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MS2 Endocrine > 10/14- Diabetes: Intro and Pathophysiology > Flashcards

10/14- Diabetes: Intro and Pathophysiology Flashcards

1
Q

T/F: The prevalence of Type I Diabetes is increasing

A

True

  • Both type I and type II diabetes are increasing
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2
Q

The rise in Type II diabetes is linked to ____

A

The rise in Type II diabetes is linked to obesity

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3
Q

What is the impact of DM?

  • Prevalence
A
  • Over 20M Americans have diabetes
  • Probably same amount are undiagnosed
  • 42M have the “Metabolic syndrome”
  • Cost (2004) was > $180B with > 20M hospital days
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4
Q

What is the definition of diabetes?

A

Chronic illness characterized by:

  • Hyperglycemia
  • Abnormalities of carbohydrate, fat, and protein metabolism
  • Propensity to develop specific renal, eye and neurologic complications, and premature occlusive vascular disease (end organ disease)
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5
Q

What are the diagnostic criteria for diabetes?

A

Any of these:

  • Symptoms + random plasma glucose > 200 mg/dl
  • Fasting plasma glucose > 126 mg/dl
  • 2h OGTT plasma glucose > 200 mg/dl
  • HbA1c > 6.5% (since 2009)
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6
Q

Why do an OGTT (oral glucose tolerance test) when you could much more easily get a fasting plasma glucose?

A

OGTT is much more precise

  • Depending only on fasting could cause you to miss ~ 25% of cases
  • Could perhaps start with fasting test and then move on to OGTT if still suspect/symptomatic
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7
Q

What constitutes “Impaired” Glycemic Control?

A

Either:

  • Fasting plasma glucose 100-126 mg/dl (Impaired Fasting Glucose)
  • 2h OGTT plasma glucose 140-200 mg/dl (Impaired Glucose Tolerance)
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8
Q

What are the risks of Impaired Glycemic Control?

A
  • Risk of developing type 2 diabetes 3%/year
  • Elevated risk (approaching that of diabetes) for macrovascular disease
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9
Q

How do you diagnose diabetes/Who should you screen?

A

Screen anyone at high risk (even asymptomatic):

  • Elderly
  • Obese
  • Positive family history
  • Non-Caucasian ethnic group
  • Hypertensive
  • Woman with babies > 9 lb at birth

Symptoms/signs of diabetes:

  • Weight loss
  • Polydypsia
  • Paresthesia
  • Nocturia
  • Hyperlipidemia
  • Lethargy
  • Poor healing of cuts
  • Recurrent skin, genital, or urinary infection
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10
Q

What should the initial screening be?

Do what depending on results?

A

Screen with Fasting Plasma Glucose (FPG)

If FPG value is:

  • Under 100 mg/dL: diabetes is unlikely
  • 100-126 mg/dL: impaired fasting glucose
  • > 126 mg/dL: diabetes mellitus
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11
Q

How is Diabetes classified? What are causes of each?

A

Type 1

  • Immune-mediated
  • Idiopathic

Type 2

  • Other specific types of diabetes
  • Monogenic defects of the β cell (rare; not autoimmune but some other reason β cells don’t develop)
  • Monogenic defects of insulin action (rare)
  • Diseases of the exocrine pancreas (developmental or severe pancreatitis)
  • Endocrinopathies
  • Cushing’s
  • Acromegaly
  • Drug- or chemical-induced diabetes
  • Other genetic syndromes sometimes associated with diabetes

Gestational DM

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12
Q

This woman has diabetes. What else is seen?

A

Diabetes due to Cushing’s actually

  • Round, reddish face (plethora)
  • Hyperpigmented around scar (melatonin)
  • Not too much central adiposity, but don’t be fooled by stereotypical body type
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13
Q

This woman has diabetes. What else is seen?

A

Diabetes possibly due to Addison’s disease

  • White hair despite young age
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14
Q

This man has diabetes. What else is seen?

A

Diabetes possibly due to Acromegaly

  • Causes hyperglycemia as well as insulin resistance
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15
Q

This man has diabetes.

What else is seen?

A

Klinefelter’s (XXY)

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16
Q

Diabetes is associated with what endocrinopathies?

