The primary mechanism by which metformin lowers blood glucose is:

• A Stimulation of pancreatic beta cell insulin release via KATP channel closure
• B Blockade of glucose reabsorption in the proximal tubule
• C Inhibition of hepatic gluconeogenesis through AMPK activation and partial inhibition of mitochondrial complex I ✓
• D Agonism at PPAR-gamma receptors in adipose tissue

Explanation

Metformin enters hepatocytes via OCT1, mildly inhibits mitochondrial complex I, raises the AMP:ATP ratio, and activates AMPK. The net effect is suppression of hepatic gluconeogenesis, which accounts for most of its glucose-lowering action. It does not stimulate insulin secretion, so it rarely causes hypoglycemia when used alone. Option A describes sulfonylureas, option B describes SGLT2 inhibitors, and option D describes thiazolidinediones.

Reference: Katzung's Basic and Clinical Pharmacology, 15th ed.

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