Diabetes Mellitus - A Brief Review for Medical PG

1. Definition & Classification

• Harrison's 22E, p. 3227; Creasy & Resnik's Maternal-Fetal Medicine, p. 1425

2. Pathophysiology

Normal Insulin Physiology

Type 1 DM - Pathogenesis

• Islet cell autoantibodies (ICA)
• Anti-insulin antibodies (IAA)
• Anti-GAD65 (glutamic acid decarboxylase)
• Anti-IA-2 (tyrosine phosphatase-related islet antigen 2)

• Stage 1: ≥2 autoantibodies present, normoglycemia
• Stage 2: Autoimmunity + dysglycemia (but below DM threshold)
• Stage 3: Overt hyperglycemia meeting DM criteria ("clinical DM")

Figure: Temporal model of T1DM - progressive beta cell loss from immunologic trigger to overt diabetes. (Harrison's 22E)

• T1DM accounts for 5-10% of all DM cases
• Up to 40% of T1DM onset occurs after age 30 - many adults are initially misdiagnosed as T2DM

Type 2 DM - Pathogenesis

1. Insulin resistance in muscle, fat, and liver - the first abnormality
2. Compensatory hyperinsulinemia - beta cells initially compensate
3. Progressive beta-cell failure - eventual pancreatic exhaustion leads to insulinopenia
4. Blunted incretin response (GLP-1/GIP)
5. Increased glucagon secretion
6. Enhanced hepatic glucose output
7. Renal glucose reabsorption (SGLT2)
8. Brain insulin resistance

• Goldman-Cecil, p. 2468: "Resistance to insulin's action, primarily in muscle and fat but also in the liver, is typically the first abnormality...over time, hyperglycemia occurs as the consequence of the inability of β cells to produce enough insulin."

• Lifetime risk: 40% with one parent affected; 70% with both parents
• Monozygotic twin concordance: ~70%; dizygotic: 20-30%
• MODY (monogenic): autosomal dominant, ≥11 gene mutations; accounts for 1-3% of DM <30 yrs
  • MODY2: glucokinase mutation (glucose sensor defect)
  • MODY3: HNF-1α mutation (most common MODY)

3. Diagnosis

• Tietz Textbook of Laboratory Medicine 7E; Barash Clinical Anesthesia 9E, p. 2756

• HbA1c reflects average glucose over ~3 months; false results with hemoglobinopathies, hemolytic anemia, iron deficiency
• OGTT is the gold standard in GDM screening; not routinely used in non-pregnant adults unless FPG/HbA1c borderline
• Impaired fasting glucose (IFG) = 100-125 mg/dL; indicates high risk for T2DM and CV disease

4. Clinical Features

Acute Symptoms (classic "polys"):

• Polyuria - osmotic diuresis from glycosuria
• Polydipsia - compensatory water intake
• Polyphagia with weight loss (esp. T1DM)
• Blurred vision (osmotic lens changes)
• Fatigue, recurrent infections (vulvovaginal candidiasis, balanitis, UTI, skin infections)

T1DM specific:

• Acute/abrupt onset, often in youth (but can be any age)
• 25-50% present with DKA at diagnosis
• Thin/normal weight; absent C-peptide

T2DM specific:

• Often asymptomatic - discovered incidentally
• Gradual onset; commonly overweight/obese
• Acanthosis nigricans (insulin resistance marker)
• Complications may be present at diagnosis

5. Hyperglycemic Emergencies

Diabetic Ketoacidosis (DKA)

1. Fluids: 0.9% NaCl 1-2 L in first hour; then 0.45% NaCl; switch to dextrose-containing fluids when glucose reaches 200-250 mg/dL
2. Insulin: IV regular insulin infusion at 0.1 U/kg/hr (after K⁺ ≥3.5 mEq/L confirmed)
3. Potassium replacement: Critical - insulin drives K⁺ intracellularly; hypokalemia is life-threatening. Replace if K⁺ <3.5; hold insulin if K⁺ <3.3
4. Bicarbonate: Only if pH <6.9 (controversial)
5. Identify and treat precipitating cause

Hyperosmolar Hyperglycemic State (HHS)

• Predominantly T2DM; elderly patients
• Profound dehydration, markedly elevated glucose (>600 mg/dL), hyperosmolarity (>320 mOsm/kg), minimal/no ketosis
• Mortality higher than DKA (~15% vs. 1-5%)
• Treatment: aggressive fluid resuscitation (deficit often 8-10 L), cautious insulin, electrolyte replacement

6. Chronic Complications

Microvascular Complications

• Leading cause of end-stage renal disease (ESRD) globally
• Stages: Hyperfiltration → microalbuminuria (30-300 mg/day) → macroalbuminuria → declining GFR → ESRD
• Histology: diffuse and nodular (Kimmelstiel-Wilson nodules) glomerulosclerosis
• Annual screening: urine ACR + eGFR
• Treatment: ACE inhibitors/ARBs (antiproteinuric + renoprotective); SGLT2 inhibitors now first-line add-on (CREDENCE, DAPA-CKD trials)

