The incretin effect is reduced in type 2 diabetes. GLP-1 receptor agonists (e.g., semaglutide) lower blood glucose by all of the following mechanisms EXCEPT:
- A Stimulating glucose-dependent insulin secretion from pancreatic beta cells
- B Suppressing glucagon release from alpha cells in a glucose-dependent manner
- C Directly inhibiting hepatic glucose-6-phosphatase to reduce gluconeogenesis ✓
- D Delaying gastric emptying, reducing post-prandial glucose spikes
Correct answer: C. Directly inhibiting hepatic glucose-6-phosphatase to reduce gluconeogenesis
Explanation
GLP-1 receptor agonists work through multiple glucose-dependent mechanisms: they enhance insulin secretion and suppress glucagon only when glucose is elevated (minimising hypoglycaemia), and they slow gastric emptying. They do not directly inhibit hepatic glucose-6-phosphatase; that is the mechanism of metformin's indirect suppression of gluconeogenesis (via AMPK activation). GLP-1 does reduce hepatic glucose output indirectly through glucagon suppression.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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