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📚 Diabetes Mellitus - Exam Notes
1. PANCREATIC ENDOCRINE ANATOMY
| Cell | Hormone | % of islet |
|---|---|---|
| B (beta) | Insulin | 70-80% |
| A (alpha) | Glucagon | ~20% |
| D (delta) | Somatostatin | 3-5% |
| F | Pancreatic polypeptide | Small |
- Islets of Langerhans = 0.7-1 million glands; ~1% of pancreatic mass
- Islets are richly vascularized (5-10x normal blood flow)
2. INSULIN
Structure: 51 amino acids; A chain (21) + B chain (30) connected by 2 disulfide bridges. MW = 5808.
Synthesis: Preproinsulin → Proinsulin → Insulin + C-peptide (in equimolar amounts)
Secretion:
- Basal: ~40-50 units/day; fasting level ~10 μU/mL
- Glucose is the most potent stimulant
- Requires calcium; cAMP is also a modulator
- Biphasic release: early phase (quick burst) + late phase (sustained)
- Half-life: 3-5 min; catabolized mostly by liver (50% first pass)
Insulin Receptors:
- α-subunit (MW 130,000): extracellular, binds insulin
- β-subunit (MW 90,000): cytoplasmic, contains tyrosine kinase
- Down-regulation: chronic high insulin → fewer receptors (obesity, high carb diet)
- Up-regulation: low insulin → more receptors (exercise, fasting)
3. GLUCOSE TRANSPORTERS (GLUTs)
| GLUT | Location | Key Function |
|---|---|---|
| GLUT1 | All tissues | Basal glucose uptake; blood-brain barrier |
| GLUT2 | Pancreas B cell, liver | Low affinity; works only when glucose is high (postprandial) |
| GLUT3 | Neurons | High affinity; CSF → neuron transport |
| GLUT4 | Skeletal muscle, adipose | Insulin-dependent; translocates to surface after insulin signal |
| GLUT5 | Small intestine | Primarily fructose transporter |
4. INSULIN EFFECTS ON METABOLISM
Carbohydrate: ↑ glucose transport into cells, ↑ glycolysis, ↑ glycogen synthesis, ↓ glycogenolysis & gluconeogenesis in liver
Fat: ↓ lipolysis, ↑ fatty acid & triglyceride synthesis, ↑ VLDL formation, ↑ lipoprotein lipase, ↓ fatty acid oxidation
Protein: ↑ amino acid transport into cells, ↑ protein synthesis, ↓ protein degradation, ↓ urea formation → anabolic hormone
Insulin-independent tissues: Brain, RBCs, retina, blood vessels, kidney - glucose uptake is NOT insulin-dependent
5. COUNTER-REGULATORY HORMONES (cause hyperglycemia)
- Glucagon - stimulates glycogenolysis, gluconeogenesis (mediated by cAMP)
- Glucocorticoids (Cortisol) - stimulate gluconeogenesis at gene level; mobilize fat
- Catecholamines (Epi/Norepi) - activate glycogen phosphorylase; stimulate glycogenolysis in muscle & liver
- Growth Hormone - stimulates glycogenolysis, inhibits hexokinase
- Thyroxine - promotes hyperglycemia by accelerating protein/fat breakdown
6. CLASSIFICATION OF DIABETES
| Type | Description |
|---|---|
| Type 1 (IDDM) | ~10% of diabetics; absolute insulin deficiency; autoimmune |
| Type 2 (NIDDM) | ~90% of diabetics; insulin resistance + relative deficiency |
| MODY | Autosomal dominant; glucokinase gene mutation (chr 7); mild hyperglycemia |
| MRDM | Malnutrition-related; severe protein malnutrition; no ketosis |
| Other types | Pancreatic disease, hormonal, drug-induced, genetic |
| IGT | Impaired Glucose Tolerance - between normal and diabetic |
| GDM | Gestational diabetes |
7. TYPE 1 vs. TYPE 2 COMPARISON
| Feature | Type 1 | Type 2 |
|---|---|---|
| Age of onset | < 20 years | > 20 years |
| Heritability | ~50% | ~80% |
