Metformin's primary mechanism of action that reduces hepatic glucose production involves activation of which intracellular pathway?

• A Activation of AMPK (AMP-activated protein kinase) via inhibition of Complex I of the mitochondrial respiratory chain, leading to inhibition of PEPCK and G6Pase ✓
• B Binding to PPAR-gamma in hepatocytes to reduce transcription of gluconeogenic enzymes
• C Inhibition of intestinal glucose transporter GLUT2 reducing glucose absorption
• D Direct inhibition of glucokinase, reducing glucose phosphorylation in the liver

Explanation

Metformin is taken up by hepatocytes via OCT1 transporter and inhibits mitochondrial Complex I, causing a modest rise in AMP:ATP ratio. This activates AMPK, which phosphorylates and inhibits TORC2 (a co-activator of CREB), thereby suppressing transcription of key gluconeogenic enzymes PEPCK and glucose-6-phosphatase. Independently, metformin may also inhibit mitochondrial glycerophosphate dehydrogenase. The result is ~30% reduction in hepatic glucose output. Metformin does not act through PPAR-gamma (that is thiazolidinediones) or directly block glucokinase.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.