---

Insulin & Oral Antidiabetic Drugs - Complete MBBS Pharmacology Guide

---

Quick Orientation - Diagnostic Criteria (Know These Cold)

---

PART 1: INSULIN

Chemistry

Exam fact: C-peptide has no known physiologic function but is a better marker of endogenous insulin secretion than plasma insulin itself (because insulin undergoes significant hepatic/renal extraction but C-peptide does not).

---

Mechanism of Insulin Secretion (Very Exam-Heavy)

1. Glucose enters beta cell via GLUT-2 transporter
2. Phosphorylated by glucokinase (the glucose sensor)
3. Glucose metabolism generates ATP
4. Elevated ATP closes ATP-sensitive K+ channels (K-ATP channels)
5. Membrane depolarization opens voltage-gated Ca2+ channels
6. Ca2+ influx triggers pulsatile insulin exocytosis

• Amino acids (leucine, arginine - gluconeogenic)
• GLP-1, GIP, glucagon, cholecystokinin
• Beta-adrenergic activity, acetylcholine
• Drugs: sulfonylureas, meglitinides, isoproterenol

• Alpha-adrenergic activity, somatostatin, leptin
• Insulin itself (feedback), IAPP (amylin)
• Drugs: diazoxide (K-ATP channel opener), phenytoin, verapamil, clonidine, vinblastine, colchicine

---

Insulin Receptor & Mechanism of Action

---

Insulin Preparations - The Most Exam-Tested Table

• Glargine: Amino acid substitutions at A21 (Asn→Gly) and B30-31 (Arg added) → precipitates at physiological pH (SC tissue) → slow absorption
• Detemir: Fatty acid chain attached → binds albumin → slow release
• Lispro: Reversal of Pro-Lys at B28-29 → prevents hexamer formation → faster absorption
• Aspart: Asp substituted at B28 → same rapid effect

Exam rule: Regular insulin is the ONLY insulin given IV. All others are subcutaneous only.

---

Adverse Effects of Insulin

1. Hypoglycemia - most common and serious
2. Weight gain
3. Lipodystrophy at injection site
   • Lipoatrophy (older animal insulins) - corrects with human insulin injection at site
   • Lipohypertrophy (still occurs) - prevent by rotating sites
4. Insulin allergy - IgE-mediated, immediate hypersensitivity, rare with modern human/analog insulins. Severe cases: anaphylaxis
5. Immune insulin resistance - IgG antibodies (usually low titer, clinically insignificant; rarely causes true resistance)
6. Hypokalemia - insulin drives K+ into cells

---

Standard vs. Intensive Insulin Therapy

Intensive therapy should not be used in: long-standing diabetes, significant microvascular complications, elderly, hypoglycemic unawareness.

---

PART 2: ORAL ANTIDIABETIC DRUGS (Type 2 Diabetes)

Categories (Katzung's 6-Group Classification)

1. Insulin secretagogues acting on K-ATP channel (sulfonylureas, meglitinides)
2. Insulin sensitizers (biguanides, thiazolidinediones)
3. Alpha-glucosidase inhibitors (delay carbohydrate absorption)
4. Incretin-based (GLP-1 receptor agonists, DPP-4 inhibitors)
5. SGLT2 inhibitors (renal glucose excretion)
6. Others (pramlintide, bromocriptine, colesevelam)

---

1. BIGUANIDES - Metformin (FIRST-LINE DRUG)

• Primarily reduces hepatic gluconeogenesis (main mechanism)
• Slows intestinal absorption of sugars
• Improves peripheral glucose uptake and utilization (increases insulin sensitivity)
• Activates AMPK (AMP-activated protein kinase) - underlying molecular mechanism
• Does NOT stimulate insulin secretion → minimal hypoglycemia risk when used alone

• Well absorbed orally, not protein-bound, not metabolized
• Excreted unchanged by kidneys

• GI (most common): nausea, diarrhea, vomiting - minimize by slow dose titration, take with meals
• Lactic acidosis (rare but serious, especially in renal failure)
• Weight loss (appetite suppression - desirable)
• Long-term use → Vitamin B12 deficiency (reduced absorption)
• Does NOT cause hypoglycemia alone

• eGFR < 30 mL/min/1.73 m² (contraindicated due to lactic acidosis risk)
• eGFR 30-45: use with caution
• Acute MI, liver disease, severe dehydration, contrast dye use (hold 48h)
• Alcoholism

