---

DIABETES MELLITUS - Full MBBS Notes

---

DEFINITION

• Robbins & Cotran Pathologic Basis of Disease, p. 1014

---

EPIDEMIOLOGY

• Affects >30 million people (~11% of population) in the USA
• ~1.9 million have Type 1 DM; the rest (~90-95%) have Type 2 DM
• ~96 million US adults have "prediabetes"
• WHO estimates 422 million people worldwide
• 7th leading cause of death in the USA
• Economic burden: ~$327 billion/year (USA)
• Higher prevalence in Native Americans, African Americans, and Hispanics (1.5-2x higher risk)

---

CLASSIFICATION

Type 1 DM (T1DM)

• Autoimmune destruction of pancreatic beta cells
• Absolute insulin deficiency
• ~5-10% of all diabetes
• Most common in patients <20 years

Type 2 DM (T2DM)

• Combination of peripheral insulin resistance + relative insulin deficiency
• ~90-95% of all diabetes
• Most are overweight/obese (80%)
• Classically "adult-onset" but now increasing in children

Other Specific Types

---

DIAGNOSTIC CRITERIA (ADA / WHO)

• Repeat confirmation required for all except a symptomatic random glucose ≥200
• Acute illness (burns, trauma, infection) can cause transient hyperglycemia - diagnosis requires persistence after resolution
• Robbins & Cotran, p. 1015

---

COMPARATIVE FEATURES: T1DM vs T2DM

---

PATHOGENESIS

Pancreatic Islet Cell Anatomy

Glucose Homeostasis

• Glucose maintained 70-120 mg/dL by 3 processes:
  1. Hepatic glucose production (gluconeogenesis, glycogenolysis)
  2. Peripheral glucose utilization (primarily skeletal muscle)
  3. Insulin and counterregulatory hormones (glucagon, cortisol, catecholamines)
• Fasting state: low insulin + high glucagon → hepatic glucose output
• Fed state: insulin rises, glucagon falls → glucose uptake in muscle, liver, adipose

Insulin Synthesis and Release

• Produced in beta cells as preproinsulin → cleavage to proinsulin → insulin + C-peptide
• C-peptide has no known metabolic function but is useful as a marker of endogenous insulin secretion
• Glucose is the primary stimulus for insulin secretion (via GLUT-2 uptake, glucokinase phosphorylation, ATP generation, KATP channel closure, membrane depolarization, Ca2+ influx)
• Other stimuli: GLP-1, GIP (incretins), amino acids, parasympathetic stimulation

Type 1 DM Pathogenesis

1. Genetic susceptibility: HLA-DR3/DR4, HLA-DQ polymorphisms (strongest risk); CTLA4, PTPN22, insulin gene VNTR
2. Environmental trigger: viral infection (Coxsackie B, mumps, rubella), dietary factors, gut microbiome
3. Breakdown of self-tolerance: autoreactive CD4+ and CD8+ T cells attack beta cells
4. Insulitis: inflammatory infiltrate (T cells and macrophages) in islets
5. Progressive beta-cell destruction → absolute insulin deficiency
6. Key autoantibodies (markers, not necessarily pathogenic): anti-GAD65, anti-IA2, anti-ZnT8, anti-insulin antibodies

• Insulitis is present for years before clinical onset; ~80-90% beta-cell loss before symptoms appear

Type 2 DM Pathogenesis

1. Genetic factors: polygenic (TCF7L2, FTO, PPARG); strong family history
2. Environmental factors: obesity (especially visceral), sedentary lifestyle, caloric excess
3. Insulin resistance: decreased sensitivity of muscle, liver, and adipose to insulin
   • Visceral fat releases free fatty acids and adipokines → impair insulin signaling
   • Mechanism: serine phosphorylation of IRS-1 by activated kinases (IKK-β, JNK) → blocks PI3K-Akt pathway
4. Compensatory hyperinsulinemia: beta cells increase insulin output initially
5. Beta-cell failure: progressive decline in beta-cell mass and function; amyloid (IAPP - islet amyloid polypeptide) deposits in islets
6. Relative insulin deficiency despite initially elevated insulin levels

---

INSULIN PREPARATIONS

• Harrison's 22E, p. 3263

---

MANAGEMENT

General Goals

• HbA1c target: <7% for most patients; individualize based on age, comorbidities
• Blood pressure: <130/80 mmHg
• LDL: <100 mg/dL (or <70 mg/dL if CVD present)
• Lifestyle: diet, exercise, weight loss

Type 1 DM Management

• Insulin is mandatory (absolute deficiency)
• Basal-bolus regimen: long-acting (basal) + rapid-acting with meals (bolus)
• Intensive management: multiple daily injections (MDI), CSII (insulin pump), sensor-augmented systems, Automated Insulin Delivery (AID) with CGM
• Goals: prevent DKA, maintain near-normal glycemia

