TYPE 2 DIABETES MELLITUS

Diagnostic Criteria for Diabetes Mellitus

• Hyperglycemia symptoms: polyuria, polydipsia, weight loss.
• Fasting plasma glucose ≥126 mg/dL on more than one occasion, or
• Random plasma glucose ≥200 mg/dL (confirmed on another occasion), or
• Impaired fasting glucose if fasting glucose is 100–125 mg/dL,
• Impaired glucose tolerance if the 2-hour post–75-g glucose load is 140–199 mg/dL.

Overview

• Three general types: Type 1, Type 2, Gestational.
• Type 2: >90% of all diabetes cases.
• Pathophysiology: Relative insulin deficiency + insulin resistance. Most are overweight/obese, typically diagnosed >30 years of age.

ETIOLOGY & PATHOGENESIS

Insulin Resistance & Genetic Factors

• Insulin resistance: Linked to polygenic factors, obesity (especially abdominal visceral fat), sedentary lifestyle, and aging.
• Family history: ~40% have ≥1 diabetic parent; concordance in identical twins ~90%.
• Genetics: Several common polymorphisms → increased T2DM risk.

Defective β-Cell Secretion

• Inadequate β-cell insulin secretion relative to glucose levels.
• Hyperglycemia magnifies insulin resistance and β-cell dysfunction.
• β-cell mass decreases via increased apoptosis.

Obesity & Metabolic Syndrome

• 80% of T2DM (in Western populations) are obese (BMI >30 kg/m²).
• ~30% of Japanese/Chinese T2DM are obese.
• Abdominal/visceral obesity → insulin resistance → hyperglycemia → hyperinsulinemia (still insufficient).
• Metabolic syndrome: central obesity, hyperglycemia, hyperinsulinemia, dyslipidemia, hypertension.

Secondary Causes of Diabetes

• Diffuse pancreatic damage: pancreatitis, trauma, carcinoma, hemochromatosis, partial pancreatectomy.
• Excess counterregulatory hormones:
  • Pheochromocytoma: catecholamines
  • Acromegaly: growth hormone
  • Glucagonoma: glucagon
  • Cushing syndrome: glucocorticoids
  • Thyrotoxicosis: thyroid hormone
  • Somatostatinoma: somatostatin
• Hyperglycemia usually resolves if the underlying disorder is treated.

Maturity-Onset Diabetes of the Young (MODY)

• 5% of T2DM have monogenic disorders of β-cell function.
• Typically not obese, onset in late childhood or young adulthood.
• 6 forms (autosomal dominant):
  1. MODY 2: Mutation in glucokinase gene → defective glucose sensing.
  2. MODY 1 & 3: Mutations in transcription factors HNF-4α (MODY 1) or HNF-1α (MODY 3).
  3. MODY 4: Mutation in IPF-1 (insulin promoter factor-1).
  4. MODY 5: Mutation in HNF-1β.
  5. MODY 6: Mutation in neuroD1 transcription factor.

TREATMENT OF TYPE 2 DIABETES MELLITUS

Goals for Glycemic Control

• HbA1c <7% (ideal if <6% without causing severe hypoglycemia).
• Fasting/premeal glucose 70–130 mg/dL,
• 2-hr postprandial <180 mg/dL.

Nonpharmacologic Therapy

1. Lifestyle modifications:
   • Balanced nutrition & caloric management
   • Regular isotonic exercise
   • Weight reduction
   • Behavior modification
2. Diabetes education: emphasis on patient self-management.
3. Self-monitoring of blood glucose (SMBG).

PHARMACOTHERAPY OPTIONS

1. Biguanides (Metformin)

• Mechanism: activates AMP-activated protein kinase, ↓ hepatic gluconeogenesis.
• No hypoglycemia risk.
• GI side effects common (nausea, diarrhea).
• Contraindications: renal insufficiency (lactic acidosis risk).

2. Thiazolidinediones (TZDs)

• Drugs: pioglitazone, rosiglitazone.
• Mechanism: Peroxisome proliferator-activated receptor (PPAR-γ) modulation → ↓ peripheral insulin resistance, ↓ serum triglycerides.
• Side effects: weight gain (subQ fat), fluid retention → edema, possible heart failure exacerbation.

3. Insulin Secretagogues

• Sulfonylureas: (1st gen: acetohexamide, chlorpropamide, tolbutamide; 2nd gen: glipizide, glyburide, glimepiride)
  • Mechanism: stimulate insulin release via SUR2 (K+ channel) on β-cells.
  • Side effects: hypoglycemia.
• Meglitinides: repaglinide, nateglinide
  • Short half-life, taken premeal, also bind SUR1 site → insulin release.
  • Side effects: hypoglycemia.

4. α-Glucosidase Inhibitors (AGIs)

• Drugs: acarbose, miglitol.
• Mechanism: inhibit final carbohydrate digestion in small intestine → delay CHO absorption → lower postprandial glucose.
• Side effects: flatulence, diarrhea.
• Must be taken at meal onset.

5. Incretin-Related Agents

• GLP-1 (glucagon-like peptide 1):
  • Increases insulin secretion, slows gastric emptying, reduces appetite.
  • Rapidly degraded by DPP-4.
• Exenatide: GLP-1 receptor agonist, resistant to DPP-4; subQ twice daily. → Nausea common.
• Liraglutide: once-daily subQ DPP-4–resistant GLP-1 analogue.
• DPP-4 Inhibitors: sitagliptin, saxagliptin, vildagliptin → mild ↑ endogenous GLP-1/GIP.

6. Amylin Analogues

• Pramlintide: co-secreted normally with insulin, subQ at meals.
• Mechanism: slows gastric emptying, reduces appetite, suppresses glucagon.

7. Insulin

• Exogenous insulin to supplement endogenous secretion.
• Types:
  • Rapid-acting (lispro, aspart, glulisine),
  • Short-acting (regular),
  • Intermediate (NPH),
  • Long-acting (glargine, detemir).
• Side effects: hypoglycemia, weight gain.

INITIAL THERAPEUTIC APPROACH

1. Metformin + Diet + Exercise typically first-line.
2. More than one agent often needed if fasting glucose >250 mg/dL at presentation.
   • e.g., Metformin plus a sulfonylurea or insulin.
3. Postprandial hyperglycemia can be targeted with:
   • AGIs,
   • Rapid-acting insulin,
   • Semaglutide, Tirzepatide (GLP-1 agonist).

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