• Made available online as an Accepted Preprint 25 September 2008
  • Accepted Preprint first posted online on 25 September 2008

TRIB3 is implicated in glucotoxicity- and oestrogen receptor-stress-induced β-cell apoptosis

  1. Jinning Lou2
  1. 1Graduate School of Peking Union Medical College, Beijing 100730, People's Republic of China2Institute of Clinical Medical Sciences, China–Japan Friendship Hospital, Beijing 100029, People's Republic of China3Department of Cell Physiology and Metabolism, University Medical Center, 1 rue Michel-Servet, CH-1211 Geneva 4, Switzerland
  1. (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 ΔΨm 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.

  • Received in final form 31 August 2008
  • Accepted 22 September 2008
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