4.7 Article

Oleate-Induced Beta Cell Dysfunction and Apoptosis: A Proteomic Approach to Glucolipotoxicity by an Unsaturated Fatty Acid

Journal

JOURNAL OF PROTEOME RESEARCH
Volume 10, Issue 8, Pages 3372-3385

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/pr101290n

Keywords

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Funding

  1. European Union [036,903, 241447, GOA 2004/10, 2009/10]
  2. Flemish Research Foundation (FWO) [G.0552.06, G.0649.08]
  3. Belgium Program on Interuniversity Poles of Attraction [IUAP P5/17, P6/40]
  4. European Foundation for the Study of Diabetes EFSD
  5. Centre of Excellence SymBioSys (Research Council K.U.Leuven) [EF/05/007]
  6. Merck Sharp Dohme
  7. Fonds National de la Recherche Scientifique (FNRS)
  8. Fonds de la Recherche Scientifique Medicale (FRSM)

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High levels of fatty acids contribute to loss of functional beta cell mass in type 2 diabetes, in particular in combination with high glucose levels. The aim of this study was to elucidate the role of the unsaturated free fatty acid oleate in glucolipotoxicity and to unravel the molecular pathways involved. INS-1E cells were exposed to 0.5 mM oleate, combined or not with 25 mM glucose, for 24 h. Protein profiling of INS-1E cells was done by 2D-DIGE, covering pH ranges 4-7 and 6-9 (n = 4). Identification of differentially expressed proteins (P < 0.05) was based on MALDI-TOF analysis using Peptide Mass Fingerprint (PMF) and fragmentation (MS/MS) of the most intense peaks of PMF and proteomic results were confirmed by functional assays. Oleate impaired glucose-stimulated insulin secretion and decreased insulin content. 2D-DIGE analysis revealed 53 and 54 differentially expressed proteins for oleate and the combination of oleate and high glucose, respectively. Exposure to oleate down-regulated chaperones, hampered insulin processing and ubiquitin-related proteasomal degradation, and induced perturbations in vesicle transport and budding. In combination with high glucose, shunting of excess amounts of glucose toward reactive oxygen species production worsened beta cell death. The present findings provide new insights in oleate-induced beta cell dysfunction and identify target proteins for preservation of functional beta cell mass in type 2 diabetes.

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