A patient on metformin develops lactic acidosis. The metabolic mechanism by which metformin can cause this is:

• A Inhibition of gluconeogenesis without effect on lactate metabolism
• B Activation of AMPK leading to excessive glycolysis
• C Renal accumulation causing proximal tubule damage and loss of lactate clearance
• D Inhibition of hepatic Complex I (NADH dehydrogenase) of the mitochondrial respiratory chain, impairing lactate oxidation ✓

Explanation

Metformin inhibits hepatic mitochondrial Complex I (NADH dehydrogenase), which impairs oxidative phosphorylation in hepatocytes and reduces pyruvate oxidation, causing lactate to accumulate. The liver normally clears 70% of circulating lactate; when this is impaired (especially with renal impairment causing metformin accumulation), lactic acidosis results. This is why metformin is contraindicated in renal failure (eGFR <30 mL/min/1.73m²), hepatic failure, and conditions reducing tissue perfusion.

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

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