Cellular Production of n-3 PUFAs and Reduction of n-6–to–n-3 Ratios in the Pancreatic β-Cells and Islets Enhance Insulin Secretion and Confer Protection Against Cytokine-Induced Cell Death

  1. Dong Wei1,2,
  2. Jie Li1,3,
  3. Miaoda Shen4,5,
  4. Wei Jia1,6,
  5. Nuoqi Chen1,
  6. Tao Chen1,3,
  7. Dongming Su1,
  8. Haoming Tian3,
  9. Shusen Zheng5,
  10. Yifan Dai7 and
  11. Allan Zhao7,1
  1. 1Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania;
  2. 2Department of Endocrinology, the Second People's Hospital of Chengdu, Chengdu, China;
  3. 3Department of Endocrinology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China;
  4. 4Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania;
  5. 5Department of Surgery, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang Province, China;
  6. 6Department of Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China;
  7. 7The Center of Metabolic Disease Research, Nanjing Medical University, Nanjing, Jiangsu Province, China.
  1. Corresponding author: Allan Zhao, azhao{at}pitt.edu.
  1. D.W., J.L., and M.S. contributed equally to this work and should be considered co–first authors.

Abstract

OBJECTIVE To evaluate the direct impact of n-3 polyunsaturated fatty acids (n-3 PUFAs) on the functions and viability of pancreatic β-cells.

RESEARCH DESIGN AND METHODS We developed an mfat-1 transgenic mouse model in which endogenous production of n-3 PUFAs was achieved through overexpressing a C. elegans n-3 fatty acid desaturase gene, mfat-1. The islets and INS-1 cells expressing mfat-1 were analyzed for insulin secretion and viability in response to cytokine treatment.

RESULTS The transgenic islets contained much higher levels of n-3 PUFAs and lower levels of n-6 PUFAs than the wild type. Insulin secretion stimulated by glucose, amino acids, and glucagon-like peptide-1 (GLP-1) was significantly elevated in the transgenic islets. When challenged with tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and γ-interferon (IFN-γ), the transgenic islets completely resisted cytokine-induced cell death. Adenoviral transduction of mfat-1 gene in wild-type islets and in INS-1 cells led to acute changes in the cellular levels of n-3- and n-6 PUFAs and recapitulated the results in the transgenic islets. The expression of mfat-1 led to decreased production of prostaglandin E2 (PGE2), which in turn contributed to the elevation of insulin secretion. We further found that cytokine-induced activation of NF-κB and extracellular signal–related kinase 1/2 (ERK1/2) was significantly attenuated and that the expression of pancreatic duodenal hemeobox-1 (PDX-1), glucokinase, and insulin-1 was increased as a result of n-3 PUFA production.

CONCLUSIONS Stable cellular production of n-3 PUFAs via mfat-1 can enhance insulin secretion and confers strong resistance to cytokine-induced β-cell destruction. The utility of mfat-1 gene in deterring type 1 diabetes should be further explored in vivo.

Footnotes

  • 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.

    • Received March 12, 2009.
    • Accepted November 11, 2009.
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  1. Diabetes vol. 59 no. 2 471-478
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