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Diabetes Mellitus — Exam-Oriented Review

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DEFINITION

• Reduced insulin secretion
• Decreased glucose utilization
• Increased hepatic glucose production

• End-stage renal disease (ESRD)
• Non-traumatic lower-extremity amputations
• Adult blindness
• Major contributor to cardiovascular disease (main cause of mortality in DM)

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CLASSIFICATION (Table 415-1, Harrison's 22E)

Other Specific Causes:

• MODY (Maturity-Onset Diabetes of the Young): Autosomal dominant, onset <25 years, impaired insulin secretion due to single gene defects
• Endocrinopathies: Acromegaly, Cushing's disease (insulin-antagonizing hormones)
• Drug-induced: Glucocorticoids, atypical antipsychotics, thiazides
• Pancreatic: Cystic fibrosis, chronic pancreatitis
• Fulminant T1DM: Rapidly progressive, Japanese predominance

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PATHOPHYSIOLOGY

Type 1 DM

• Autoimmune destruction of pancreatic β-cells by T-lymphocytes
• HLA associations: HLA-DR3, HLA-DR4 (strongest risk); HLA-DQ alleles
• Autoantibodies (markers): islet cell antibodies (ICA), anti-insulin (IAA), anti-GAD65, anti-IA-2 (anti-tyrosine phosphatase), anti-ZnT8
• Defined in 3 stages:
  • Stage 1: Autoantibodies present, normoglycemia
  • Stage 2: Autoantibodies + dysglycemia (prediabetes range)
  • Stage 3: Clinical hyperglycemia → DM diagnosis
• Environmental triggers: viral infections (Coxsackievirus B), early cow's milk exposure (proposed)
• Result: Absolute insulin deficiency → dependence on exogenous insulin

Type 2 DM

• Heterogeneous disorder; multifactorial (genetic + environmental)
• Core defects:
  1. Insulin resistance in skeletal muscle, liver, and adipose tissue
  2. Impaired β-cell insulin secretion (progressive β-cell dysfunction/loss)
  3. Increased hepatic glucose production
• Insulin resistance → compensatory hyperinsulinemia → eventual β-cell exhaustion
• Peripheral glucose uptake (via GLUT4 translocation in skeletal muscle/fat) is impaired
• Insulin receptor signaling defect: ↓ PI3-kinase pathway activity → impaired GLUT4 translocation
• Progression: prediabetes (IFG/IGT) → overt T2DM
• Obesity (especially visceral/central) is the major modifiable risk factor

Normal Glucose-Stimulated Insulin Secretion (Key Mechanism):

• GLP-1 and GIP (incretins) amplify glucose-stimulated insulin secretion via cAMP; basis for incretin-based therapy

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DIAGNOSIS (ADA/WHO Criteria)

Key rule: Any single abnormal test must be confirmed on repeat (on a different day) unless the patient has unequivocal hyperglycemia with symptoms or is in acute metabolic crisis.

Prediabetes:

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CLINICAL FEATURES

Symptoms of Hyperglycemia (Acute):

• Polyuria (osmotic diuresis)
• Polydipsia
• Polyphagia
• Weight loss (especially T1DM — catabolic state)
• Fatigue, weakness
• Blurred vision (lens water content changes — reversible with treatment)
• Recurrent infections: vaginal candidiasis, skin fungal infections
• Slow wound healing

Physical Examination in Known DM Should Include:

• Weight/BMI, blood pressure (orthostatic), retinal examination
• Foot exam: pedal pulses, 10-g monofilament testing, vibratory sense (128-Hz tuning fork at base of great toe), ankle reflexes
• Skin inspection, injection sites, periodontal health

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MONITORING GLYCEMIC CONTROL

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MANAGEMENT

1. Medical Nutrition Therapy (MNT)

• Reduce caloric intake, low glycemic index foods, Mediterranean-style diet
• Weight loss target in T2DM: ≥5% body weight to meaningfully improve glycemia

2. Exercise

• Increases insulin sensitivity, promotes weight loss
• Aerobic + resistance training recommended

3. Pharmacologic — Type 1 DM

4. Pharmacologic — Type 2 DM

GLP-1 RAs and SGLT-2 inhibitors have proven cardiovascular mortality benefit in T2DM with established ASCVD and should be prioritized in such patients, independent of HbA1c.

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ACUTE COMPLICATIONS

1. Diabetic Ketoacidosis (DKA)

• Predominantly T1DM (occasionally T2DM)
• Precipitated by: infection, missed insulin, new T1DM onset
• Pathogenesis: Absolute insulin deficiency + ↑ counter-regulatory hormones → lipolysis → ketogenesis (acetoacetate, β-hydroxybutyrate) → anion gap metabolic acidosis
• Triad: Hyperglycemia (typically >11 mmol/L / 200 mg/dL), Ketosis, Metabolic acidosis (pH <7.3, bicarbonate <18)
• Features: Nausea/vomiting, abdominal pain, Kussmaul breathing, fruity breath, altered consciousness
• Management: IV fluids, insulin infusion, potassium replacement, bicarbonate (if pH <6.9)

2. Hyperosmolar Hyperglycemic State (HHS)

• Predominantly T2DM in elderly
• Extreme hyperglycemia (>33 mmol/L / 600 mg/dL), severe dehydration, serum osmolality >320 mOsm/kg
• Absent ketosis (residual insulin prevents lipolysis)
• Higher mortality than DKA

