DPP-4 inhibitors (gliptins) are weight-neutral and do not cause hypoglycemia. The molecular mechanism involves inhibiting DPP-4 from cleaving the N-terminal dipeptide of which endogenous substrate?

• A Glucagon, preventing glucagon-stimulated hepatic glucose output
• B Insulin, preventing its inactivation in the portal circulation
• C GLP-1 and GIP, preventing their rapid inactivation and prolonging incretin effect ✓
• D Peptide YY, preventing appetite stimulation

Explanation

DPP-4 (dipeptidyl peptidase-4) is a serine protease that rapidly cleaves the two N-terminal amino acids from GLP-1 (7-36 amide) and GIP, the primary incretin hormones. Intact active GLP-1 and GIP normally have plasma half-lives of only 1-2 minutes because of DPP-4. Gliptins prevent this inactivation, prolonging incretin action, which stimulates glucose-dependent insulin secretion and suppresses glucagon only in hyperglycemic states — hence no fasting hypoglycemia. DPP-4 does not directly inactivate insulin or glucagon.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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