Alterations in MicroRNA Expression Contribute to Fatty Acid–Induced Pancreatic β-Cell Dysfunction

  1. Pascal Lovis1,
  2. Elodie Roggli1,
  3. D. Ross Laybutt2,
  4. Sonia Gattesco1,
  5. Jiang-Yan Yang13,
  6. Christian Widmann13,
  7. Amar Abderrahmani14 and
  8. Romano Regazzi1
  1. 1Department of Cell Biology and Morphology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
  2. 2Diabetes and Obesity Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, Australia
  3. 3Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
  4. 4Service of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
  1. Corresponding author: Dr. Romano Regazzi, romano.regazzi{at}unil.ch

Abstract

OBJECTIVE—Visceral obesity and elevated plasma free fatty acids are predisposing factors for type 2 diabetes. Chronic exposure to these lipids is detrimental for pancreatic β-cells, resulting in reduced insulin content, defective insulin secretion, and apoptosis. We investigated the involvement in this phenomenon of microRNAs (miRNAs), a class of noncoding RNAs regulating gene expression by sequence-specific inhibition of mRNA translation.

RESEARCH DESIGN AND METHODS—We analyzed miRNA expression in insulin-secreting cell lines or pancreatic islets exposed to palmitate for 3 days and in islets from diabetic db/db mice. We studied the signaling pathways triggering the changes in miRNA expression and determined the impact of the miRNAs affected by palmitate on insulin secretion and apoptosis.

RESULTS—Prolonged exposure of the β-cell line MIN6B1 and pancreatic islets to palmitate causes a time- and dose-dependent increase of miR34a and miR146. Elevated levels of these miRNAs are also observed in islets of diabetic db/db mice. miR34a rise is linked to activation of p53 and results in sensitization to apoptosis and impaired nutrient-induced secretion. The latter effect is associated with inhibition of the expression of vesicle-associated membrane protein 2, a key player in β-cell exocytosis. Higher miR146 levels do not affect the capacity to release insulin but contribute to increased apoptosis. Treatment with oligonucleotides that block miR34a or miR146 activity partially protects palmitate-treated cells from apoptosis but is insufficient to restore normal secretion.

CONCLUSIONS—Our findings suggest that at least part of the detrimental effects of palmitate on β-cells is caused by alterations in the level of specific miRNAs.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 15 July 2008.

    P.L. and E.R. contributed equally to this work.

    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 June 28, 2008.
    • Received September 3, 2007.
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  1. Diabetes vol. 57 no. 10 2728-2736
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