Review Volume 12, Issue 9 pp 8742—8759

Figure 2. Molecular mechanisms of metformin-associated lactic acidosis (MALA). Metformin (1) inhibits mitochondrial respiratory chain complex I, reducing Krebs cycle flux and shifting metabolism toward glycolysis, increasing the pyruvate level; (2) partly inhibits gluconeogenesis through the AMPK pathway, further contributing to pyruvate accumulation and increasing the conversion of accumulated pyruvate to lactate; and (3) inhibits mGPD, blocking the G3P pathway and altering the cytoplasmic redox state, inhibiting the conversion of lactate to pyruvate, resulting in MALA. (AMPK, AMP-activated protein kinase; LKB1, liver kinase B1; G3P, glycerol-3-phosphate; DHAP, dihydroxyacetone phosphate; mGPD, mitochondrial glycerophosphate dehydrogenase; cGPD, cytosolic glycerophosphate dehydrogenase).