Insulin and Oral Hypoglycemic Agents

Insulin Types & Action - Sweet Regulator

• Mechanism: Binds tyrosine kinase receptor → GLUT4 translocation (muscle, fat) → ↑ glucose uptake.
• Effects: ↑ Glycogenesis, ↑ protein synthesis, ↑ lipogenesis; ↓ Gluconeogenesis, ↓ glycogenolysis.

Insulin Therapy & Risks - Prickly Points

• Risks:
  • Hypoglycemia (<70 mg/dL): Common. Adrenergic/neuroglycopenic signs. Rule of 15.
  • Lipodystrophy: Rotate injection sites.
  • Weight gain, edema.
• Pearls:
  • Somogyi (rebound) vs. Dawn (GH surge): Check 3 AM glucose.
  • Injection: SC. Rotate sites (abdomen, thigh, arm, buttock).
  • Storage: Unopened refrigerated; open vial room temp ≤28 days.

⭐ Severe hypoglycemia (<40 mg/dL): IV Dextrose or Glucagon.

Secretagogues & Metformin - Oral Workhorses

• Secretagogues: ↑Insulin secretion.
  • Sulfonylureas (SUs): Close K-ATP channels on β-cells.
    • 1st Gen: Chlorpropamide (SIADH).
    • 2nd Gen: Glipizide (shortest), Glibenclamide (↑hypoglycemia), Glimepiride.
    • SE: Hypoglycemia, weight gain.
  • Meglitinides (Glinides): Repaglinide, Nateglinide. Rapid onset, short duration. For postprandial spikes.
• Metformin (Biguanide): First-line T2DM.
  • MoA: ↓Hepatic gluconeogenesis, ↑Peripheral glucose uptake (AMPK activation).
  • Benefits: Euglycemic, weight neutral/loss, ↓CV risk.
  • SE: GI upset (most common), lactic acidosis (rare, ⚠️ eGFR < 30 mL/min/1.73m²), B12 deficiency.

  ⭐ Metformin: first-line T2DM, typically no hypoglycemia when used as monotherapy.

Glitazones & Glucosidase Blockers - Cellular & Gut Tactics

• Glitazones (TZDs): e.g., Pioglitazone
  • Mechanism: PPAR-γ agonists → ↑ insulin sensitivity (muscle, fat). Slow onset (weeks).
  • Side Effects: Weight gain, edema (⚠️ CHF exacerbation), hepatotoxicity, ↑ fracture risk. Pioglitazone: ?Bladder Ca risk.
  • Benefits: ↓ TGs, ↑ HDL (Pioglitazone).
• α-Glucosidase Inhibitors: e.g., Acarbose, Voglibose
  • Mechanism: Inhibit intestinal α-glucosidase → delay carbohydrate digestion/absorption → ↓ postprandial glucose.
  • Side Effects: GI distress (flatulence, diarrhea). Take with first bite of meal.

  ⭐ If hypoglycemia occurs (with combination therapy), treat with glucose (dextrose), not sucrose.

Incretins, Gliptins & Flozins - New Wave Agents

• Incretin Mimetics (GLP-1 Agonists): E.g., Liraglutide, Semaglutide.
  • MOA: ↑ Insulin, ↓ Glucagon, ↓ Gastric emptying, ↑ Satiety.
  • Benefits: Weight ↓, CV protection. Injectable.
  • SE: GI upset, pancreatitis risk.
• Gliptins (DPP-4 Inhibitors): E.g., Sitagliptin, Linagliptin.
  • MOA: Inhibit DPP-4 → ↑ GLP-1/GIP. Oral.
  • Benefits: Weight neutral. 📌 "Gliptins keep GLP-1 intact."
  • SE: Nasopharyngitis, rare pancreatitis.
• Flozins (SGLT2 Inhibitors): E.g., Dapagliflozin, Empagliflozin.
  • MOA: Block SGLT2 in kidney → Glucosuria. Oral.
  • Benefits: Weight ↓, BP ↓.
  • SE: UTIs, genital infections, euglycemic DKA risk.

  ⭐ SGLT2 inhibitors demonstrate significant cardiovascular and renal protective benefits.

High‑Yield Points - ⚡ Biggest Takeaways

• Rapid-acting insulins (lispro, aspart) for prandial; long-acting (glargine, detemir) for basal.
• Metformin: first-line T2DM, ↓ hepatic gluconeogenesis; risk: lactic acidosis.
• Sulfonylureas (glimepiride): ↑ insulin secretion; risk: hypoglycemia, weight gain.
• SGLT2 inhibitors (empagliflozin): glucosuria, CV benefit, weight loss; risk: UTIs, euglycemic DKA.
• GLP-1 agonists (liraglutide): ↑ insulin, ↓ glucagon, promote weight loss.
• DPP-4 inhibitors (sitagliptin): ↑ incretin levels, weight neutral.
• Thiazolidinediones (pioglitazone): PPAR-γ agonist, ↑ insulin sensitivity; risk: edema, HF, fractures.