Metformin exerts part of its glucose-lowering effect by inhibiting Complex I of the mitochondrial ETC in hepatocytes. The downstream effect on hepatic gluconeogenesis is mediated through:

• A Increased NADH:NAD+ ratio, reducing availability of NAD+ for glyceraldehyde-3-phosphate dehydrogenase in gluconeogenesis
• B Direct inhibition of phosphoenolpyruvate carboxykinase (PEPCK) gene expression
• C Increased ROS production from Complex I inhibition that oxidises TORC2/CRTC2, activating CREB-mediated gluconeogenesis
• D Activation of AMP kinase (AMPK) by rising AMP:ATP ratio, which phosphorylates and inhibits gluconeogenic enzymes ✓

Explanation

Metformin's Complex I inhibition reduces mitochondrial ATP production, raising the ADP and AMP:ATP ratio. Elevated AMP allosterically activates AMP kinase (AMPK). Activated AMPK phosphorylates and inhibits CRTC2 (CREB-regulated transcription coactivator 2), reducing CREB-dependent transcription of PEPCK and G6Pase — the key gluconeogenic enzymes. AMPK also inhibits mTORC1, reducing overall hepatic biosynthesis. While increased NADH does impair gluconeogenesis, the AMPK pathway is the primary mechanism attributed to metformin.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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