Inhibitory effects of metformin on insulin and glucagon action in rat hepatocytes involve post-receptor alterations.

The effect of the hypoglycaemic biguanide, metformin, on insulin binding and insulin action was investigated in rat hepatocyte monolayers. The binding of insulin was not modified in cultured cells exposed for 24 or 48 h to metformin at concentrations ranging from 1 mumol/l to 1 mmol/l, and no effect could be detected on insulin-induced down regulation. Metformin did not alter insulin stimulation of amino acid transport but the stimulatory effect of insulin on glycogen synthesis was reduced by 20%, 30% and 63% for metformin at 0.01, 0.1 and 1 mmol/l, respectively. Both responsiveness and sensitivity were altered by the biguanide. Metformin also inhibited basal glycogen synthesis and cellular glycogen contents were markedly decreased after exposure of cells to metformin (0.01-1 mmol/l). We also investigated the effect of metformin on glucagon action and metformin (0.1-1 mmol/l) was found to decrease the stimulatory effect of glucagon on amino acid uptake and on gluconeogenesis from alanine. These inhibitory effects of the biguanide were still observed when glucagon was replaced by dibutyryl cAMP. These in vitro studies demonstrate that: 1) metformin has no direct effect on insulin binding in hepatocytes, indicating that alteration of insulin stimulation of glycogen synthesis is due to modifications at the post receptor level. 2) metformin alters the action of glucagon in hepatocytes at a post AMP cyclase step. They also suggest that one of the mechanism of action of metformin may be to antagonize the effect of glucagon rather than to potentiate the action of insulin.