부산대학교 도서관

Progressive β cell dysfunction and a decrease of the β cell mass are pathophysiologic features of type 2 diabetes. Failure of the β cells to overcome insulin resistance is a key factor behind these changes. Enhanced oxidative stress caused by hyperglycemia and hyperlipidemia is another probable underlying mechanism. In this study, we investigated the effect of combined therapy with nateglinide (NT) and telmisartan (TEL) on the progression of β cell dysfunction and β cell loss in Zucker fatty (ZF) rats, which develop hyperinsulinemia, hyperlipidemia, and postprandial hyperglycemia. ZF rats and Zucker lean (ZL) rats were fed commercial rat chow twicw a day. ZF rats were orally administered the vehicle, NT(50mg/kg), TEL(5mg/kg), or both drugs just before each meal for 6 weeks from 10 weeks of age. ZF rats developed postprandial hyperglycemia and hyperlipidemia with delayed and excessive insulin secretion that peaked at 1hr after meals. NT stimulated early-phase insulin secretion, with a peak at 0.5hr after meals, and suppressed postprandial hyperglycemia. TEL had no effect on the postprandial blood glucose level, but excessive insulin secretion at 1hr after meals was suppressed. The combination of NT and TEL suppressed postprandial hyperglycemia more effectively than either type of monotherapy, as well as restoring early-phase insulin secretion and suppressing excessive insulin secretion at 1hr after meals. Six weeks of combined therapy with NT and TEL also lowered the fasting plasma levels of insulin, triglycerides, and free fatty acids. Pancreatic islets were isolated from each rat and glucose-stimulated insulin secretion (GSIS) was evaluated. Insulin secretion in response to 2.8mM glucose was unchanged among all groups. In the VEH-treated rats, however, β cell mass was decreased by 1/4 and the expression of three SNARE proteins (SNAP25, syntaxin1A, and VAMP2) was downregulated to 1/5 to 1/10 of that in the islets of ZL rats. Insulin secretion in response to 5.6 and 16.7mM glucose was also diminished. Although expression of the SNAREs was upregulated by NT monotherapy, the fl cell mass and GSIS were not restored. TEL suppressed the reduction oft cell mass, but did not influence the expression of SNAREs and GSIS. Combined therapy with NT and TEL restored GSIS along with normalization of SNAREs levels and preservation of the β cell mass. These results suggest that the combination of NT and TEL has a long-term beneficial effect by promoting the preservation of pancreatic β cell mass and β cell function. [ABSTRACT FROM AUTHOR]