The ob gene product leptin over the concentration range 0.1-100 nM demonstrated a U-shaped dose-response inhibition of glucose-stimulated insulin secretion by rat pancreatic islets. Thus, leptin (1 and 10 nM) produced a significant inhibition whereas 100 nM was ineffective. The inhibitory effect of leptin was glucose dependent, had a rapid onset and was readily reversed upon removal of leptin. Sub-chronic exposure of islets to leptin (10 nM) reduced both insulin secretion and the level of insulin transcript. These findings support the hypothesis that excessive production of leptin by adipose tissue could play a role in the development of non-insulin dependent diabetes in obese subjects.