Effect of chronic tolbutamide administration on normal and obese-hyperglycemic mice: evidence for post-receptor potentiation of insulin action.

Obese-hyperglycemic mice (genotype ob/ob) have hyperglycemia, hyperinsulinemia, increased resistance to insulin action and decreased insulin receptors on their liver, fat cell and muscle plasma membranes. Hypoglycemic sulfonylureas are reported to improve diabetic control by decreasing the insulin resistance of subjects with Type II diabetes mellitus: however, it is not clear if their mechanism is to increase plasma membrane insulin receptors or to decrease post-receptor insulin resistance. In this study we treated obese-hyperglycemic mice and their normal weight litter mates with the oral hypoglycemic sulfonylurea tolbutamide for 28 to 34 weeks. Tolbutamide administration to normal mice resulted in the following changes that were indicative of increased insulin action: (1) increased body weight; (2) increased epididymal fat-pad weight; (3) increased 2-deoxyglucose transport into the intact diaphragm muscle preparation. There was no alteration in plasma glucose, plasma insulin or pancreatic insulin content suggesting that the tolbutamide effect was an extrapancreatic effect that was probably not mediated by increased insulin secretion. There was no change in the insulin receptor number or affinity of liver cell membranes prepared from tolbutamide treated mice supporting the notion that the extrapancreatic effect of tolbutamide may occur at a post-insulin receptor location. In contrast to the normal mice, tolbutamide did not increase the body weight, epididymal fat pad weight, the already increased 2-deoxyglucose transport into diaphragm muscle or the decreased number of insulin receptors on hepatic plasma membranes. The tolbutamide caused a striking decrease in pancreatic insulin concentration and degranulation of the islets in obese but not normal mice. This is compatible with previous information that the obese mice have abnormal islets that are not under the normal feed-back control of ambient insulin concentration as are the islets of normal mice. We conclude that tolbutamide potentiates insulin action in normal, but not obese, mice and that this potentiation may be due to a post-insulin receptor action.