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This Article Accepted manuscript (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 Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Qian, B. Articles by Lou, J. Search for Related Content PubMed PubMed Citation Articles by Qian, B. Articles by Lou, J.

B Qian, Graduate School of Peking Union Medical College, Beijing, China
H Wang, Department of Cell Physiology and Metabolism, University Medical Center, Geneva, Switzerland
X Men, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
W Zhang, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
H Cai, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
S Xu, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
Y Xu, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
L Ye, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
C Wollheim, Department of Cell Physiology and Metabolism, University Medical Center, Geneva, Switzerland
J Lou, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China

Correspondence: Wenjian Zhang, Email: zhang_china{at}live.cn

Abstract

We found that TRB3, an endogenous inhibitor of Akt (PKB), is expressed in pancreatic β-cells. The TRB3 expression is significantly increased in islets isolated from hyperglycemic GK rats comparing with normal-glycemic controls. In vitro high glucose treatment also resulted in increased TRB3 expression in rat INS-1 cells. To investigate the role of TRB3 in the regulation of β-cell function, we established an INS-1 stable cell line allowing inducible expression of TRB3. We demonstrated that over-expression of TRB3 mimicked the glucotoxic effects on insulin secretion and cell growth in INS-1 cells. Moreover, induction of TRB3 also synergistically enhanced high glucose elicited apoptosis in INS-1 cells, whereas siRNA knock-down of TRB3 showed the opposite effects. We also confirmed that the M of mitochondria was decreased, caspase-3 activity was up-regulated and ROS content was increased in TRB3 over-expressing beta cells in high glucose condition. Most interestingly, the ER-stress-inducer, thapsigargin, mimicked the high glucose effects on up-regulation of TRB3 and generation of apoptosis in cultured INS-1 cells. These effects were specifically prevented by siRNA knock down of TRB3. We therefore conclude that TRB3 is implicated in glucotoxicity- and ER-stress-induced β-cell failure. TRB3 could be a potential pharmacological target for prevention and treatment of type 2 diabetes.