A patient on metformin develops severe lactic acidosis after an iodinated contrast procedure. The mechanism by which metformin predisposes to lactic acidosis is:

• A Metformin activates hepatic gluconeogenesis, shunting lactate away from the TCA cycle
• B Metformin competitively inhibits lactate dehydrogenase (LDH), preventing lactate-to-pyruvate conversion
• C Metformin induces renal tubular acidosis, reducing lactate clearance
• D Metformin inhibits mitochondrial complex I (NADH dehydrogenase), impairing oxidative phosphorylation and increasing anaerobic lactate production ✓

Explanation

Metformin's principal mechanism involves inhibition of hepatic mitochondrial complex I of the electron transport chain. This impairs oxidative phosphorylation and shifts cellular metabolism toward anaerobic glycolysis, increasing lactate production. Simultaneously, metformin inhibits hepatic gluconeogenesis from lactate. Combined with reduced renal elimination of metformin (e.g., during contrast-induced AKI), plasma metformin rises, further inhibiting mitochondrial function and causing life-threatening type B lactic acidosis.

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

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