Metformin reduces hepatic glucose production. The molecular mechanism by which metformin activates AMPK in hepatocytes is:

• A Metformin directly activates the AMPK catalytic domain by phosphorylation
• B Metformin activates LKB1 (AMPK kinase) directly by binding its regulatory domain
• C Metformin inhibits mitochondrial complex I, raising the cellular AMP:ATP ratio, which activates AMPK ✓
• D Metformin chelates zinc, releasing inhibition of AMPK

Explanation

Metformin weakly inhibits mitochondrial complex I of the electron transport chain, mildly reducing ATP synthesis and raising the AMP:ATP and ADP:ATP ratios; elevated AMP/ADP allosterically activates AMPK (as well as promoting LKB1-mediated AMPK phosphorylation), which then phosphorylates and inactivates key gluconeogenic enzymes. This explains why metformin's effect requires cellular metabolism and why it does not cause hypoglycemia (it targets hepatic glucose output only when gluconeogenesis is inappropriately elevated).

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

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