Journal
JOURNAL OF DIABETES RESEARCH
Volume 2015, Issue -, Pages -Publisher
HINDAWI LTD
DOI: 10.1155/2015/280615
Keywords
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Funding
- National Health and Medical Research Council of Australia (NHMRC) [APP1071350]
- Juvenile Diabetes Research Foundation (JDRF) fellowship
- Operational Infrastructure Support Scheme of the Government of Victoria
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Pancreatic beta-cell loss induced by saturated free fatty acids (FFAs) is believed to contribute to type 2 diabetes. Previous studies have shown induction of endoplasmic reticulum (ER) stress, increased ubiquitinated proteins, and deregulation of the Bcl-2 family in the pancreas of type 2 diabetic patients. However, the precisemechanism of beta-cell death remains unknown. In the present study we demonstrate that the FFA palmitate blocks the ubiquitin-proteasome system (UPS) and causes apoptosis through induction of ER stress and deregulation of Bcl-2 proteins. We found that palmitate and the proteasome inhibitor MG132 induced ER stress in beta-cells, resulting in decreased expression of the prosurvival proteins Bcl-2, Mcl-1, and Bcl- XL, and upregulation of the prodeath BH3-only protein PUMA. On the other hand, pharmacological activation of the UPS by sulforaphane ameliorated ER stress, upregulated prosurvival Bcl-2 proteins, and protected beta-cells from FFA-induced cell death. Furthermore, transgenic overexpression of Bcl-2 protected islets from FFA-induced cell death in vitro and improved glucose-induced insulin secretion in vivo. Together our results suggest that targeting the UPS and Bcl-2 protein expression may be a valuable strategy to prevent beta-cell demise in type 2 diabetes.
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