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Diabetes Mellitus

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Title: Diabetes Mellitus


1
Diabetes Mellitus
  • Talya Wolak

2
Overview
  • Diabetes mellitus is a chronic disorder
    characterized by the impaired metabolism of
    glucose
  • Late development of vascular and neuropathic
    complications

3
Classification
  • Type 1 -A. Immune-mediated
  •  B. Idiopathic
  • Type 2
  • Other specific types
  • Gestasional diabetes mellitus

4
Other Specific Types Of Diabetes
  • Endocrinopathiesacromegaly, cushing's syndrome,
    glucagonoma, pheochromocytoma, hyperthyroidism,
    somatostatinoma, aldosteronoma
  • Genetic defects of cell function MODY
  • Drug- or chemical-inducedVacor, pentamidine,
    nicotinic acid, glucocorticoids, thyroid hormone,
    diazoxide, -adrenergic agonists, thiazides,
    phenytoin, -interferon, protease inhibitors,
    clozapine, beta blockers

5
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

6
Terminology
  • Diabetes Mellitus -DM
  • Fasting plasma glucose -FPG
  • Impaired fasting glucose IFG
  • Impaired glucose tolerance IGT

7
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.

8
Diabetes Mellitus IGFIGT Normal
FPGgt126 mg/dL IGF- FPG 100-126 mg/dL FPGlt100 mg/dL
2H-PGgt200 mg/dL IGT - 2H-PG 140-200 mg/dL 2H-PGlt140 mg/dL
PGgt200 SYMPTOMS
9
Impaired Glucose Tolerance -IGT
  • Category between normality and diabetes
  • Subjects with IGT are at increased risk of
    developing overt diabetes and atherosclerotic
    vascular disease

10
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

11
Type 2 DM Screening
  • The FPG as a screening test for type 2 DM is
    recommended

12
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.

13
  • 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

14
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

15
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

16
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17
Type IA Pthogenesis
18
Decline
19
  • 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.

20
  • 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).

21
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22
"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

23
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

24
Autoimmune Factors
  • The pancreatic islets are infiltrated with
    lymphocytes - Insulitis
  • Pancreatic islet molecules targeted by the
    autoimmune process include insulin, glutamic acid
    decarboxylase

25
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.

26
Testing for ICAs
  • Classifying the type of DM as type IA
  • Identifying nondiabetic individuals at risk for
    developing type 1A DM

27
ICAs Are Present
  • In individuals diagnosed with new-onset type 1A
    DM (gt75)
  • In individuals with newly diagnosed type 2 DM (5
    to 10)
  • Individuals with GDM (lt5)
  • 3 to 4 of first-degree relatives of individuals
    with type 1A DM

28
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

29
Prediction Of Type 1A DM
  • ICAs In combination with impaired insulin
    secretion after intravenous glucose tolerance
    testing, they predict a gt50 risk of developing
    type 1A DM within 5 years

30
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

31
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 Trialtype 1 recently
    concluded that administering insulin to
    individuals at high risk did not prevent type 1A
    DM

32
Type II Pthogenesis
33
Type 2 DM
  • Insulin resistance
  • Abnormal insulin secretion
  • Insulin resistance precedes insulin secretory
    defects
  • Diabetes develops only if insulin secretion
    becomes inadequate

34
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

35
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

36
Pathophysiology -Type 2 DM
  • Peripheral insulin resistance
  • Impaired insulin secretion
  • Excessive hepatic glucose production

37
Insulin Resistance
  • Insulin resistance is a state in which a given
    concentration of insulin is associated with a
    subnormal glucose response

38
Early Stages
  • Insulin resistance
  • Pancreatic beta cells compensate by increasing
    insulin output - hyperinsulinisim
  • Glucose tolerance remains normal

39
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

40
Diabetes Mellitus
  • A further decline in insulin secretion
  • An increase in hepatic glucose production
  • Fasting hyperglycemia
  • Overt diabetes mellitus

41
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

42
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

43
  • 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).

44
Insulin Resistance-hyperglycemia
  • Impairs glucose utilization by insulin-sensitive
    tissues
  • Increases hepatic glucose output
  • Both effects contribute to the hyperglycemia.

45
FPG Versus IGT
  • Increased hepatic glucose output predominantly
    accounts for increased FPG levels
  • Decreased peripheral glucose usage results in
    postprandial hyperglycemia - IGT

46
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

47
Free Fatty Acids
  • Free fatty acids a common feature of obesity
  • Can impair glucose utilization in skeletal muscle
  • Promote glucose production by the liver
  • Impair beta cell function

48
Obesity
49
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.

50
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

51
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

52
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.

53
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

54
  • Insulin secretory abnormalities
  • Insulin resistance in skeletal muscle.
  • Increased hepatic glucose production .

55
Insulin Resistance Syndromes
  • The metabolic syndrome
  • The insulin resistance syndrome
  • Syndrome X

56
Definition
  • The presence of any three of the following
    traits
  • Abdominal obesity- a waist circumference in men
    gt102 cm and in women gt88 cm
  • Serum triglycerides 150 mg/dL
  • Serum HDL cholesterol lt40 mg/dL in men and lt50
    mg/dL in women.

57
Definition con.
  • 4. Blood pressure gt130/85 mmHg.
  • 5. Fasting plasma glucose gt 110 mg/dL

58
Rare Forms Of Severe Insulin Resistance
  • Include features of type 2 DM or IGT
  • Type A- young women
  • Type B- middle-aged women
  • Severe hyperinsulinemia, obesity, and features of
    hyperandrogenism

59
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

60
Prevention in IGT
  • Intensive changes in life-style in individuals
    with
  • Diet
  • Exercise for 30 min/day five times/week
  • Prevented or delayed the development of type 2
    diabetes by 58 compared to placebo

61
Prevention in IGT con.
  • Metformin prevented or delayed diabetes by 31
    compared to placebo

62
For Who?
  • Strong family history
  • IFG or IGT
  • Strongly encouraged to maintain a normal body
    mass index (BMI) and engage in regular physical
    activity.
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