---

2. SULFONYLUREAS (Insulin Secretagogues)

• 1st generation (older): Tolbutamide, chlorpropamide, tolazamide
• 2nd generation (preferred): Glibenclamide (glyburide), glipizide, glimepiride, gliclazide

• Bind to sulfonylurea receptor (SUR-1) on beta cell K-ATP channels
• Block K+ efflux → membrane depolarization → Ca2+ influx → insulin release
• Require functional beta cells to work (useless in Type 1 DM)
• Some extrapancreatic effects (↑ insulin receptor sensitivity) - minor

• All well-absorbed orally, highly protein-bound (albumin)
• Chlorpropamide: longest half-life (~35h), renally excreted - avoid in elderly/renal disease
• Glipizide: short-acting, preferred in elderly
• Glimepiride: once-daily, weight neutral

• Hypoglycemia - most important (especially chlorpropamide, glyburide - long-acting)
• Weight gain
• GI upset, skin reactions
• Disulfiram-like reaction with alcohol (chlorpropamide especially)
• Hyponatremia (SIADH - chlorpropamide)
• Cholestatic jaundice (rare)
• Hemolytic anemia in G6PD deficiency

• Potentiated by: NSAIDs, sulfonamides, warfarin, fluconazole (displace from protein binding)
• Inhibited by: thiazides, corticosteroids, phenytoin, rifampicin

---

3. MEGLITINIDES (Glinides)

• Also bind SUR-1 (different binding site than sulfonylureas) → close K-ATP channels → insulin release
• Glucose-dependent - only effective when glucose is elevated
• Short-acting - taken just before meals, cover postprandial glucose

• Shorter action = less hypoglycemia risk
• More flexibility (can skip dose if skipping meal)
• Can be used in mild renal impairment

---

4. THIAZOLIDINEDIONES (TZDs / Glitazones)

• Bind PPARγ (peroxisome proliferator-activated receptor gamma) - a nuclear receptor
• Alter gene transcription → ↑ insulin sensitivity in muscle, liver, adipose tissue
• ↑ GLUT-4 expression, ↑ adiponectin, ↓ FFA levels
• Do NOT stimulate insulin secretion
• Require insulin to be present to work

• Weight gain (fluid retention + increased fat mass)
• Fluid retention / edema → can precipitate or worsen heart failure (contraindicated in heart failure)
• Rosiglitazone: associated with increased risk of MI - significantly restricted/withdrawn in many countries
• Pioglitazone: associated with increased risk of bladder cancer (prolonged use)
• Bone fractures (increased in women, especially at distal extremities)
• Elevated LFTs (hepatotoxicity - troglitazone withdrawn for this reason)
• Anemia (hemodilution)

---

5. ALPHA-GLUCOSIDASE INHIBITORS

• Reversibly inhibit alpha-glucosidase enzymes (sucrase, maltase, etc.) in the brush border of the small intestine
• Delay digestion and absorption of complex carbohydrates
• Lower postprandial glucose (not fasting glucose)

• Flatulence, abdominal bloating, diarrhea (most common - undigested carbs fermented by gut bacteria)
• Rarely: elevated liver enzymes (high doses of acarbose)
• Do NOT cause hypoglycemia alone

Important: If hypoglycemia occurs in a patient on acarbose + insulin/sulfonylurea, treat with glucose (dextrose), NOT sucrose - because acarbose blocks sucrase!

---

6. DPP-4 INHIBITORS (Gliptins)

• Inhibit dipeptidyl peptidase-4 (DPP-4) enzyme
• DPP-4 normally degrades incretin hormones (GLP-1, GIP) - they have half-life of ~2 minutes
• Inhibiting DPP-4 → ↑ endogenous GLP-1 and GIP levels
• → ↑ glucose-dependent insulin secretion, ↓ glucagon
• Glucose-dependent → low hypoglycemia risk

• Generally well tolerated
• Nasopharyngitis, upper respiratory tract infections
• Pancreatitis (risk - black box warning)
• Joint pain (arthralgia)
• Saxagliptin: increased risk of heart failure hospitalizations

---

7. GLP-1 RECEPTOR AGONISTS (Incretin Mimetics)

• Mimic GLP-1 (incretin hormone from gut L-cells)
• Glucose-dependent ↑ insulin secretion, ↓ glucagon
• Slow gastric emptying (reduces postprandial glucose)
• Decrease appetite (central satiety effect) → weight loss
• Some: cardioprotective effects (MACE reduction - liraglutide, semaglutide)

• Nausea, vomiting (most common - usually transient)
• Pancreatitis risk
• Risk of thyroid C-cell tumors (rodent data - avoid in medullary thyroid cancer, MEN2)
• Weight loss (beneficial in obese T2DM)

Exam fact: GLP-1 agonists are not broken down by DPP-4 because they are structurally modified - they are "DPP-4 resistant."

