Postreceptor Regulation of Insulin Action in Primary Cultures of Rat Hepatocytes by Oral Hypoglycemic Agents: Effects of Linogliride and Chlorpropamide

Summary

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.

Insulin - Hepatocytes - Chlorpropamide - Oral Hypoglycemic Agents - Sulfonylurea Agents - Lipogenesis