---

Diabetes Mellitus - Complete USMLE Guide

---

1. DEFINITION & CLASSIFICATION

ADA Classification (Box 47.2 - Tietz Lab Medicine)

---

2. TYPE 1 DIABETES MELLITUS

Epidemiology

• ~5-10% of all DM cases
• Peak incidence: childhood/adolescence; ~75% diagnosed before age 18
• Onset can occur at any age (not a classification criterion)

Pathophysiology

• Chronic autoimmune destruction of pancreatic islet beta-cells
• Results in absolute insulin deficiency (insulinopenia)
• Autoantibodies (key for USMLE):
  • Islet cell antibodies (ICA)
  • Anti-glutamic acid decarboxylase (anti-GAD65) - most common
  • Insulin autoantibodies (IAA)
  • IA-2 (tyrosine phosphatase-related) antibodies
  • ZnT8 antibodies

3 Stages of Type 1 DM (ADA)

• Stage 1: Normoglycemic + multiple islet autoantibodies present
• Stage 2: Dysglycemia (IFG and/or IGT) + autoantibodies
• Stage 3: Symptomatic diabetes (clinical disease)

Genetics

• HLA: DR3, DR4 (highest risk); DR3/DR4 heterozygotes = highest risk
• HLA-DQ alleles also important

Presentation

• Abrupt onset: polyuria, polydipsia, polyphagia, rapid weight loss
• ~30% present with diabetic ketoacidosis (DKA)
• Prone to ketosis (unlike Type 2)
• Dependent on insulin to survive and prevent ketosis

Treatment

• Insulin is mandatory (absolute requirement)
• Goal: mimic physiologic insulin secretion (basal + bolus)

---

3. TYPE 2 DIABETES MELLITUS

Epidemiology

• ~90% of all DM cases - most common form
• Onset usually after age 40, but increasingly seen in younger patients/children (obesity driven)
• Strong genetic component + environmental triggers

Pathophysiology - Two Core Defects

1. Insulin resistance - reduced insulin-mediated glucose uptake in peripheral tissue (muscle, liver, adipose)
2. Beta-cell dysfunction - impaired insulin secretion; beta-cell apoptosis from glucotoxicity, fatty acids, cytokines

Obesity (especially visceral/abdominal) is the most important risk factor; causes insulin resistance via excess free fatty acids, adipokines, inflammation.

Key Concept - "Ominous Octet" (USMLE)

Presentation

• Often asymptomatic (insidious onset) - many have complications at diagnosis
• Minimal symptoms: mild polyuria/polydipsia
• Not prone to ketosis (some residual insulin secretion suppresses lipolysis/ketogenesis)
• May progress to HHS (hyperosmolar hyperglycemic state) under stress

---

4. DIAGNOSTIC CRITERIA (ADA - Harrison's 22e Table)

USMLE Pearl: With classic symptoms (polyuria, polydipsia, weight loss), a single random glucose ≥200 mg/dL is diagnostic - no need for confirmation. Without symptoms, repeat testing is required.

Fasting = no caloric intake for at least 8 hours

Prediabetes Categories

• IFG: Fasting glucose 100-125 mg/dL
• IGT: 2-hr OGTT glucose 140-199 mg/dL
• Both significantly increase risk of progression to DM and cardiovascular disease

---

5. GESTATIONAL DIABETES (GDM)

• Glucose intolerance in 2nd or 3rd trimester (1st trimester = preexisting DM)
• Prevalence: ~6-8% of pregnancies in the US
• Screening: 24-28 weeks gestation (50g GCT, then 100g OGTT if positive)
• Most revert to normal postpartum but 35-60% develop T2DM within 10-20 years
• Children of GDM mothers: increased risk of metabolic syndrome + T2DM

---

6. SECONDARY (SPECIFIC TYPE) DIABETES - HIGH-YIELD

• Autosomal dominant; young patient; no autoantibodies; often no obesity
• MODY 2 (glucokinase gene) and MODY 3 (HNF-1a) are most common

