Effectiveness of nateglinide on in vitro insulin secretion from rat pancreatic islets desensitized to sulfonylureas.

Shiling Hu,Beth E Dunning,Shuya Wang

doi:10.1155/edr.2001.73

Abstract

Chronic exposure of pancreatic islets to sulfonylureas (SUs) is known to impair the ability of islets to respond to subsequent acute stimulation by SUs or glucose. Nateglinide (NAT) is a novel insulinotropic agent with a primarily site of action at β-cell KATP channels, which is common to the structurally diverse drugs like repaglinide (REP) and the SUs. Earlier studies on the kinetics, glucosedependence and sensitivity to metabolic inhibitors of the interaction between NAT and KATP channels suggested a distinct signaling pathways with NAT compared to REP, glyburide (GLY) or glimepiride (GLI). To obtain further evidence for this concept, the present study compared the insulin secretion in vitro from rat islets stimulated acutely by NAT, GLY, GLI or REP at equipotent concentrations during 1-hr static incubation following overnight treatment with GLY or tolbutamide (TOL). The islets fully retained the responsiveness to NAT stimulation after prolonged pretreatment with both SUs, while their acute response to REP, GLY, and GLI was markedly attenuated, confirming the desensitization of islets. The insulinotropic efficacy of NAT in islets desensitized to SUs may result from a distinct receptor/effector mechanism, which contributes to the unique pharmacological profile of NAT.

Highlights

Sulfonylureas (SUs) are widely used in the treatment of non-insulin-dependent (Type 2) diabetes
While SUs exert hypoglycemic action via a direct stimulation of insulin release during short term administration in type 2 diabetic patients, their activity declines during long term applica-tion, which has been suggested to be directly attributable to a desensitization of /-cells to SUs. [4,5,6,7] In vitro chronic exposure of pancreatic islets to SUs is known to cause impairment of secretory response to subsequent stimulation by glucose or SUs. [8,9,10,11] The mechanisms underlying
The effectiveness of four hypoglycemic agents, NAT, GLY, GLI, and REP, to stimulate insulin release from islets cultured overnight (18 hours) in the presence of 100nM GLY was evaluated and was compared to that from overnight cultured islets without GLY to determine the magnitude of desensitization induced by GLY

Summary

Introduction

Sulfonylureas (SUs) are widely used in the treatment of non-insulin-dependent (Type 2) diabetes. They stimulate insulin secretion by closing ]-cell plasma membrane KATp channels, [1] which are formed by the molecular interaction between a high-affinity SU receptor, SUR1, and an inwardly rectifying K + channel. KAT SUs to act on P channels in pancreatic ]B-cells This drug, compared to other marketed KATP channel-blocking hypoglycemic agents, has demonstrated unique characteristics including a rapid onset, short duration of action, sensitivity to ambient glucose, and resistance to metabolic inhibition, suggesting some aspects of the signaling pathway(s) mediating NAT’s action are novel and distinct from those mediating the effects of SUs and REP. This study was designed to evaluate the ability of NAT and the com-parators, glyburide (GLY), glimepiride (GLI), and repaglinide (REP)

Methods

Results

Conclusion