levels and tyrosine kinase
activity in skeletal muscle are reduced, not primary defect
• Postreceptor defects are believed to play
the predominant role in insulin resistance
Free Fatty Acids
•
Free fatty acids a common feature of
obesity :
1. Can impair glucose utilization in skeletal
muscle
2. Promote glucose production by the liver
3. Impair beta cell function
Obesity
Obesity
• Visceral or central obesity (as evidenced
by the hip-waist ratio), is very common in
type 2 DM.
• Adipocytes secrete a number of biologic
products (leptin, TNF- , free fatty acids,
resistin, and adiponectin)
• Modulate insulin secretion, insulin action,
and body weight contribute to the insulin
resistance.
Impaired Insulin Secretion
• Insulin secretion initially increases in
response to insulin resistance to maintain
normal glucose tolerance
• The insulin secretory defect progresses to
a state of grossly inadequate insulin
secretion
Why?
• Excluded mutations in islet candidate
genes
• Islet amyloid polypeptide found in the
islets of individuals with long-standing type
2 DM
• Glucose toxicity
• Lipotoxicity
Glucose Toxicity
& Lipotoxicity
• Chronic hyperglycemia paradoxically
impairs islet function
• Leads to a worsening of hyperglycemia.
• Improvement in glycemic control
associated with improved islet function
• Elevation of free fatty acid levels and
dietary fat also worsen islet function.
Increased Hepatic Glucose
Production
• Insulin resistance in the liver - failure of
hyperinsulinemia to suppress
gluconeogenesis
• Fasting hyperglycemia
• Decreased glycogen storage by the liver in
the postprandial state
• Insulin secretory abnormalities
• Insulin resistance in skeletal muscle.
• Increased hepatic glucose production .
Insulin Resistance
Syndromes
• The metabolic syndrome
• The insulin resistance syndrome
• Syndrome X
Definition
• The presence of any three of the following
traits:
1. Abdominal obesity- a waist circumference
in men >102 cm and in women >88 cm
2. Serum triglycerides 150 mg/dL
3. Serum HDL cholesterol <40 mg/dL in men
and <50 mg/dL in women.
Definition con.
4. Blood pressure >130/85 mmHg.
5. Fasting plasma glucose > 110 mg/dL
Rare Forms Of Severe Insulin
Resistance
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Include features of type 2 DM or IGT
Type A- young women
Type B- middle-aged women
Severe hyperinsulinemia, obesity, and
features of hyperandrogenism
Polycystic Ovary Syndrome
PCOS
• Premenopausal women - chronic
anovulation and hyperandrogenism
• Insulin resistance
• Increases the risk for type 2 DM.
• Both metformin and the thiazolidinediones
attenuate hyperinsulinemia, ameliorate
hyperandrogenism, induce ovulation, and
improve plasma lipids
Prevention in IGT
•
Intensive changes in life-style in
individuals with :
1. Diet
2. Exercise for 30 min/day five times/week
• Prevented or delayed the development of
type 2 diabetes by 58% compared to
placebo
Prevention in IGT con.
• Metformin prevented or delayed diabetes
by 31% compared to placebo
For Who?
• Strong family history
• IFG or IGT
• Strongly encouraged to maintain a normal
body mass index (BMI) and engage in
regular physical activity.