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
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 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 is seen here?
Islet Cell Antibodies in Type I DM
What is seen here?
Islet Beta Cell Destruction in type I DM
What.
What is shown here?
Acanthosis nigricans
- Physical feature of insulin resistance (?)
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