3. Hypoglycemia

• Threshold: <3.0 mmol/L (<54 mg/dL) for significant hypoglycemia
• Causes: Excess insulin, missed meals, exercise, alcohol, renal failure
• Symptoms: Adrenergic (sweating, tremor, palpitations) → Neuroglycopenic (confusion, seizure, coma)
• T1DM: ~2 symptomatic episodes/week; 6–10% die from hypoglycemia
• Hypoglycemia-Associated Autonomic Failure (HAAF): Recurrent hypoglycemia impairs counter-regulatory hormone release (esp. epinephrine) → hypoglycemia unawareness → risk of severe events

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CHRONIC COMPLICATIONS

Mechanism Linking Hyperglycemia to Microvascular Complications:

1. Polyol pathway (sorbitol accumulation via aldose reductase)
2. Advanced Glycation End-products (AGEs)
3. Protein kinase C (PKC) activation
4. Hexosamine pathway flux

Microvascular Complications

A. Diabetic Retinopathy

• Leading cause of new blindness in adults (developed world)
• Stages:
  • Non-proliferative (NPDR): Microaneurysms, hard exudates, cotton-wool spots, venous beading, IRMA (intraretinal microvascular abnormalities)
  • Proliferative (PDR): Neovascularization → vitreous hemorrhage → tractional retinal detachment
  • Diabetic macular edema (DME): Most common cause of visual loss in DM; can occur at any stage
• Screening: Annual dilated funduscopic exam; begin 5 years after T1DM diagnosis, at diagnosis in T2DM
• Treatment: Laser photocoagulation, intravitreal anti-VEGF agents, vitrectomy

B. Diabetic Nephropathy

• Leading cause of ESRD in developed countries
• Natural history (Mogensen stages):
  1. Hyperfiltration (↑ GFR)
  2. Silent (normal GFR, normal albumin)
  3. Incipient (microalbuminuria: 30–300 mg/day)
  4. Overt nephropathy (macroalbuminuria >300 mg/day, ↓ GFR)
  5. End-stage renal disease (dialysis/transplant)
• Pathology: Glomerular basement membrane thickening, mesangial expansion, Kimmelstiel-Wilson nodules (nodular glomerulosclerosis — pathognomonic)
• Management: ACE inhibitors/ARBs (reduce proteinuria and slow progression), SGLT-2 inhibitors (finerenone in diabetic CKD), tight glycemic control, BP control <130/80

C. Diabetic Neuropathy (~50% of long-standing DM)

• Risk factors: Duration of DM, poor glycemic control, BMI, smoking, hypertension, dyslipidemia

1. Distal Symmetric Polyneuropathy (DSPN) — most common
   • Sensory > motor; "stocking-glove" pattern; begins distally
   • Symptoms: Numbness, tingling, burning pain, worse at night
   • Leads to Loss of Protective Sensation (LOPS) → foot ulceration, Charcot arthropathy, amputation
   • Exam: ↓ vibration sense (tuning fork), ↓ 10-g monofilament, ↓ ankle reflexes
2. Autonomic Neuropathy
   • Cardiovascular: Resting tachycardia, orthostatic hypotension, decreased HRV, ↑ QTc
   • GI: Gastroparesis (early satiety, nausea, postprandial bloating), diarrhea
   • Genitourinary: Neurogenic bladder, erectile dysfunction
   • Sudomotor: Anhidrosis (feet) → dry cracked skin; hyperhidrosis (upper body)
   • Hypoglycemia unawareness
3. Mononeuropathy / Cranial Neuropathy: CN III palsy (sparing pupil — differentiates from posterior communicating artery aneurysm), CN VI, ulnar, median nerve entrapment
4. Diabetic amyotrophy (Bruns-Garland syndrome): Asymmetric proximal weakness, painful, older T2DM patients; usually self-limiting

• Screening: At T1DM diagnosis (annually from 5 years post-diagnosis); at T2DM diagnosis (annually thereafter)
• Treatment: Glycemic control, pain management — pregabalin, duloxetine (first-line ADA), amitriptyline, gabapentin; capsaicin cream

Macrovascular Complications

• ASCVD (coronary artery disease, stroke, PAD) is the leading cause of mortality in DM
• DM women with ASCVD lose the cardioprotective effect of female sex
• Pathogenesis: Dyslipidemia (↑ TG, ↓ HDL, small dense LDL), hypertension, endothelial dysfunction, hypercoagulability
• Management: Statins (high-intensity), ACE inhibitors/ARBs, aspirin in established CVD, GLP-1 RAs and SGLT-2 inhibitors (proven CV mortality reduction)

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SCREENING FOR TYPE 2 DM (ADA Criteria)

• Family history of DM (first-degree relative)
• High-risk ethnicity (African American, Latino, Native American, Asian American, Pacific Islander)
• Hypertension (BP ≥130/80)
• HDL <35 mg/dL or TG >250 mg/dL
• PCOS or acanthosis nigricans
• History of CVD
• Physical inactivity
• History of GDM or delivery of baby >4 kg
• Previously identified IFG, IGT, or HbA1c 5.7–6.4% → screen annually

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HIGH-YIELD EXAM POINTS

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GLYCEMIC TARGETS SUMMARY (ADA 2024)

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