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Modulation of Insulin Secretion by Fatty Acyl Analogs

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

Abbreviations: ArgSIS, arginine-stimulated insulin secretion; Cl-DICA, ,'-tetrachloro-tetradecanedioic acid; DICA, ,-dicarboxylic acid; GPR40, G-protein coupled receptor 40; GSIS, glucose-stimulated insulin secretion; K_ATP channel, ATP-sensitive K⁺ channel; KSIS, K⁺-stimulated insulin secretion; LCFA, long-chain fatty acid; M16, ß,ß'-tetramethyl-hexadecanedioic acid; M16SIS, M16-stimulated insulin secretion; PKC, protein kinase C; RIA, radioimmunoassay; VGCC, voltage-gated calcium channel

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 ß,ß'-tetramethyl-hexadecanedioic acid (M16) and ,'-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. ß-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.

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