Role of glucose and insulin in thiazolidinedione-induced alterations in hepatic gluconeogenesis

Previous studies from our laboratory as well as from others have suggested that the thiazolidinediones have the capacity to act as insulinomimetic age nts, especially in the liver. In order to further characterize this insulin omimetic action, we evaluated the effect of troglitazone, a representative thiazolidinedione, on lactate- and glucagon-stimulated gluconeogenesis, in the presence or absence of insulin (10 nM) in isolated rat hepatocytes. The antigluconeogenic effect of troglitazone under basal (lactate-stimulated) conditions was found to be due to an elevation in the fructose 2,6-bisphosp hate content, which was, however, not mediated by an activation of 6-phosph ofructo 2-kinase. Troglitazone (125 and 250 muM) in the absence of insulin, produced a dose-dependent reduction in glucagon-stimulated gluconeogenesis , thereby suggesting an insulinomimetic effect. In addition, troglitazone ( 125 and 250 muM), in combination with insulin, produced an additive inhibit ion of gluconeogenesis during glucagon-stimulated conditions. However, unli ke insulin, the metabolic mechanism responsible for these effects (in the p resence or absence of insulin) does not involve fructose 2,6-bisphosphate. (C) 2000 Elsevier Science B.V. All rights reserved.