• Most common cause of new blindness in working-age adults in developed countries
• Non-proliferative (NPDR): microaneurysms, dot-blot hemorrhages, hard exudates, cotton-wool spots
• Proliferative (PDR): neovascularization → vitreous hemorrhage, tractional retinal detachment
• Macular edema: leading cause of visual impairment in DM
• Annual dilated fundus exam; treatment: laser photocoagulation, anti-VEGF (ranibizumab, bevacizumab)

• Most common complication; affects ~50% with longstanding DM
• Types:
  • Distal symmetric sensorimotor polyneuropathy (DSPN): "stocking-glove" pattern; positive/negative symptoms; risk of Charcot foot
  • Autonomic neuropathy: gastroparesis, orthostatic hypotension, resting tachycardia, erectile dysfunction, neurogenic bladder, gustatory sweating
  • Mononeuropathies: CN III palsy (pupil sparing - important exam point), carpal tunnel, femoral neuropathy
• Treatment: glycemic control (prevention), pregabalin/gabapentin, duloxetine, TCAs for pain

Macrovascular Complications

• Coronary artery disease: 2-4x increased risk; DM is CAD-equivalent in many risk scores
• Stroke: 2-3x increased risk
• Peripheral artery disease (PAD): Leads to diabetic foot, gangrene, amputation
• Aggressive CV risk factor control: statins, antihypertensives (target BP <130/80), antiplatelet therapy
• Diabetic foot: Neuropathy + vasculopathy + infection triad → most common cause of non-traumatic lower limb amputation

7. Management

Glycemic Targets (ADA 2024)

Non-Pharmacological Management

• T1DM: carbohydrate counting + insulin-to-carb ratio; minimize weight gain
• T2DM: caloric restriction, weight loss of at least 5-10%, reduced carbohydrate; very-low-carb diets show rapid glucose-lowering
• Sodium <2300 mg/day; attend to chrononutrition

• 150 min/week of moderate aerobic exercise, distributed over ≥3 days (no gaps >2 consecutive days)
• Resistance training + flexibility training also advised
• Reduces CV risk, BP, body fat, and improves insulin sensitivity

Pharmacological Management

Type 1 DM - Insulin Therapy

• Basal insulin: Glargine (U-100/U-300), Detemir, Degludec - once or twice daily
• Bolus (prandial) insulin: Lispro, Aspart, Glulisine - before each meal
• Inhaled insulin (Afrezza): Rapid-acting, ultrashort; not for patients with lung disease
• Insulin pump (CSII): Continuous subcutaneous insulin infusion; reduces hypoglycemia vs. MDI
• Closed-loop systems (artificial pancreas): CGM + CSII with automated dosing - now commercially available

Type 2 DM - Stepwise Approach

• Established CVD or high CV risk: GLP-1 RA or SGLT2 inhibitor
• Heart failure or CKD: SGLT2 inhibitor first
• Weight management priority: GLP-1 RA (semaglutide most potent for weight loss)
• Hypoglycemia risk: Avoid sulfonylureas; prefer DPP-4i, GLP-1 RA, or SGLT2i

8. Special Situations

Gestational Diabetes Mellitus (GDM)

• Screening: 24-28 weeks; 50g GCT (1-hr ≥140 mg/dL → proceed to 100g OGTT / or 75g OGTT directly)
• Management: dietary modification first; insulin if targets not met (glyburide/metformin used off-label)
• Risk: 50-70% develop T2DM within 5-10 years postpartum
• Fetal risks: macrosomia, shoulder dystocia, neonatal hypoglycemia, stillbirth

MODY (Maturity-Onset Diabetes of the Young)

• MODY2 (glucokinase): mild stable hyperglycemia; rarely needs pharmacotherapy
• MODY3 (HNF-1α): sensitive to sulfonylureas; often misdiagnosed as T1DM

Latent Autoimmune Diabetes in Adults (LADA)

• Slow-onset T1DM in adults; initially appears like T2DM
• GAD65 antibodies positive; C-peptide low-normal initially
• Eventually requires insulin

9. Monitoring

10. Key High-Yield Points for PG Exams

1. Whipple's triad for hypoglycemia: symptoms + low glucose + relief with glucose correction
2. Somogyi effect (rebound hyperglycemia after nocturnal hypoglycemia) vs. Dawn phenomenon (early morning hyperglycemia from GH/cortisol surge) - distinguished by 3 AM glucose monitoring
3. Kussmaul breathing is deep, labored breathing - a respiratory compensation for metabolic acidosis in DKA (not hyperventilation per se)
4. Pseudo-hyponatremia in DKA: correct Na⁺ by adding 1.6 mEq/L per 100 mg/dL glucose above 100
5. CN III palsy in DM - pupil-sparing (ischemic etiology) vs. pupil-involved (surgical emergency - posterior communicating artery aneurysm)
6. Kimmelstiel-Wilson nodules = pathognomonic of diabetic nephropathy (nodular glomerulosclerosis)
7. HbA1c falsely low in: hemolytic anemia, sickle cell, blood transfusions; falsely high in: iron deficiency anemia
8. DKA can occur in T2DM - especially with SGLT2 inhibitors (euglycemic DKA), stress, surgery
9. Insulin is the only safe drug in pregnancy (metformin/glyburide used off-label)
10. SGLT2 inhibitors have independent renal and cardiac benefits beyond glycemic control