---

7. ACUTE COMPLICATIONS

A. Diabetic Ketoacidosis (DKA)

• Predominantly Type 1 DM (can occur in T2DM - "ketosis-prone")
• Triad: Hyperglycemia + Metabolic acidosis (anion gap) + Ketosis
• Pathophysiology: Absolute insulin deficiency → unopposed glucagon/cortisol/catecholamines → lipolysis → free fatty acids → hepatic ketogenesis (acetoacetate, beta-hydroxybutyrate, acetone)

1. IV fluids - Normal saline first (0.9% NaCl); switch to D5 0.45% NS when glucose reaches ~200 mg/dL
2. Insulin - Regular insulin IV infusion (0.1 units/kg/hr); never start insulin before potassium is ≥3.5 mEq/L
3. Potassium replacement - Critical: insulin drives K+ intracellularly, total body K+ is depleted
4. Monitor: glucose, electrolytes (especially K+), pH, urine output
5. Bicarbonate only if pH < 6.9

KEY USMLE TRAP: Serum K+ may be normal/high on presentation (due to acidosis shifting K+ out of cells), but total body K+ is ALWAYS depleted. Replace K+ before or with insulin!

B. Hyperosmolar Hyperglycemic State (HHS)

• Predominantly Type 2 DM
• Profound hyperglycemia (often >600 mg/dL), severe dehydration, hyperosmolality (>320 mOsm/kg)
• No significant ketoacidosis (residual insulin prevents lipolysis)
• Higher mortality than DKA (~15% vs 1-5%)
• Treatment: IV fluids aggressively; insulin; electrolyte replacement

C. Hypoglycemia

• Most common complication of insulin therapy
• Symptoms: adrenergic (sweating, palpitations, tremor) then neuroglycopenic (confusion, seizure, coma)
• Glucose threshold for symptoms: ~60 mg/dL
• "Whipple's triad": symptoms + low glucose + resolution with glucose administration

---

8. CHRONIC COMPLICATIONS

Microvascular (diabetes-specific)

• Leading cause of end-stage renal disease (ESRD) in the US
• Stages:
  1. Hyperfiltration (↑GFR)
  2. Silent phase (normal GFR/albumin)
  3. Microalbuminuria (30-300 mg/day) - earliest clinical sign
  4. Macroalbuminuria (>300 mg/day, overt proteinuria)
  5. ESRD
• Histology: Kimmelstiel-Wilson nodules (nodular glomerulosclerosis) - pathognomonic
• Treatment: ACE inhibitor or ARB (first-line regardless of blood pressure)

• Leading cause of new blindness in working-age adults
• Nonproliferative (NPDR): microaneurysms, dot/blot hemorrhages, hard exudates, cotton-wool spots, macular edema
• Proliferative (PDR): neovascularization (NV), vitreous hemorrhage, traction retinal detachment
• Treatment: laser photocoagulation; anti-VEGF injections for diabetic macular edema

• Most common: distal symmetric polyneuropathy (stocking-glove distribution)
• Symptoms: numbness, tingling, burning, pain (worse at night)
• Autonomic neuropathy: gastroparesis (nausea, early satiety), orthostatic hypotension, erectile dysfunction, neurogenic bladder, hypoglycemia unawareness (most dangerous)
• Charcot joint (neuropathic arthropathy): joint destruction from loss of protective sensation
• Treatment: glycemic control; gabapentin, pregabalin, duloxetine, tricyclics for pain

Macrovascular Complications

• ASCVD (atherosclerotic cardiovascular disease): #1 cause of death in DM
• DM is considered a "CAD equivalent" (high-risk status)
• Peripheral arterial disease (PAD) → non-traumatic lower extremity amputation
• Cerebrovascular disease (stroke risk 2-4x higher)
• Heart failure (both systolic and diastolic)

USMLE Pearl: A diabetic patient with T2DM and established ASCVD should receive an SGLT2 inhibitor (empagliflozin/canagliflozin) or GLP-1 agonist (liraglutide/semaglutide) due to proven CV mortality benefit.

