Int. Jnl. Experimental Diab. Res., Vol. 2, pp. 73-79 Reprints available directly from the publisher Photocopying permitted by license only (C) 2001 OPA (Overseas Publishers Association) N.V. Published by license under the Harwood Academic Publishers imprint, part of Gordon and Breach Publishing, member of the Taylor & Francis Group. Printed in the United States. Effectiveness of Nateglinide on In Vitro Insulin Secretion from Rat Pancreatic Islets Desensitized to Sulfonylureas SHILING HU*, SHUYA WANG and BETH E. DUNNING Metabolic and Cardiovascular Diseases, Novartis Institutefor Biomedical Research, Summit, USA (Received 6 December 2000; In finalform 5 February 2001) Chronic exposure of pancreatic islets to sulfony- lureas (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 /3-cell KATP channels, which is common to the structurally diverse drugs like repaglinide (REP) and the SUs. Earlier studies on the kinetics, glucose- dependence 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. Keywords: Rat pancreatic islet; Static incubation; In vitro insulin secretion; Nateglinide; Islet desensitization 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 chan- nels, [1] which are formed by the molecular interaction between a high-affinity SU receptor, SUR1, and an inwardly rectifying K + channel subunit, Kir6.2. [2] The closure of KATP channels leads to the opening of voltage-dependent Ca2 + channels, Ca2 + influx and stimulation of Ca2 +- exocytosis.[3] dependent 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. [4-7] In vitro chronic exposure of pancreatic islets to SUs is also known to cause impairment of secretory response to subsequent stimulation by glucose or SUs. [8-11] The mechanisms underlying *Address for correspondence: Metabolic and Cardiovascular Diseases, Novartis Institute for Biomedical Research, 556 Morris Avenue, Summit, NJ 07901, USA. Tel.: 908-277-5703, Fax: 908-277-4756, e-maih shiling.hu@pharma.novartis.com 73