Sulfonylurea and glinide reduce insulin content, functional expression of K(ATP) channels, and accelerate apoptotic beta-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(+) (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.
Takahashi
Akira
A
Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Nagashima
Kazuaki
K
Hamasaki
Akihiro
A
Kuwamura
Naomitsu
N
Kawasaki
Yukiko
Y
Ikeda
Hiroki
H
Yamada
Yuichiro
Y
Inagaki
Nobuya
N
Seino
Yutaka
Y
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015220:Calcium Channels / Q000187:drug effects; D003510:Cyclohexanes / Q000009:adverse effects*; D007004:Hypoglycemic Agents / Q000009:adverse effects; D007328:Insulin / Q000032:analysis*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects*; D054086:KATP Channels / Q000187:drug effects*; D051379:Mice; D000077715:Nateglinide; D010649:Phenylalanine / Q000009:adverse effects / Q000031:analogs & derivatives*; D013453:Sulfonylurea Compounds / Q000009:adverse effects*; D013997:Time Factors
D015220:Calcium Channels; D003510:Cyclohexanes; D007004:Hypoglycemic Agents; D007328:Insulin; D054086:KATP Channels; D013453:Sulfonylurea Compounds; D000077715:Nateglinide; D010649:Phenylalanine