| Beta cells | Destroyed | Normal |
| Circulating insulin | Absent | Normal/high/low |
| Tissue insulin response | Normal | Reduced |
| Fasting hyperglycemia | Severe | Variable |
| Metabolic complication | DKA | Hyperosmolar nonketotic coma |
| Treatment | Insulin injections | Diet, oral agents, or insulin |
Type 1 HLA associations: DR3, DR4, DQ (increased risk); DR2, DR7 (decreased)
Type 1 autoimmune markers: Islet cell antibodies (ICAs), Insulin autoantibodies (IAAs), Anti-GAD antibodies (present in ~80% at diagnosis)
Type 2 risk factors: Obesity (especially central/"android"), physical inactivity, high-fat diet
8. CLINICAL FEATURES
| Symptom | Type 1 | Type 2 |
|---|---|---|
| Polyuria & thirst | ++ | + |
| Weakness/fatigue | ++ | + |
| Polyphagia + weight loss | ++ | - |
| Blurred vision | + | ++ |
| Vulvovaginitis/pruritus | + | ++ |
| Peripheral neuropathy | + | ++ |
| Often asymptomatic | - | ++ |
9. DIAGNOSIS
Fasting plasma glucose > 140 mg/dL (7.8 mmol/L) on more than one occasion = Diabetes
Oral Glucose Tolerance Test (OGTT):
- Preparation: 150-200g carbs/day for 3 days before
- Adults: 75g glucose in 300 mL water
- Normal: Fasting < 115 mg/dL; 2-hour < 140 mg/dL; no value > 200 mg/dL
- Diabetes: 2-hour > 200 mg/dL + one other value > 200 mg/dL
- IGT: Values between normal and diabetic thresholds
HbA1c:
- Normal: 4-6% of total hemoglobin
- Reflects glycemia over past 8-12 weeks (RBC lifespan ~120 days)
- Good control: 5-8%; Poor control: 12-15%
- Preferred diagnostic test (per 2009 expert committee)
C-peptide: Used to assess residual beta cell function in insulin-treated patients
Microalbuminuria: 20-200 μg/min = early marker of nephropathy
10. CHRONIC COMPLICATIONS
Diabetic Retinopathy
Stages:
- Background - microaneurysms (earliest sign), hard exudates, dot/blot hemorrhages
- Preproliferative - cotton-wool spots, venous beading, retinal ischemia
- Proliferative - new vessel formation (neovascularization) - can cause vitreous hemorrhage, retinal detachment
- Maculopathy - most common cause of diabetes-related blindness
Treatment: Laser photocoagulation (panretinal)
In Type 1: retinopathy rare in first 5 years; ~90% prevalence after 15 years
Diabetic Nephropathy
Phases: Hyperfiltration → Microalbuminuria → Overt proteinuria → End-stage renal failure
- Microalbuminuria: 20-200 μg/min (20x higher risk of progression to overt nephropathy)
- Overt nephropathy: albumin > 300 mg/24h → GFR progressively declines
- Treatment: ACE inhibitors (e.g., enalapril) - dilate efferent arteriole; reduce microalbuminuria even without hypertension
- Low-protein diet (0.8 g/kg/day)
- ESRD = major cause of death in Type 1
Diabetic Neuropathy
Pathogenesis:
- Sorbitol/fructose accumulation via polyol pathway → nerve swelling + demyelination
- Myoinositol deficiency → impaired Na+/K+-ATPase
- Glycosylation of nerve proteins
- Endoneurial microangiopathy
Types:
- Distal polyneuropathy (most common) - "stocking and glove" sensory loss, pain at night, absent Achilles reflex
- Mononeuropathy - pressure palsies, sudden cranial nerve palsies (CN III, VI most common)
- Femoral (proximal motor) neuropathy - hip/knee weakness, affects patients >50y; good prognosis (recovery in 12-24 months)
- Autonomic neuropathy:
- Cardiovascular: resting tachycardia (90-130/min), fixed cardiac rhythm, orthostatic hypotension, silent MI
