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 Yang1,3,
  6. Christian Widmann1,3,
  7. Amar Abderrahmani1,4 and
  8. Romano Regazzi (Romano.Regazzi{at}unil.ch)1
  1. 1 Department of Cell Biology and Morphology, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 9, CH-1005 Lausanne
  2. 2 Diabetes and Obesity Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, Australia
  3. 3 Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 7, CH-1005 Lausanne
  4. 4 Service of Internal Medicine, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland

    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, a class of non-coding RNAs regulating gene expression by sequence-specific inhibition of mRNA translation.

    Research design and methods: We analyzed microRNA expression in insulin-secreting cell lines or pancreatic islets exposed to palmitate for thee days and in islets from diabetic db/db mice. We studied the signaling pathways triggering the changes in microRNA expression and determined the impact of the microRNAs 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 microRNAs are observed also 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 VAMP2, a key player in β-cell exocytosis. Higher miR146 levels do not affect the capacity to release insulin but contribute to increase 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 microRNAs.

    Footnotes

      • Received September 3, 2008.
      • Accepted June 28, 2008.

    This Article

    1. Diabetes
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