10/14- Diabetes: Intro and Pathophysiology Flashcards Preview

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Flashcards in 10/14- Diabetes: Intro and Pathophysiology Deck (46):

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


- Both type I and type II diabetes are increasing


The rise in Type II diabetes is linked to ____

The rise in Type II diabetes is linked to obesity


What is the impact of DM?

- Prevalence

- Over 20M Americans have diabetes

- Probably same amount are undiagnosed

- 42M have the "Metabolic syndrome"

- Cost (2004) was > $180B with > 20M hospital days


What is the definition of diabetes?

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)


What are the diagnostic criteria for diabetes?

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)


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

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


What constitutes "Impaired" Glycemic Control?


- Fasting plasma glucose 100-126 mg/dl (Impaired Fasting Glucose)

- 2h OGTT plasma glucose 140-200 mg/dl (Impaired Glucose Tolerance)


What are the risks of Impaired Glycemic Control?

- Risk of developing type 2 diabetes 3%/year

- Elevated risk (approaching that of diabetes) for macrovascular disease


How do you diagnose diabetes/Who should you screen?

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


What should the initial screening be?

Do what depending on results?

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


How is Diabetes classified? What are causes of each?

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


This woman has diabetes. What else is seen? 

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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


This woman has diabetes. What else is seen?

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Diabetes possibly due to Addison's disease

- White hair despite young age


This man has diabetes. What else is seen?

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Diabetes possibly due to Acromegaly

- Causes hyperglycemia as well as insulin resistance


This man has diabetes.

What else is seen? 

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Klinefelter's (XXY)


Diabetes is associated with what endocrinopathies?

Other genetic diseases?

- Cushing's dz

- Addison's dz

- Acromegaly

- Klinefelter's syndrome

- Turner's dz

- (Increased risk with Down's syndrome)

- Myotonic dystrophy


This woman has diabetes.

What else is seen? 

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Turner's (-X)

- Increased risk of Down's syndrome


This man has diabetes.

Experience inability to quickly relax muscles.

What is expected? 

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Myotonic dystrophy?

- Decreased insulin resistance as well as decreased insulin secretion


What condition?

- Thick, dark, skin

- Really high glucose (always on edge of DKA) 

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? Complete loss of insulin receptor


The distinction of type I diabetes means what treatment?

Type II?

Must be on insulin with type I

- Much more flexible with type II


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?

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Describe gestational diabetes

- 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


What are the inherited risks for developing type I diabetes?

- 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%


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

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


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


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 

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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...

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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 

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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”


What is seen here?

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Islet Cell Antibodies in Type I DM


T/F: If Type I DM diagnosed early (via circulating Abs, etc), risk of diabetes can be decreased


- Diagnosis so far outweighs what we can do about it


What is seen here? 

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Islet Beta Cell Destruction in type I DM


How much beta cell mass do you have to lose before becoming hypo/hyperglycemic?

90-95%; have a pretty good functional reserve


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”)


What factors are associated with progression of IGT to type II diabetes?

- Not readily measurable

- Readily measurable


- Insulin resistance/hyperinsulinemia

- Beta cell dysfunction


- Central obesity

- Hypertriglyceridemia

- HDL cholesterol under 35 mg/dl

- Hypertension

- Family history of type 2 diabetes

- History of gestational diabetes mellitus (GDM)


What are the clinical correlates of these risk factors?

Causing insulin resistance!

- Genetic abnormalities

- Obesity/inactivity

- Aging

- Medications (e.g. corticosteroids)

- Fat cell defects


What other affects (apart from Type II DM) can be helped/decreased by treating insulin resistance?

- Hypertension

- Dyslipidemia

- Atherosclerosis

- PCOS (Polycystic Ovary Syndrome)


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What is shown here?

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Acanthosis nigricans

- Physical feature of insulin resistance (?)


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


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%


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

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What are some common ("polygenic") forms of pre-disposing genetics for Type II diabetes?

Current standing from GWAS:

- 22 genetic loci

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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

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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


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