- Urogenital: bladder atony, erectile dysfunction, retrograde ejaculation
- GI: gastroparesis, diabetic diarrhea (watery, early morning, intermittent), gustatory sweating
Macrovascular Disease
- Atherosclerosis of coronary, cerebral, and peripheral arteries
- CAD: 2-3x more common; 9x higher mortality in Type 1 men, 14x in women vs general population
- LDL glycosylation → ↓ LDL receptor binding → ↑ vascular invasion
- Peripheral vascular disease: 5x more frequent; leads to gangrene
Diabetic Foot
- Due to combination of neuropathy + angiopathy + infection
- Leg amputation 15x more frequent than general population
- Three forms: neuropathic, neuroischemic, mixed
11. METABOLIC SYNDROME X ("Lethal Quartet")
- Obesity + impaired glucose tolerance/Type 2 DM + hyperlipidemia + arterial hypertension
- Also called "Syndrome X" in British-American literature
12. LABORATORY FINDINGS
- Normal fasting whole blood glucose: 60-110 mg/dL (3.3-6.1 mmol/L)
- Normal fasting plasma glucose: 70-120 mg/dL (3.9-6.7 mmol/L)
- Renal threshold for glycosuria: ~180-200 mg/dL (not reliable for monitoring)
- Dipstick for glycosuria uses glucose oxidase + chromogen reaction; sensitive to ≥100 mg/dL
13. TREATMENT
Diet Principles
- Obese: caloric restriction to achieve ideal weight
- Carbohydrates: reduced from previous 55-60% to lower (high carb → hyperglycemia + ↑ triglycerides)
- Simple sugars: limited to 5-15% of total calories
- Protein: 10-20% of total calories
- Fiber: 20-35g/day recommended
- Cholesterol: < 300 mg/day
Oral Antidiabetic Agents
| Drug | Mechanism | Key Points |
|---|---|---|
| Sulfonylureas (glipizide, glyburide, glimepiride) | Close K+ channels on beta cells → depolarization → Ca²⁺ influx → insulin release | Risk: hypoglycemia + weight gain; Not for Type 1; 2nd gen preferred |
| Metformin (biguanide) | ↓ hepatic glucose output, ↓ gluconeogenesis, ↑ peripheral glucose uptake | No hypoglycemia; ↓ weight; Contraindicated in renal failure, liver disease, alcoholism, hypoxia. Risk: lactic acidosis |
| Meglitinides (Repaglinide) | Same K+ channel mechanism as sulfonylureas | Taken with meals; good for postprandial spikes |
| Alpha-glucosidase inhibitors (Acarbose) | Delay carb absorption in gut | ↓ postprandial hyperglycemia by 50%; No hypoglycemia alone; Main SE: flatulence, diarrhea |
| Thiazolidinediones (Rosiglitazone, Pioglitazone) | Bind nuclear receptor (PPAR-γ); ↓ insulin resistance in muscle/fat/liver | Monitor liver function; Contraindicated in liver disease, CHF |
Oral agents are contraindicated in: Type 1 DM, pregnancy, severe illness, significant renal/liver disease
Insulin Types
| Type | Onset | Peak | Duration |
|---|---|---|---|
| Rapid analogs (Lispro, Aspart, Glulisine) | 10-15 min | 1.5-2 h | 3-4 h |
| Regular (short-acting) | 15 min | 1-3 h | 5-7 h |
| NPH (intermediate) | ~2 h | 6-12 h | 18-24 h |
| Glargine (Lantus) | 1-2 h | Peakless | ~24 h |
| Detemir (Levemir) | 1-2 h | Minimal | ~17 h |
- Insulin glargine: inject any time of day; provides flat 24h basal coverage
- Only regular insulin can be given IV or in infusion pumps (use buffered Velosulin for pumps)
14. ACUTE COMPLICATIONS
Diabetic Ketoacidosis (DKA)
Pathogenesis: Insulin deficiency → ↑ glucagon → ↑ ketogenesis (acetoacetate, β-hydroxybutyrate, acetone) + ↑ gluconeogenesis → hyperglycemia + metabolic acidosis
Clinical features:
