A Paradoxical Effect of Chlorpropamide on the Plasma Glucose and Immunoreactive Insulin Response to Intravenous Glucose in Normal Dogs

The effect of various doses of chlorpropamide on plasma glucose and immunoreactive insulin responses to an acute intravenous glucose challenge has been studied in normal dogs. The effects of chlorpropamide were compared to those of placebo in each dog. The administration of 375 mg. of chlorpropamide for four days decreased the ability of the dogs to dispose of a glucose load, and the deterioration in glucose tolerance was accompanied by a marked suppression of the plasma insulin response. Administration of 125 mg. of chlorpropamide for four days led to changes that were qualitatively similar but quantitatively less striking. These results indicate that excessive amounts of chlorpropamide can lead to deterioration in glucose tolerance; this effect seems analogous to induction of glucose intolerance in normal subjects by administration of insulin, as first described by Somogyi. When the chlorpropamide was decreased to a daily dose of 50 mg., dogs were able to dispose of the intravenous glucose load more efficiently than normal. However, this improvement in glucose tolerance was not associated with a significant rise in plasma insulin response. Thus, although it seems reasonable to attribute deterioration in glucose tolerance after excessive doses of chlorpropamide at least partly to inhibition of insulin release, the improvement that occurs after smaller doses does not appear to be due to an absolute increment in the plasma insulin response to glucose.