A type 2 diabetic patient on metformin develops recurrent hypoglycaemia after adding a drug that increases GLP-1 receptor stimulation by preventing GLP-1 degradation. Which enzyme does this new drug inhibit, and what is its substrate specificity?
- A DPP-4 (dipeptidyl peptidase-4), a serine protease cleaving X-Pro dipeptides from N-termini ✓
- B Neprilysin (NEP), a zinc metalloprotease that cleaves GLP-1 at multiple sites
- C PCSK9, a proprotein convertase that degrades GLP-1 receptor on islet beta cells
- D Kynurenine aminotransferase-II, converting GLP-1 to inactive metabolites
Explanation
DPP-4 inhibitors (gliptins) inhibit dipeptidyl peptidase-4, a serine protease of the prolyl oligopeptidase family that cleaves dipeptides from the N-terminus of proteins containing a proline or alanine at the penultimate position. GLP-1 has an Ala-Glu dipeptide at its N-terminus (His7-Ala8), making it an ideal DPP-4 substrate; DPP-4 inactivates GLP-1 within 1-2 minutes of secretion. By inhibiting DPP-4, gliptins double or triple active GLP-1 concentrations. Note that DPP-4 inhibitors alone cause minimal hypoglycaemia, but the question's scenario with added insulin secretagogue effect explains recurrence — the drug described is a gliptin. Neprilysin, PCSK9, and kynurenine aminotransferase are not involved in GLP-1 degradation.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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