- Polyuria, polydipsia, nausea, vomiting, abdominal pain
- Kussmaul respirations (deep, rapid) when pH ≤ 7.1
- "Fruity" acetone breath
- Dehydration, postural hypotension, tachycardia
Labs:
- Glucose: 350-900 mg/dL
- Low pH (6.9-7.2), low bicarbonate (5-15 mEq/L)
- Serum K+ normal or slightly high (despite total body depletion - shifts out of cells in acidosis)
- Serum Na+ low (~125-130 mEq/L)
- Serum osmolality formula: mosm/L = 2[Na⁺] + glucose(mg/dL)/18
Treatment (DKA):
- Fluids: 2L normal saline in first 2-3 hours; switch to 0.45% saline after 2L; switch to 5% dextrose when glucose reaches 250 mg/dL
- Insulin: Loading 0.3 units/kg IV bolus → 0.1 units/kg/h continuous infusion (only regular insulin IV)
- Bicarbonate: If pH ≤ 7.0; give until pH reaches 7.1 (stop at 7.1 - risk of rebound alkalosis)
- Potassium: 10-30 mEq/h when acidosis resolves and urine output is adequate
- Phosphate: Only if severe hypophosphatemia (< 1 mg/dL)
Hyperglycemic Hyperosmolar Nonketotic (HHNK) State
- Middle-aged/elderly Type 2 patients
- Severe hyperglycemia: 800-2400 mg/dL
- Serum osmolality > 330-440 mosm/L
- No ketosis (residual insulin prevents lipolysis)
- Dehydration is profound; consciousness impaired when osmolality > 330 mosm/L
Treatment HHNK (vs DKA differences):
- Start with 0.45% (hypotonic) saline (not isotonic)
- Less insulin needed than DKA; initial 15 units IV regular, then 10-25 units every 4h
- Search for precipitating cause (pneumonia, MI, stroke, drugs like phenytoin/thiazides)
Hypoglycemia
Causes: Excess insulin/sulfonylurea dose, missed meal, unusual exercise
Signs/symptoms:
- Neuroglycopenia: confusion, bizarre behavior, stupor, coma
- Autonomic: tachycardia, sweating, tremor, nausea, hunger
Counterregulation:
- Glucagon is first line of defense (lost in Type 1 within a few years of diagnosis)
- Then catecholamines/sympathetic system
Somogyi effect vs Dawn phenomenon:
| 10 PM | 3 AM | 7 AM | |
|---|---|---|---|
| Somogyi effect | 90 | 40 (low) | 200 (rebound) |
| Dawn phenomenon | 110 | 110 | 150 |
| Waning insulin | 110 | 190 | 220 |
Treatment:
- Conscious patient: orange juice, glucose tablets, sugary food
- Unconscious patient: 50 mL of 50% glucose IV over 3-5 minutes, OR 1 mg glucagon IM (restores consciousness in 10-15 min)
Lactic Acidosis
- Plasma lactate > 5-6 mmol/L (normal ~1 mmol/L)
- Profound acidosis; low or absent ketones
- Associated with metformin use in patients with renal/hepatic/cardiorespiratory failure or tissue hypoxia
- Treatment: treat underlying cause; IV sodium bicarbonate to keep pH > 7.2; ensure oxygenation
15. KEY NUMBERS TO REMEMBER
| Value | What it represents |
|---|---|
| 4-6% | Normal HbA1c |
| 5-8% | Good diabetic control (HbA1c) |
| 8-12 weeks | Period reflected by HbA1c |
| 120 days | RBC lifespan |
| 20-200 μg/min | Microalbuminuria range |
| 300 mg/24h | Overt proteinuria threshold |
| > 140 mg/dL fasting | Diagnostic for diabetes |
| > 200 mg/dL at 2h OGTT | Diagnostic for diabetes |
| 10 μU/mL | Normal fasting insulin |
| 3-5 min | Insulin half-life |
| ~50% | Insulin removed on first pass through liver |
Good luck on your exam! The highest-yield areas for questions are usually: DKA vs HHNK differences, insulin types, oral drug mechanisms/contraindications, complications pathogenesis, and diagnostic criteria.
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