INSULIN SENSITIZATION IN DIABETIC RAT-LIVER BY AN ANTIHYPERGLYCEMIC AGENT

This study aimed to demonstrate directly that the thiazolidinedione pi oglitazone acts as an insulin sensitizer. We tested the hypothesis tha t pioglitazone treatment of diabetic rats alters liver function such t hat responsiveness of selected genes to subsequent insulin regulation is enhanced. Although flux through gluconeogenic/glycolytic pathways i nvolves regulation of many enzymes, we presently report the effects of insulin on expression of two key enzymes in these metabolic pathways, ie, phosphoenolpyruvate carboxykinase (PEPCK) and glucokinase (GK). R ats were either studied as nondiabetic controls or injected with strep tozotocin as a model for insulin-deficient diabetes. Diabetic animals were treated without or with pioglitazone and subsequently examined fo r acute responses to insulin. Pioglitazone treatment of diabetic anima ls significantly enhanced the effects of insulin to reverse elevated b lood glucose. Although the mean level of liver mRNA transcripts encodi ng PEPCK was increased to nearly 300% in diabetic animals as compared with nondiabetic controls (100%), it was significantly lower in piogli tazone-treated diabetic rats (119% of control) than in diabetic rats w ithout pioglitazone (223% of control) after insulin treatment. By cont rast, mRNA transcripts encoding GK were not detectable in diabetic ani mals, but were increased markedly by insulin treatment in all animal g roups. Insulin-enhanced expression of GK was significantly greater in liver from animals that were treated earlier with pioglitazone (291% o f control) than in liver from those that were untreated (214% of contr ol). An amplified acute response of liver to insulin thus established pioglitazone as an insulin sensitizer. Our findings further showed tha t such sensitization can be developed even in the insulin deficient st ate. These observations underscore the potential for agents with this action to reverse the insulin-resistant state characteristic of non-in sulin-dependent diabetes. Copyright (C) 1995 by W.B. Saunders Company