---

8. SGLT2 INHIBITORS (Gliflozins / Flozins)

• Inhibit Sodium-Glucose Co-Transporter 2 (SGLT2) in the proximal renal tubule
• SGLT2 is responsible for ~90% of renal glucose reabsorption
• Inhibition → glucosuria (glucose excreted in urine) → lowers blood glucose
• Also causes natriuresis → reduces blood pressure and preload
• Insulin-independent mechanism

• Cardiovascular: Reduce hospitalization for heart failure, mortality (empagliflozin and dapagliflozin approved for heart failure with and without diabetes)
• Renal: Slow progression of CKD (dapagliflozin beneficial even without diabetes)
• Weight loss (calorie loss in urine)

• Genital mycotic infections (women > men) - most common
• Urinary tract infections, pyelonephritis, urosepsis
• Euglycemic diabetic ketoacidosis (rare - especially if Type 1 off-label or very insulin-deficient T2DM)
• Necrotizing fasciitis of perineum (Fournier gangrene) - rare but serious
• Hypotension / volume depletion
• Canagliflozin: increased fracture risk, increased amputation risk (toes)
• Modest LDL increase (canagliflozin, empagliflozin)

---

9. AMYLIN ANALOG

• Synthetic analog of amylin (IAPP - co-secreted with insulin from beta cells)
• Delays gastric emptying, ↓ postprandial glucagon, ↑ satiety
• SC injection before meals

• Nausea, vomiting, anorexia
• Severe hypoglycemia - reduce mealtime insulin dose by 50% when starting
• Cannot be mixed in same syringe as insulin
• Contraindicated in: gastroparesis, hypoglycemic unawareness

---

PART 3: KEY COMPARISONS & EXAM TABLES

Adverse Effects Summary Chart

Which Drugs Cause Hypoglycemia?

Weight Effects

---

Drug Choice in Special Situations (High-Yield Exam Topics)

---

Contraindications Summary

---

Mechanism Quick Reference

---

PART 4: HIGH-YIELD EXAM POINTS (Don't Miss These)

1. C-peptide = better measure of endogenous insulin (insulin undergoes hepatic first-pass; C-peptide does not). Equimolar with insulin secretion.
2. Glucokinase = the glucose sensor of beta cells (not hexokinase - glucokinase has low affinity, not saturated at normal glucose, acts only when glucose is high).
3. Regular insulin = only insulin for IV use. Used in emergencies (DKA, HHS, hyperkalemia).
4. NPH = Neutral Protamine Hagedorn - protamine is added to retard absorption (intermediate-acting, cloudy).
5. Glargine = peakless - precipitates at physiological pH in SC tissue due to its pH modification (prepared at pH 4, precipitates at pH 7.4).
6. Lactic acidosis with metformin = most feared adverse effect, especially with renal failure (drug accumulates).
7. Disulfiram-like reaction = chlorpropamide (1st generation SU) + alcohol.
8. Hyponatremia/SIADH = chlorpropamide (1st gen SU, potentiates ADH).
9. Rosiglitazone = associated with MI (restricted globally). Pioglitazone = bladder cancer risk. Both TZDs worsen heart failure.
10. Acarbose + hypoglycemia = treat with dextrose (glucose), NOT sucrose (blocked by acarbose).
11. GLP-1 half-life = ~2 min (degraded by DPP-4). Synthetic GLP-1 analogs are modified to resist DPP-4.
12. Euglycemic DKA = SGLT2 inhibitor complication - glucose is normal but pH is low. Dangerous because patient/doctor may be misled by normal glucose.
13. Fournier gangrene = necrotizing fasciitis of perineum - rare SGLT2 inhibitor adverse effect.
14. Pramlintide + mealtime insulin = reduce insulin dose by 50% to avoid severe hypoglycemia.
15. Incretin effect = oral glucose causes much greater insulin secretion than IV glucose (due to gut incretin hormones GLP-1, GIP) - this effect is reduced in Type 2 DM.

---