EFFECT OF TROGLITAZONE (REZULIN) ON FRUCTOSE 2,6-BISPHOSPHATE CONCENTRATION AND GLUCOSE-METABOLISM IN ISOLATED RAT HEPATOCYTES

The effect of troglitazone, an orally effective thiazolidinedione, on lactate-and glucagon-stimulated gluconeogenesis (in the absence of ins ulin) was examined in hepatocytes isolated from rats under different n utritional states. Hepatocytes obtained from fed or 20-24 hr fasted ma le Sprague-Dawley rats were incubated in Krebs-Henseleit Bicarbonate b uffer (KHBC) (in presence or absence of 10.0 mM glucose) containing 2. 0 mM [U-C-14]lactate (0.1-0.25 mu Ci) with or without 10.0 nM glucagon and troglitazone (30.0 mu M) or the appropriate vehicle. Aliquots wer e removed at specified endpoints and assayed for glucose and fructose 2,6-bisphosphate (F-2,6-P-2) concentrations. In 20-24 hour starved hep atocytes, troglitazone produced a 26.1% inhibition of lactate-stimulat ed gluconeogenesis. This inhibitory effect of troglitazone on hepatic gluconeogenesis was further potentiated by incubation of the cells wit h glucose in vitro. In hepatocytes obtained from fasted rats (and incu bated with 10 mM glucose in vitro) troglitazone reduced lactate-and gl ucagon-stimulated gluconeogenesis by 53% and 56%, respectively. This r eduction in hepatic glucose production was associated with 1.06 and 1. 04 fold increase in the hepatocyte F-2,6-P-2 content. In isolated hepa tocytes from fed animals and incubated with 10 mM glucose in vitro, tr oglitazone (15 and 30 mu M) did not have any effect on either lactate- or glucagon-stimulated gluconeogenesis. However, 30 mu M troglitazone significantly enhanced (36%) F-2,6-P-2 concentrations during lactate-s timulated gluconeogenesis. These findings demonstrate that troglitazon e decreases hepatic glucose production through alterations in the acti vity of one or more gluconeogenic/glycolytic enzymes, depending upon t he nutritional state of the animal and the presence or absence of horm onal modulation. All of the effects of troglitazone in the present stu dy were observed in the absence of insulin, suggesting an ''insulinomi metic'' effect. However, this does not exclude the possibility that tr oglitazone may also function as an ''insulin sensitizer'' in hepatic a nd certain other tissues. (C) 1998 Elsevier Science Inc.