期刊
DIABETES RESEARCH AND CLINICAL PRACTICE
卷 77, 期 3, 页码 343-350出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.diabres.2006.12.021
关键词
insulinotropic agents; chronic exposure; K-ATP channel; insulin secretion; secondary sulfonylurea failure
We previously found that chronic exposure to glibenclamide inhibits acute glibenclamide-induced insulin secretion by reducing the number of functional ATP-sensitive K+ (K-ATP) channels on the plasma membrane of pancreatic beta-cells. In the present study, we compared suffonylurea-induced and glinide-induced insulin secretion in pancreatic beta-cells chronically exposed to these widely used oral hypoglycemic agents. Chronic exposure of pancreatic beta-cells to suffortylureas (glibenclamide or tolbutamide) and glinide (nateglinide) similarly impaired their acute effectiveness by reducing the insulin content and the number of functional K-ATP channels on the plasma membrane. Functional expression of the voltage-dependent Ca2+ channels (VDCCs), ion channels that play a critical role in the K-ATP channel dependent insulin secretory pathway, was similar to that in drug-untreated cells. Chronic exposure to each of the three agents similarly accelerated apoptotic beta-cell death. Thus, reduction of the insulin content, reduction of the number of functional K-ATP channels on the plasma membrane, and acceleration of apoptotic P-cell death all are involved in impaired insulinotropic agent-induced acute insulin secretion in the chronic phase of suffonylurea and glinide treatment. These findings help to clarify the mechanism of secondary failure after long-term therapy by these hypoglycemic agents, and should have important clinical implications regarding pharmacotherapy for type 2 diabetes. (c) 2007 Elsevier Ireland Ltd. All rights reserved.
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