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This Article Full Text Full Text (PDF) All Versions of this Article: JOE-08-0331v1 199/3/407    most recent Alert me when this article is cited Alert me if a correction is posted Services 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 Qian, B. Articles by Lou, J. PubMed PubMed Citation Articles by Qian, B. Articles by Lou, J.

¹ Graduate School of Peking Union Medical College, Beijing 100730, People's Republic of China² Institute of Clinical Medical Sciences, China–Japan Friendship Hospital, Beijing 100029, People's Republic of China³ Department of Cell Physiology and Metabolism, University Medical Center, 1 rue Michel-Servet, CH-1211 Geneva 4, Switzerland

(Correspondence should be addressed to J Lou; Email: lou.j{at}mail.com)

We found that TRIB3, an endogenous inhibitor of Akt (PKB), is expressed in pancreatic β-cells. The TRIB3 expression is significantly increased in islets isolated from hyperglycemic Goto–Kakizaki rats compared with normal glycemic controls. In vitro high glucose treatment also resulted in increased TRIB3 expression in rat INS1 cells. To investigate the role of TRIB3 in the regulation of β-cell function, we established an INS1 stable cell line allowing inducible expression of TRIB3. We demonstrated that overexpression of TRIB3 mimicked the glucotoxic effects on insulin secretion and cell growth in INS1 cells. Moreover, induction of TRIB3 also synergistically enhanced high-glucose-elicited apoptosis in INS1 cells, whereas siRNA knock-down of TRIB3 showed the opposite effects. We also confirmed that the m of mitochondria was decreased, caspase-3 activity was up-regulated and reactive oxygen species content was increased in TRIB3 overexpressing β cells in high glucose condition. Most interestingly, the oestrogen receptor (ER) stress inducer, thapsigargin, mimicked the high glucose effects on up-regulation of TRIB3 and generation of apoptosis in cultured INS1 cells. These effects were specifically prevented by siRNA knock down of TRIB3. We therefore conclude that TRIB3 is implicated in glucotoxicity- and ER stress-induced β-cell failure. TRIB3 could be a potential pharmacological target for prevention and treatment of type 2 diabetes.