A patient on metformin presents with severe lactic acidosis. The primary cellular mechanism of metformin-induced lactic acid accumulation is:
- A Inhibition of mitochondrial complex I (NADH dehydrogenase), shifting cellular energy metabolism toward anaerobic glycolysis with lactate production, while also inhibiting hepatic gluconeogenesis from lactate ✓
- B Inhibition of lactate dehydrogenase, preventing pyruvate conversion to acetyl-CoA
- C Competitive inhibition of the monocarboxylate transporter-1 (MCT1), blocking lactate efflux from muscles
- D Activation of AMPK causing phosphorylation and inhibition of pyruvate dehydrogenase complex
Explanation
Metformin accumulates in mitochondria and inhibits complex I of the electron transport chain (NADH:ubiquinone oxidoreductase). This impairs oxidative phosphorylation, reduces mitochondrial NADH oxidation, and creates an NADH/NAD+ imbalance that drives pyruvate to lactate. Simultaneously, metformin inhibits hepatic gluconeogenesis (which normally clears circulating lactate), leading to lactate accumulation. Risk is greatest when metformin accumulates due to impaired renal clearance (contraindicated when eGFR <30 mL/min), tissue hypoxia, or iodinated contrast administration (which transiently reduces GFR). Metformin also activates AMPK, but AMPK activation does not inhibit PDH.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.