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¹ Prince Henry's Institute of Medical Research, PO Box 5152, Clayton, Victoria 3168, Australia² Department of Physiology, Fourth Military Medical University, Xi'an 710032, China³ School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072, Australia

(Correspondence should be addressed to C Chen; Email: chen.chen{at}uq.edu.au)

ATP-sensitive potassium channels (K_ATP channels) determine the excitability of pancreatic β-cells and importantly regulate glucose-stimulated insulin secretion (GSIS). Long-chain free fatty acids (FFAs) decrease GSIS after long-term exposure to β-cells, but the effects of exogenous FFAs on K_ATP channels are not yet well clarified. In this study, the effects of linoleic acid (LA) on membrane potential (MP) and K_ATP channels were observed in primary cultured rat pancreatic β-cells. LA (20 µM) induced hyperpolarization of MP and opening of K_ATP channels, which was totally reversed and inhibited by tolbutamide, a K_ATP channel blocker. Inhibition of LA metabolism by acyl-CoA synthetase inhibitor, triacsin C (10 µM), partially inhibited LA-induced opening of K_ATP channels by 64%. The non-FFA G protein-coupled receptor (GPR) 40 agonist, GW9508 (40 µM), induced an opening of K_ATP channels, which was similar to that induced by LA under triacsin C treatment. Blockade of protein kinases A and C did not influence the opening of K_ATP channels induced by LA and GW9508, indicating that these two protein kinase pathways are not involved in the action of LA on K_ATP channels. The present study demonstrates that LA induces hyperpolarization of MP by activating K_ATP channels via both intracellular metabolites and activation of GPR40. It indicates that not only intracellular metabolites of FFAs but also GPR40-mediated pathways take part in the inhibition of GSIS and β-cell dysfunction induced by FFAs.