Functional effects of acute and prolonged (48 h) exposure to the biguanide drug metformin were examined in the clonal pancreatic beta-cell line, BRIN-BD11. Effects of metformin on prolonged exposure to excessive increased concentrations of glucose and palmitic acid were also assessed. In acute 20-min incubations, 12.5-50 mu M metformin did not alter basal (1.1 mM glucose) or glucose-stimulated (16.7 mM glucose) insulin secretion. However, higher concentrations of metformin (100-1000 mu M) increased (1.3-1.5-fold; p<0.001) insulin release at basal glucose concentrations, but had no effect on glucose-stimulated insulin secretion. There were no apparent acute effects of metformin on intracellular Ca2+ concentrations, but metformin enhanced (p<0.05 to p<0.01) the acute insulinotropic actions of GIP and GLP-1. Exposure for 48 h to 200 beta M metformin improved aspects of b-cell insulin secretory function, whereas these benefits were lost at 1 mM metformin. Prolonged glucotoxic and lipotoxic conditions impaired beta-cell viability and insulin release in response to glucose and to a broad range of insulin secretagogues. Concomitant culture with 200 mu M metformin partially reversed many of the adverse effects of prolonged glucotoxic conditions. However, there were no beneficial effects of metformin under prolonged culture with elevated concentrations of palmitic acid. The results suggest that metformin exerts direct effects on beta-cell viability, function and survival that could contribute to the use of this agent in the treatment of type 2 diabetes.