Loss of multidrug and toxin extrusion 1 (MATE1) is associated with metformin-induced lactic acidosis

摘要: BACKGROUNDS AND PURPOSE Lactic acidosis is a fatal adverse effect of metformin, but the risk factor remains unclear. Multidrug and toxin extrusion 1 (MATE1) expressed in luminal membrane kidney liver. MATE1 was revealed to be responsible for tubular biliary secretion metformin. Therefore, some MATE polymorphisms, that cause it function abnormally, are hypothesized induce lactic acidosis. The purpose this study clarify association between dysfunction metformin-induced acidosis. EXPERIMENTAL APPROACH Blood lactate, pH bicarbonate ion (HCO3-) levels were evaluated during continuous administration 3 mg·mL−1 metformin drinking water using Mate1 knockout (−/−), heterozygous (+/−) wild-type (+/+) mice. To determine tissue accumulation mice given 400 mg·kg−1 orally. Furthermore, blood lactate data obtained from diabetic patients metformin. KEY RESULTS Seven days after water, significantly higher lower HCO3- observed Mate1−/− mice, not Mate1+/− affected with variant (MATE1-L125F, MATE1-G64D, MATE2-K-G211V). Sixty minutes (400 mg·kg−1, p.o.) hepatic concentration markedly than Mate1+/+ mice. CONCLUSION IMPLICATIONS MATE1 caused marked elevation liver led acidosis, suggesting homozygous could one factors