Sulfonylurea and Glinide Reduce Insulin Content, Functional Expression of K(ATP) Channels, and Accelerate Apoptotic Beta-Cell Death in the Chronic Phase

Diabetes Res Clin Pract. 2007 Sep;77(3):343-50. doi: 10.1016/j.diabres.2006.12.021. Epub 2007 Feb 20.

Abstract

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 sulfonylurea-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 sulfonylureas (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 Ca(2+) 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 beta-cell death all are involved in impaired insulinotropic agent-induced acute insulin secretion in the chronic phase of sulfonylurea 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Calcium Channels / drug effects
  • Cyclohexanes / adverse effects*
  • Hypoglycemic Agents / adverse effects
  • Insulin / analysis*
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / drug effects*
  • KATP Channels / drug effects*
  • Mice
  • Nateglinide
  • Phenylalanine / adverse effects
  • Phenylalanine / analogs & derivatives*
  • Sulfonylurea Compounds / adverse effects*
  • Time Factors

Substances

  • Calcium Channels
  • Cyclohexanes
  • Hypoglycemic Agents
  • Insulin
  • KATP Channels
  • Sulfonylurea Compounds
  • Nateglinide
  • Phenylalanine