PR002400 (Project)

Description:Metformin is a medicinal biguanide with broad therapeutic utility. A major clinical effect of this drug, which is primarily prescribed for type II diabetes, is enhanced intestinal glucose uptake. However, the underlying mechanism is unknown. Here, using an orthogonal genetics approach in mice, we demonstrate that metformin drives glucose uptake and glycolysis in intestinal epithelium by inhibiting mitochondrial complex I of the electron transport chain. Complex I inhibition by metformin suppresses citrulline synthesis and triggers a glycolytic switch in intestinal epithelial cells, demonstrating selective impairment of mitochondrial ATP production. Accordingly, metformin-induced clearance of excess blood glucose and subsequent glucose-to-lactate conversion require intestinal mitochondrial complex I inhibition. Likewise, the blood glucose-lowering effects of phenformin, another biguanide, and berberine, a structurally unrelated dietary supplement, depend on mitochondrial complex I inhibition in intestinal epithelium. Thus, whole-body glycemic control can be improved by inhibiting mitochondrial complex I in intestinal epithelium with small molecules.