Mechanism of Action of Exenatide

Introduction

Exenatide is an incretin-based antidiabetic drug classified as a glucagon-like peptide-1 (GLP-1) receptor agonist. It is used in the management of type 2 diabetes mellitus to improve glycemic control, particularly in patients with inadequate response to oral antidiabetic agents. Exenatide is exam-relevant because it mimics endogenous GLP-1, enhances glucose-dependent insulin secretion, promotes weight loss, and has a low risk of hypoglycemia.

Mechanism of Action (Step-wise)

Exenatide lowers blood glucose by mimicking the physiological actions of GLP-1.

Step 1: Binding to GLP-1 receptors
Exenatide binds to GLP-1 receptors located on pancreatic β-cells, α-cells, gastrointestinal tract, and central nervous system.

Step 2: Glucose-dependent insulin secretion
Activation of GLP-1 receptors increases intracellular cAMP in β-cells, enhancing insulin release only in the presence of elevated blood glucose.

Step 3: Suppression of glucagon secretion
Exenatide inhibits glucagon release from pancreatic α-cells, reducing hepatic glucose output.

Step 4: Delayed gastric emptying
It slows gastric emptying, leading to reduced postprandial glucose absorption.

Step 5: Appetite suppression and weight loss
Central GLP-1 receptor activation increases satiety and reduces appetite, contributing to weight reduction.

Exam pearl:
Exenatide does not stimulate insulin secretion during hypoglycemia.

Pharmacokinetics

• Route of administration: Subcutaneous injection
• Bioavailability: High after SC administration
• Protein binding: Minimal
• Onset of action: Rapid
• Half-life: ~2–4 hours
• Metabolism: Proteolytic degradation
• Excretion: Renal
• Dosing: Twice daily (short-acting); once weekly (extended-release formulation)

Clinical Uses

• Type 2 diabetes mellitus (monotherapy or add-on therapy)
• Patients with obesity and T2DM (favorable weight effect)
• Inadequate control with metformin or sulfonylureas

Exenatide is ineffective in type 1 diabetes mellitus.

Adverse Effects

Gastrointestinal (most common):

• Nausea
• Vomiting
• Diarrhea

Metabolic:

• Hypoglycemia (rare; increased with sulfonylureas)

Pancreatic:

• Acute pancreatitis (rare but serious)

Others:

• Injection site reactions
• Antibody formation (may reduce efficacy)

Comparative Analysis

Exenatide vs Sitagliptin vs Insulin

Explanation:
Exenatide directly activates GLP-1 receptors, whereas sitagliptin prolongs endogenous GLP-1 action. Insulin lacks glucose dependency, explaining its higher hypoglycemia risk.

MCQs

1. Exenatide is an analog of:
   a) Insulin
   b) Amylin
   c) GLP-1
   d) GIP

Answer: c) GLP-1

2. Insulin secretion with exenatide occurs only when:
   a) Insulin levels are low
   b) Blood glucose is elevated
   c) Glucagon is present
   d) Food intake is absent

Answer: b) Blood glucose is elevated

3. Exenatide reduces postprandial glucose mainly by:
   a) Increasing insulin resistance
   b) Delaying gastric emptying
   c) Increasing hepatic glucose output
   d) Stimulating glycogenolysis

Answer: b) Delaying gastric emptying

4. Major site of action of exenatide is the:
   a) Liver
   b) Muscle
   c) Pancreatic β-cells
   d) Kidney

Answer: c) Pancreatic β-cells

5. Hypoglycemia risk with exenatide alone is low because it:
   a) Suppresses insulin synthesis
   b) Is rapidly metabolized
   c) Acts glucose-dependently
   d) Blocks insulin receptors

Answer: c) Acts glucose-dependently

6. Exenatide causes weight loss primarily by:
   a) Increasing metabolism
   b) Reducing appetite
   c) Increasing insulin resistance
   d) Promoting glucosuria

Answer: b) Reducing appetite

7. Route of administration of exenatide is:
   a) Oral
   b) Intravenous
   c) Subcutaneous
   d) Intramuscular

Answer: c) Subcutaneous

8. Exenatide is contraindicated in:
   a) Type 2 diabetes
   b) Obesity
   c) Type 1 diabetes
   d) Metabolic syndrome

Answer: c) Type 1 diabetes

9. Rare but serious adverse effect of exenatide is:
   a) Hepatitis
   b) Pancreatitis
   c) Nephrolithiasis
   d) Retinopathy

Answer: b) Pancreatitis

10. Extended-release exenatide is administered:
    a) Daily
    b) Twice daily
    c) Weekly
    d) Monthly

Answer: c) Weekly

FAQs

1. Why does exenatide not cause hypoglycemia alone?
Because insulin release is glucose-dependent.

2. Does exenatide promote weight loss?
Yes, by delaying gastric emptying and reducing appetite.

3. Can exenatide be used in type 1 diabetes?
No, it requires functioning β-cells.

4. What is the major safety concern with exenatide?
Risk of pancreatitis.

5. Why is exenatide injectable?
Because it is a peptide and would be degraded orally.

References

• Goodman & Gilman’s The Pharmacological Basis of Therapeutics
  https://accesspharmacy.mhmedical.com
• Katzung BG. Basic and Clinical Pharmacology
  https://accessmedicine.mhmedical.com
• Tripathi KD. Essentials of Medical Pharmacology
• Harrison’s Principles of Internal Medicine
  https://accessmedicine.mhmedical.com

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