Palmitate Impairs and Eicosapentaenoate Restores Insulin Secretion Through Regulation of SREBP-1c in Pancreatic Islets

  1. Toyonori Kato1,
  2. Hitoshi Shimano12,
  3. Takashi Yamamoto1,
  4. Mayumi Ishikawa1,
  5. Shin Kumadaki1,
  6. Takashi Matsuzaka12,
  7. Yoshimi Nakagawa12,
  8. Naoya Yahagi2,
  9. Masanori Nakakuki1,
  10. Alyssa H. Hasty3,
  11. Yoshinori Takeuchi1,
  12. Kazuto Kobayashi1,
  13. Akimitsu Takahashi1,
  14. Shigeru Yatoh1,
  15. Hiroaki Suzuki1,
  16. Hirohito Sone1 and
  17. Nobuhiro Yamada1
  1. 1Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan
  2. 2Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan
  3. 3Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
  1. Corresponding author: Hitoshi Shimano, shimano-tky{at}umin.ac.jp

Abstract

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 caused inhibition of both glucose- and potassium-stimulated insulin secretion, but addition of eicosapentaenoate (EPA) restored both inhibitions. Concomitantly, palmitate activated and EPA abolished both mRNA and nuclear protein of SREBP-1c, accompanied by reciprocal changes of SREBP-1c target genes such as insulin receptor substrate-2 (IRS-2) and granuphilin. These palmitate-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 constitutively active Akt compensated it. Uncoupling protein-2 (UCP-2) also plays a crucial role in the palmitate inhibition of insulin secretion, as confirmed by knockdown experiments, but SREBP-1c contribution to UCP-2 regulation was partial. The palmitate-EPA regulation of insulin secretion was similarly observed in islets from C57BL/6 mice pretreated with dietary manipulations. Furthermore, administration of EPA to diabetic KK-Ay mice ameliorated impairment of insulin secretion in their islets.

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

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 5 May 2008.

    Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

    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 April 23, 2008.
    • Received December 29, 2006.
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  1. Diabetes vol. 57 no. 9 2382-2392
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