Other genetic diseases?

A
  • Cushing’s dz
  • Addison’s dz
  • Acromegaly
  • Klinefelter’s syndrome
  • Turner’s dz
  • (Increased risk with Down’s syndrome)
  • Myotonic dystrophy
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17
Q

This woman has diabetes.

What else is seen?

A

Turner’s (-X)

  • Increased risk of Down’s syndrome
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18
Q

This man has diabetes.

Experience inability to quickly relax muscles.

What is expected?

A

Myotonic dystrophy?

  • Decreased insulin resistance as well as decreased insulin secretion
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19
Q

What condition?

  • Thick, dark, skin
  • Really high glucose (always on edge of DKA)
A

? Complete loss of insulin receptor

20
Q

The distinction of type I diabetes means what treatment?

Type II?

A

Must be on insulin with type I

  • Much more flexible with type II
21
Q

What are the clinical distinctions between type I and II diabetes

  • Age
  • Obesity
  • Response to stress
  • Insulin response to glucose
  • Sensitivity to insulin
  • Response to diet alone
  • Response to oral hypoglycemic agents
  • Require insulin to survive?
22
Q

Describe gestational diabetes

A
  • Pregnancy induces insulin resistance
  • 2-13% of pregnant women develop diabetes, usually in 2-3rd TM

(All get insulin resistant, but not everyone gets diabetes- thus, problem on supply end as well. Beta cells can’t always compensate)

  • GDM is associated with increased fetal and maternal morbidity
  • Excess morbidity can be erased by maintaining normoglycemia
  • Distinct diagnostic criteria by OGTT
  • After delivery, risk of type 2 diabetes is 30-40% in 10 years
23
Q

What are the inherited risks for developing type I diabetes?

A
  • No family history: 1%
  • One parent with type I DM
  • Father: 6%
  • Mother: 4% (if mom under 25) or 1% (mom > 25 yo)
  • Sibling with type I: 5-10%
  • Two 1’ relatives with type I: 20%
  • Identical twin with type I: 25-50%
24
Q

What genes are associated with Autoimmune Type I diabetes (don’t memorize details)?

A

Many with HLA, esp Type II MHC

  • HLA (6p21): DQA1, DQB1, DRB1
  • Cytokines: IL-1B, IFN-y, TNF-a
  • T cell: CD4, Fas, Fas-L
  • Beta cell: Insulin