---

9. PHARMACOLOGIC TREATMENT

Type 1 DM - Insulin Only

• Rapid-acting analogs (lispro/aspart) should be given immediately before meals
• Glargine cannot be mixed with other insulins (precipitates)
• Dawn phenomenon: early morning hyperglycemia due to GH surge overnight (treat: increase basal insulin)
• Somogyi effect: rebound hyperglycemia after nocturnal hypoglycemia (treat: decrease evening dose)

Type 2 DM - Stepwise Approach

USMLE High-Yield Drug Combos with Specific Indications:

• DM + ASCVD → GLP-1 agonist (liraglutide/semaglutide) or SGLT2 inhibitor (empagliflozin/canagliflozin)
• DM + Heart Failure → SGLT2 inhibitor (empagliflozin, dapagliflozin)
• DM + CKD (proteinuria) → ACE inhibitor/ARB + SGLT2 inhibitor (dapagliflozin, canagliflozin)
• DM + Obesity (weight loss desired) → GLP-1 agonist or SGLT2 inhibitor

---

10. GLYCEMIC TARGETS (ADA Standards)

---

11. SCREENING GUIDELINES

• Screen all adults ≥35 years (ADA 2023); earlier if overweight/obese with one additional risk factor
• Screen all overweight/obese adults with any of: family history, hypertension, dyslipidemia, polycystic ovary syndrome (PCOS), history of GDM, certain ethnicities (Hispanic, Black, Native American, Asian)
• Repeat every 3 years if normal; annually if prediabetes
• GDM: screen at 24-28 weeks; postpartum screen at 4-12 weeks and every 3 years lifelong

---

12. MONITORING

HbA1c Limitations (USMLE): False LOW in hemolytic anemia, pregnancy, recent blood transfusion, hemoglobin variants. False HIGH in iron deficiency anemia, B12 deficiency, splenectomy. Use fructosamine in these cases.

---

13. KEY USMLE MNEMONICS & PEARLS

1. 3 P's of DM: Polyuria, Polydipsia, Polyphagia
2. DKA vs HHS:
   • DKA: T1DM, glucose ~250-600, pH <7.3, large ketones, osmolality normal/mildly elevated
   • HHS: T2DM, glucose >600, pH >7.3, minimal ketones, osmolality >320, profound dehydration
3. Kimmelstiel-Wilson nodules = pathognomonic for diabetic nephropathy
4. First microvascular complication to appear: microalbuminuria (nephropathy can be detected earliest)
5. Insulin + potassium: Never give insulin if K+ <3.5 mEq/L (risk of fatal hypokalemia)
6. Metformin = do NOT give with IV contrast (hold 48 hours before/after - risk of lactic acidosis from acute kidney injury)
7. Charcot joint = neuropathic joint (most commonly ankle/foot in DM) - painless despite severe destruction
8. Dawn phenomenon: Morning hyperglycemia from overnight GH surge → treat by increasing basal insulin or giving evening NPH
9. MODY: Autosomal dominant, no obesity, no autoantibodies, family history, young age at diagnosis
10. Autonomic neuropathy sign: Resting tachycardia (loss of cardiac parasympathetic tone) → fixed heart rate that does not vary
11. Necrobiosis lipoidica diabeticorum: Skin complication - yellowish-brown waxy plaques on shins; strongly associated with T1DM
12. Acanthosis nigricans: Velvety, hyperpigmented skin folds (neck, axilla, groin) = insulin resistance marker → T2DM risk

---

14. DIABETIC FOOT - CLINICAL POINTS

• Peripheral neuropathy + PAD = two key pathologic processes
• Charcot foot: warmth, erythema, bony deformity without pain - distinguish from cellulitis/osteomyelitis
• Wound/ulcer management: offloading, debridement, infection control (polymicrobial including anaerobes)
• ABI (ankle-brachial index) <0.9 = PAD
• Indications for amputation: non-healing ulcers, wet gangrene, life-threatening infection

---