Modulation of Insulin Secretion by Fatty Acyl Analogs

Modulation of Insulin Secretion by Fatty Acyl Analogs Guy Las , Nina Mayorek , Kobie Dickstein and Jacob Bar-Tana From the Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel Address correspondence and reprint requests to Jacob Bar-Tana, Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, P.O. box 12272, Israel 91120. E-mail: bartanaj{at}cc.huji.ac.il Abstract The secretagogue, the incretin-like, and the suppressive activities of long-chain fatty acids (LCFAs) in modulating insulin secretion in vivo and in cultured islets were simulated here by β,β′-tetramethyl-hexadecanedioic acid (M16) and α,α′-tetrachloro-tetradecanedioic acid (Cl-DICA). M16, but not Cl-DICA, serves as a substrate for ATP-dependent CoA thioesterification but is not further metabolized. M16, but not Cl-DICA, acted as a potent insulin secretagogue in islets cultured in basal but not high glucose. Short-term exposure to M16 or Cl-DICA resulted in activation of glucose- but not arginine-stimulated insulin secretion. Long-term exposure to M16, but not to Cl-DICA, resulted in suppression of glucose-, arginine-, and K + -stimulated insulin secretion; inhibition of glucose-induced proinsulin biosynthesis; and depletion of islets insulin. β-Cell mass and islet ATP content remained unaffected. Hence, nonmetabolizable LCFA analogs may highlight discrete LCFA metabolites and pathways involved in modulating insulin secretion, which could be overlooked due to the rapid turnover of natural LCFA. ArgSIS, arginine-stimulated insulin secretion Cl-DICA, α,α′-tetrachloro-tetradecanedioic acid DICA, α,ω-dicarboxylic acid GPR40, G-protein coupled receptor 40 GSIS, glucose-stimulated insulin secretion KATP channel, ATP-sensitive K+ channel KSIS, K+-stimulated insulin secretion LCFA, long-chain fatty acid M16, β,β′-tetramethyl-hexadecanedioic acid M16SIS, M16-stimulated insulin secretion PKC, protein kinase C RIA, radioimmunoassay VGCC, voltage-gated calcium channel Footnotes G.L. and N.M. contributed equally to this work. J.B.-T. is affiliated with SyndromeX, a company that has partially financed this article’s research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted September 6, 2006. Received May 17, 2006. DIABETES