Sulfonylurea and glinide reduce insulin content, functional expression of KATP channels, and accelerate apoptotic β-cell death in the chronic phase

We previously found that chronic exposure to glibenclamide inhibits acute glibenclamide-induced insulin secretion by reducing the number of functional ATP-sensitive K+ (KATP) channels on the plasma membrane of pancreatic β-cells. In the present study, we compared sulfonylurea-induced and glinide-induced insulin secretion in pancreatic β-cells chronically exposed to these widely used oral hypoglycemic agents. Chronic exposure of pancreatic β-cells to sulfonylureas (glibenclamide or tolbutamide) and glinide (nateglinide) similarly impaired their acute effectiveness by reducing the insulin content and the number of functional KATP channels on the plasma membrane. Functional expression of the voltage-dependent Ca2+ channels (VDCCs), ion channels that play a critical role in the KATP channel dependent insulin secretory pathway, was similar to that in drug-untreated cells. Chronic exposure to each of the three agents similarly accelerated apoptotic β-cell death. Thus, reduction of the insulin content, reduction of the number of functional KATP channels on the plasma membrane, and acceleration of apoptotic β-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.