Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain

Although metformin is widely used for the treatment of noninsulin-dependent diabetes, its mode of action remains unclear. Here we provide evidence tha t its primary site of action is through a direct inhibition of complex 1 of the respiratory chain. Metformin (50 mu M) inhibited mitochondrial oxidati on of glutamate+malate in hepatoma cells by 13 and 30% after 24 and 60h exp osure respectively, but succinate oxidation was unaffected. Metformin also caused time-dependent inhibition of complex 1 in isolated mitochondria, whe reas in submitochondrial particles inhibition was immediate but required ve ry high metformin concentrations (K-0.5, 79 mM). These data are compatible with the slow membrane-potential-driven accumulation of the positively char ged drug within the mitochondrial matrix leading to inhibition of complex 1 . Metformin inhibition of gluconeogenesis from L-lactate in isolated rat he patocytes was also time- and concentration-dependent, and accompanied by ch anges in metabolite levels similar to those induced by other inhibitors of gluconeogenesis acting on complex 1. Freeze-clamped livers from metformin-t reated rats exhibited similar changes in metabolite concentrations. We conc lude that the drug's pharmacological effects are mediated, at least in part , through a lime-dependent, self-limiting inhibition of the respiratory cha in that restrains hepatic gluconeogenesis while increasing glucose utilizat ion in peripheral tissues. Lactic acidosis, an occasional side effect, can also be explained in this way.