Decreased responsiveness of gluconeogenesis to the modulation by sulfonylureas in hepatocytes isolated from obese (fa/fa) zucker rats

The influence of the hypoglycemic agent glipizide (0-100 muM) on the rate o f gluconeogenesis from lactate, as well as on the levels of fructose 2,6-bi sphosphate, has been investigated in hepatocytes isolated from genetically obese (fa/fa) Zucker rats and from their corresponding lean (Fa/- ) litterm ates. As compared to lean rat hepatocytes, liver cells isolated from obese animals showed a lower rate of basal gluconeogenesis (0.9 +/- 0.2 vs 5.4 +/ - 0.5 mu mol of lactate converted to glucose/g cell x 30 min, n=4) and high er levels of fructose 2,6-bisphosphate (11.5 +/- 1.0 vs 5.9 +/- 0.4 nmol/g cell, n= 8-9). In lean rat hepatocytes, the presence of glipizide in the in cubation medium caused a dose-dependent inhibition of the rate of lactate c onversion to glucose (maximal inhibition=46%; EC50 value=26 muM), and simul taneously raised the cellular content of fructose-2,6-bisphosphate (maximal increment=40%; EC50 value=10 muM). In contrast, in hepatocytes isolated fr om obese rats, the inhibition of gluconeogenesis and the increment in fruct ose-2,6-bisphosphate levels elicited by glipizide were significantly reduce d (maximal effects of 22 and 13%, respectively). Similarly, the activation of glycogen phosphorylase and the increase in hexose 6-phosphate levels in response to glipizide were less marked in obese rat hepatocytes than in liv er cells isolated from lean animals. These results demonstrate that the eff icacy of sulfonylureas as inhibitors of hepatic gluconeogenesis is reduced in the genetically obese (fa/fa) Zucker rat. (C) 2001 Elsevier Science Inc. All rights reserved.