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Palmitate impairs and eicosapentaenoate restores insulin secretion through regulation of SREBP-1c in pancreatic islets

¹Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences and
²Center for Tsukuba Advanced Research Alliance, University of Tsukuba
³Department of Molecular Physiology and Biophysics, Vanderbilt University

Objective: Chronic exposure to fatty acids causes β-cell failure, often referred to as lipotoxicity. We investigated its mechanisms focusing on contribution of SREBP-1c, a key transcription factor for lipogenesis.

Research Design and Methods: We studied in vitro and in vivo effects of saturated and polyunsaturated acids on insulin secretion, insulin-signaling and expression of genes involved in β-cell functions. Pancreatic islets isolated from C57BL/6 control and SREBP-1-null mice, and adenoviral gene-delivery or -knockdown systems of related genes were used.

Results: Incubation of C57BL/6 islets with palmitate (PA) caused inhibition of both glucose- and potassium-stimulated insulin secretion, but addition of eicosapentaenoate (EPA) restored both inhibitions. Concomitantly, PA activated, and EPA abolished both mRNA and nuclear protein of SREBP-1c, accompanied by reciprocal changes of SREBP-1c-target genes such as IRS-2 and granuphilin. These PA-EPA effects on insulin secretion were abolished in SREBP-1-null islets. Suppression of IRS-2/Akt pathway could be a part of the downstream mechanism for the SREBP-1c-mediated insulin secretion defect because adenoviral constitutive-active Akt compensated it. UCP-2 also plays a crucial role in the PA inhibition of insulin secretion as confirmed by knockdown experiments, but SREBP-1c-contribution to UCP-2-regulation was partial. The PA-EPA regulation of insulin secretion was similarly observed in islets from C57BL/6 mice pretreated with dietary manipulations. Furthermore, administration of EPA to diabetic KKAy mice ameliorated impairment of insulin secretion in their islets.

Conclusions: SREBP-1c plays a dominant role in PA-mediated insulin secretion defect, and EPA prevents it through SREBP-1c inhibition, implicating a therapeutic potential for diabetes related to lipotoxicity.

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