10/14- Diabetes: Intro and Pathophysiology Flashcards
T/F: The prevalence of Type I Diabetes is increasing
True
- 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?
Either:
- 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?
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?
Diabetes possibly due to Addison’s disease
- White hair despite young age
This man has diabetes. What else is seen?
Diabetes possibly due to Acromegaly
- Causes hyperglycemia as well as insulin resistance
This man has diabetes.
What else is seen?
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?
Turner’s (-X)
- Increased risk of Down’s syndrome
This man has diabetes.
Experience inability to quickly relax muscles.
What is expected?
Myotonic dystrophy?
- Decreased insulin resistance as well as decreased insulin secretion
What condition?
- Thick, dark, skin
- Really high glucose (always on edge of DKA)
? 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?
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
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…
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
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?
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
False
- Diagnosis so far outweighs what we can do about it
What is seen here?
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
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)
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)
What.
What is shown here?
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
What are some common (“polygenic”) forms of pre-disposing genetics for Type II diabetes?
Current standing from GWAS:
- 22 genetic loci
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
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
