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Title

TRIB3 [corrected] is implicated in glucotoxicity- and endoplasmic reticulum-stress-induced [corrected] beta-cell apoptosis

Authors
Qian, Bo
Men, Xiuli
Zhang, Wenjian
Cai, Hanqing
Xu, Shiqing
Xu, Yaping
Ye, Liya
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Published in Journal of Endocrinology. 2008, vol. 199, no. 3, p. 407-416
Abstract We found that TRIB3, [corrected] an endogenous inhibitor of Akt (PKB), is expressed in pancreatic beta-cells. The TRIB3 [corrected] 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 [corrected] expression in rat INS1 cells. To investigate the role of TRIB3 [corrected] in the regulation of beta-cell function, we established an INS1 stable cell line allowing inducible expression of TRIB3. [corrected] We demonstrated that overexpression of TRIB3 [corrected] mimicked the glucotoxic effects on insulin secretion and cell growth in INS1 cells. Moreover, induction of TRIB3 [corrected] also synergistically enhanced high-glucose-elicited apoptosis in INS1 cells, whereas siRNA knock-down of TRIB3 [corrected] showed the opposite effects. We also confirmed that the DeltaPsim of mitochondria was decreased, caspase-3 activity was up-regulated and reactive oxygen species content was increased in TRIB3 [corrected] overexpressing beta cells in high glucose condition. Most interestingly, the oestrogen receptor (ER) stress inducer, thapsigargin, mimicked the high glucose effects on up-regulation of TRIB3 [corrected] and generation of apoptosis in cultured INS1 cells. These effects were specifically prevented by siRNA knock down of TRIB3. [corrected] We therefore conclude that TRIB3 [corrected] is implicated in glucotoxicity- and ER stress-induced beta-cell failure.TRIB3 [corrected] could be a potential pharmacological target for prevention and treatment of type 2 diabetes.
Keywords AnimalsApoptosis/*drug effectsBlotting, WesternCaspase 3/metabolismCell LineCell Proliferation/drug effectsDNA FragmentationFlow CytometryGene Expression/drug effects/geneticsGlucose/*toxicityIn Situ Nick-End LabelingInsulin/metabolismInsulin-Secreting Cells/*cytology/drug effects/*metabolismIslets of Langerhans/metabolismMembrane Potential, MitochondrialOxidative Stress/drug effects/geneticsProtein Kinases/genetics/metabolism/*physiologyRNA InterferenceRatsReactive Oxygen SpeciesThapsigargin/pharmacologyXanthine Oxidase/metabolism
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PMID: 18818302
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QIAN, Bo et al. TRIB3 [corrected] is implicated in glucotoxicity- and endoplasmic reticulum-stress-induced [corrected] beta-cell apoptosis. In: Journal of Endocrinology, 2008, vol. 199, n° 3, p. 407-416. https://archive-ouverte.unige.ch/unige:19135

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Deposited on : 2012-03-27

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