Type 2 DM - Oral & Injectable Agents

---

COMPLICATIONS

MICROVASCULAR (Diabetes-specific)

1. Diabetic Nephropathy (Diabetic Kidney Disease)

• Leading cause of end-stage renal disease (ESRD) in the developed world
• Mechanism: hyperfiltration → glomerular hypertension → mesangial expansion → GBM thickening → proteinuria
• Nodular glomerulosclerosis (Kimmelstiel-Wilson lesion): pathognomonic
• Stages: microalbuminuria (30-300 mg/day) → macroalbuminuria → declining GFR → ESRD
• Management: ACE inhibitors/ARBs (first-line), SGLT-2 inhibitors, glycemic and BP control

2. Diabetic Retinopathy

• Most common cause of new-onset blindness in working-age adults
• Non-proliferative (NPDR): microaneurysms, hard exudates, cotton-wool spots, intraretinal hemorrhages
• Proliferative (PDR): neovascularization (new vessel formation) → vitreous hemorrhage, retinal detachment
• Diabetic macular edema (DME): can occur at any stage
• Screening: annual dilated fundoscopy; treatment: laser photocoagulation, anti-VEGF injections

3. Diabetic Neuropathy

• Most common complication overall
• Distal symmetric polyneuropathy: most common; "glove and stocking" sensory loss; loss of vibration/position sense; painful neuropathy; risk of foot ulcers
• Mononeuropathy: CN III most common (pupil-sparing; diabetic CN III palsy)
• Autonomic neuropathy: gastroparesis, diabetic diarrhea, urinary retention, erectile dysfunction, orthostatic hypotension, hypoglycemia unawareness, Charcot foot

MACROVASCULAR (Atherosclerotic Cardiovascular Disease)

• 2-4x higher risk of coronary artery disease (CAD), stroke, and peripheral arterial disease (PAD)
• ASCVD may precede hyperglycemia in T2DM
• Dyslipidemia (high TG, low HDL, small dense LDL), hypertension, and hyperglycemia all contribute
• Heart failure risk is significantly increased
• Management: statins, ACE inhibitors, SGLT-2 inhibitors (heart failure benefit), aspirin in high-risk patients

ACUTE COMPLICATIONS

Diabetic Ketoacidosis (DKA)

• Mainly in T1DM (occasionally T2DM)
• Precipitants: infections, missed insulin, new diagnosis
• Mechanism: absolute insulin deficiency → lipolysis → excess free fatty acids → ketogenesis → ketonemia + metabolic acidosis
• Features: polyuria, polydipsia, Kussmaul breathing, fruity breath, vomiting, abdominal pain, altered consciousness
• Diagnosis: Blood glucose >250 mg/dL + ketones + pH <7.3 + bicarbonate <15 mEq/L
• Management: IV fluids (normal saline), insulin infusion, potassium replacement, treat precipitant

Hyperosmolar Hyperglycemic State (HHS)

• Mainly in T2DM; older patients
• Extreme hyperglycemia (>600 mg/dL) without significant ketosis
• Serum osmolality >320 mOsm/kg
• Profound dehydration, neurological changes
• Mortality higher than DKA
• Management: aggressive IV fluid replacement, insulin, electrolyte correction

Hypoglycemia

• Blood glucose <70 mg/dL
• Caused by excess insulin, missed meals, exercise
• Adrenergic symptoms: sweating, tremor, palpitations, anxiety
• Neuroglycopenic symptoms: confusion, seizures, coma
• Treatment: 15g fast-acting carbohydrate; IV dextrose or glucagon injection if severe
• Hypoglycemia unawareness: loss of warning symptoms with repeated episodes (autonomic neuropathy)

OTHER COMPLICATIONS

---

GESTATIONAL DIABETES MELLITUS (GDM)

• Defined as any degree of glucose intolerance first recognized during pregnancy
• Affects 6-7% of pregnancies
• Mechanism: placental hormones (hPL, progesterone, cortisol) cause insulin resistance
• Screening: 24-28 weeks gestation (50g GCT; if positive → 100g OGTT)
• Risk to fetus: macrosomia, birth trauma, neonatal hypoglycemia, stillbirth, respiratory distress
• Risk to mother: 50% risk of developing T2DM within 10 years
• Management: diet + exercise first; insulin if targets not met (metformin and glyburide may be used but cross placenta)

---

MONITORING

---

PREVENTION

Type 1 DM

• No established prevention; trials with immunosuppression are ongoing

Type 2 DM (Diabetes Prevention Program)

• Lifestyle modification (7% weight loss + 150 min/week exercise): reduced incidence by 58%
• Metformin: reduced incidence by 31%
• GLP-1 agonists, bariatric surgery also highly effective

---

HIGH-YIELD POINTS FOR EXAMS

---