GWAS: about 20 additional loci

25
Acute infection of _____ may lead to increased risk of Type I diabetes?
Acute infection of **Coxsackie B** may lead to increased risk of Type I diabetes
26
Describe the broad pathogenesis of Type I diabetes
Interplay between genetics and environment shaping the immune system (also independently causing Beta cell destruction) - Immune system shapes humoral and cellular responses - These responses mediate beta cell destruction
27
Detailed pathogenesis of beta cell destruction?
GAD is the best known mediator of beta cell destruction - Antibodies against this are effective treatment - GAD/insulin may trigger dendritic cell (DC) - DC may release co-stimulatory signals to activate T and B cell clonal expansion - This leads to Th1 cell activation and production of cytokines...
28
Cytokine mediation of beta-cell destruction?
- Decreased energy generation in mitochondria - Increased NO production - Decreased insulin production/beta cell function - Increased apoptosis - Decreased defense, increased repair
29
What are circulating antibody markers of autoimmune Type I DM?
- Insulin (IAA) - Glutamic Acid Decarboxylase (GAD65 Ab) - Tyrosine Phosphatase (IA-2 Ab) - Zinc Transporter (ZnT8 Ab) - “Islet Cell Antibodies”
30
What is seen here?
Islet Cell Antibodies in Type I DM
31
**T/F:** If Type I DM diagnosed early (via circulating Abs, etc), risk of diabetes can be decreased
**False** - Diagnosis so far outweighs what we can do about it
32
What is seen here?
Islet Beta Cell Destruction in type I DM
33
How much beta cell mass do you have to lose before becoming hypo/hyperglycemic?
90-95%; have a pretty good functional reserve
34
What are risk factors for developing Type II diabetes?
- Racial/ethnic group: Native Americans \> Mexican-Americans \> African Americans \> Caucasians - Obesity - “Metabolic syndrome” (IGT/IFG) - Environment (sedentary lifestyle, “fast foods”)
35
What factors are associated with progression of IGT to type II diabetes? - Not readily measurable - Readily measurable
_NOT READILY MEASURABLE:_ - Insulin resistance/hyperinsulinemia - Beta cell dysfunction _READILY MEASURABLE:_ - Central obesity - Hypertriglyceridemia - HDL cholesterol under 35 mg/dl - Hypertension - Family history of type 2 diabetes - History of gestational diabetes mellitus (GDM)
36
What are the clinical correlates of these risk factors?
Causing insulin resistance! - Genetic abnormalities - Obesity/inactivity - Aging - Medications (e.g. corticosteroids) - Fat cell defects
37
What other affects (apart from Type II DM) can be helped/decreased by treating insulin resistance?
- Hypertension - Dyslipidemia - Atherosclerosis - PCOS (Polycystic Ovary Syndrome)
38
What.
39
What is shown here?
Acanthosis nigricans - Physical feature of insulin resistance (?)
40
Describe the "progression" of defects underlying type II DM - Implications for treatment
- Type II DM becomes like Type I DM after enough time - If beta cells could expand indefinitely, there would be no Type II DM - As person goes from overweight -\> obese -\> diabetic, have lower insulin sensitivity - As insulin sensitivity drops, beta cell responds by producing more and more insulin - Eventually beta cell fails and produces less insulin - Type II diabetic initially has high insulin, but low insulin (like Type I) at the end _Implications for treatment_ (sensitivity and secretion): - Want to treat insulin insensitivity - Want to prevent Beta cell loss
41
What are the inherited risks for developing Type II diabetes?
- No family history: 11% - One parent with type II * Dx under 50 yo: 14% * Dx over 50 yo: 8% - Both parents with type II: * Dx under 50 yo: 45% * Dx over 50 yo: 20% - Sibling with type II: * Dx under 50 yo: 14% * Dx over 50 yo: 8% - Identical twin with type II: 60-70%
42
Describe the genetics of type II diabetes: monogenic syndromes
Genetics of Type II DM are COMPLEX _Secretion side:_ **- "Maturity Onset Diabetes of Youth", MODY** * MODY 1-8 * Glucokinase mutation in MODY2 * All genes related to beta cell **- Neonatal diabetes** (diabetes under 6 mo) **- Mitochondrial diabetes** - Other _Action side:_ **- Severe insulin resistance** * Insulin receptor * Akt **- Lipoatrophic Diabetes**
43
What are some common ("polygenic") forms of pre-disposing genetics for Type II diabetes?
Current standing from GWAS: - 22 genetic loci
44
What are the 2 principal defects in Type II DM?
**1. Insulin resistance** **2. B-cell dysfunction/failure** - Both influenced by genes (early) and type II DM (after started) - Lead to IGT with/out environmental contributions - Results in type II DM - Type II DM -\> gluco/lipo-toxicity
45
Describe Lean-Ketosis-Resistant Diabetes (KRDY) - History - Presentation - Age of onset
Aka **"Protein deficient pancreatic diabetes"** - History of **malnutrition** - Poor SES - Lean or “wasted” at presentation - Age at onset **\< 30 years** - **Absence** of ketosis on withdrawal of insulin - Features of pancreatic exocrine insufficiency, - **Islet cell specific autoantibodies:** variable frequency (less than among patients diagnosed with “type 1” diabetes) - **HLA association: similar to type 1** diabetes in some populations, different in others
46
Describe Obese, Ketosis-Prone Diabetes - Demographic - Presentation - Age of onset
Aka "**Unprovoked A-B + KPD), or "Ketosis-prone type 2 diabetes** - **Non-White** populations - Low SES - Age at onset **\> 40 years** - **Obese** at presentation - Presentation with ketosis or ketoacidosis - **Male** sex preponderance - Ability to withdraw from insulin without ketosis - Islet cell specific autoantibodies **absent** - **HLA association:** high frequency of protective alleles and low frequency of susceptibility alleles

MS2 Endocrine (25 decks)

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