TRIB3 [corrected] is implicated in glucotoxicity- and endoplasmic reticulum-stress-induced [corrected] beta-cell apoptosis
| Autor: | Bo, Qian, Haiyan, Wang, Xiuli, Men, Wenjian, Zhang, Hanqing, Cai, Shiqing, Xu, Yaping, Xu, Liya, Ye, Claes B, Wollheim, Jinning, Lou |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Xanthine Oxidase
endocrine system Insulin/metabolism Insulin-Secreting Cells/*cytology/drug effects/*metabolism Blotting Western Gene Expression Apoptosis DNA Fragmentation Protein Serine-Threonine Kinases Protein Kinases/genetics/metabolism/*physiology Cell Line Cell Proliferation/drug effects Glucose/*toxicity Islets of Langerhans Insulin-Secreting Cells Gene Expression/drug effects/genetics In Situ Nick-End Labeling Insulin Animals Thapsigargin/pharmacology Oxidative Stress/drug effects/genetics Xanthine Oxidase/metabolism Cell Proliferation Membrane Potential Mitochondrial Caspase 3 Apoptosis/*drug effects Flow Cytometry Rats Oxidative Stress Glucose Thapsigargin RNA Interference Islets of Langerhans/metabolism Reactive Oxygen Species Protein Kinases Caspase 3/metabolism |
| Zdroj: | Journal of Endocrinology, Vol. 199, No 3 (2008) pp. 407-416 |
| ISSN: | 0022-0795 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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