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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 297/3/E812    most recent 00053.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Alberti, A. Articles by Charonis, A. PubMed PubMed Citation Articles by Alberti, A. Articles by Charonis, A.

ERp46 is reduced by high glucose and regulates insulin content in pancreatic β-cells

Division of Histology, Center for Basic Research I, and Center for Experimental Surgery, Biomedical Research Foundation of the Academy of Athens, Athens, Greece

Submitted 27 January 2009 ; accepted in final form 20 July 2009

Our studies focus on ERp46, an endoplasmic reticulum (ER) component, and analyze its involvement in glucose toxicity and in insulin production. Differences in pancreatic β-TC-6 cell proteome under conditions of low vs. high glucose were examined by proteomic approaches, including two-dimensional gel electrophoresis, image analysis, and mass spectrometry. Among differentially expressed proteins, ERp46, a novel endoplasmic reticulum component, was examined further. The expression of ERp46 in pancreatic sections was analyzed by immunocytochemistry, and high glucose-induced alterations of expression were evaluated in cultured β-cells, in isolated pancreatic islets, and in the pancreas of db/db diabetic animals. Inhibition of ERp46 expression by siRNA was performed to study its role in insulin production, in secretion, and in ER stress. Proteomic analysis led to identification of 46 differentially expressed spots corresponding to 23 proteins. Since ERp46 is a novel protein with a possible crucial role in secretory cells, we further analyzed its role in β-cell function. ERp46 expression is reduced in high glucose concentration in β-TC-6 cells and in isolated murine islets. Further analysis revealed high expression of ERp46 in pancreatic islets compared with exocrine tissue. Interestingly, a marked decrease in ERp46 expression was found in the pancreatic islets of db/db mice. Most importantly, siRNA-mediated knockdown of ERp46 in cultured β-cells led to a significant decrease in the insulin content; however, no alterations in insulin mRNA levels were observed under these conditions. In addition, reduced expression of ERp46 by siRNA increased the expression of CHOP and peIF2a, indicating development of ER stress. We conclude that ERp46 may be an important component in the phenomenon of "glucose toxicity" involved in insulin production at the posttranslational level.

diabetes; glucose toxicity; proteomics; endoplasmic reticulum