We have previously demonstrated the ability of the sulfonylurea tolazamide to potentiate insulin action in primary cultures of hepatocytes prepared from normal and streptozotocin-diabetic rats. To determine whether the pirogliride derivative linogliride, a non-sulfonylurea orally effective hypoglycemic agent, can potentiate insulin action, we evaluated the ability of linogliride to affect insulin-stimulated lipogenesis in primary cultures of hepatocytes prepared from normal rats. In addition, we also evaluated the ability of the sulfonylurea chlorpropamide to affect insulin-stimulated lipogenesis in the same in vitro system. The exposure of hepatocytes for 18 h to either linogliride (100 ug/ml) or chlorpropamide (175 ug/ml) resulted in dose-dependent (0.1 to 100 nM insulin) increases in insulin-stimulated lipogenesis, although the effects of chlorpropamide are approximately two times those of linogliride. This increase in insulin responsiveness was not associated with any change in insulin sensitivity (ED50) or insulin binding. The results provide evidence for an extra-pancreatic effect of linogliride and chlorpropamide in the liver and indicate that these structurally unrelated oral hypoglycemic agents enhance insulin responsiveness through postbinding mechanisms.