Hepatic insulin resistance in non-insulin-dependent diabetes mellitus and the effects of a sulfonylurea in potentiating insulin action.

We have utilized primary cultures of rat hepatocytes to study insulin resistance in the liver of nonketotic streptozotocin-diabetic animals. Diabetes mellitus is associated with insulin resistance with regard to hepatic lipogenesis. This resistance is profound at serum glucose levels above 400 mg/dl and, below that, inversely related to the serum glucose. The insulin resistance can be reversed by in vivo treatment of animals with insulin, indicating that the resistance to insulin is secondary to the diabetic state. However, the in vitro treatment of primary cultures of hepatocytes with insulin, a variety of glycolytic intermediates, or a combination of the two does not reverse the resistance to insulin. Thus, in contrast to cells from fasted animals, in vivo factors other than insulin are important to the recovery of hepatic insulin responsiveness. With regard to the mechanism of this insulin resistance, insulin binding is normal to increased, suggesting postbinding mechanisms. To further define the mechanism(s) of insulin resistance, we evaluated the ability of insulin to release the putative second messenger of insulin action from a liver particulate fraction. Insulin reproducibly and significantly enhanced the release of mediator from the liver particulate fraction of control animals, but the particulate fraction from diabetic animals was resistant to this effect of insulin. Insulin treatment of animals restored the ability of liver particulate fractions to release mediator in response to insulin. These data support the concept that alterations at or near the plasma membrane can be responsible for or accompany the insulin resistance observed in the liver in diabetes mellitus.(ABSTRACT TRUNCATED AT 250 WORDS)