TRIB3 [corrected] is implicated in glucotoxicity- and endoplasmic reticulum-stress-induced [corrected] beta-cell apoptosis.
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.
Qian
Bo
B
Graduate School of Peking Union Medical College, Beijing 100730, People's Republic of China.
Wang
Haiyan
H
Men
Xiuli
X
Zhang
Wenjian
W
Cai
Hanqing
H
Xu
Shiqing
S
Xu
Yaping
Y
Ye
Liya
L
Wollheim
Claes B
CB
Lou
Jinning
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D053938:DNA Fragmentation; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000633:toxicity*; D020287:In Situ Nick-End Labeling; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D034622:RNA Interference; D051381:Rats; D017382:Reactive Oxygen Species; D019284:Thapsigargin / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000378:metabolism
D007328:Insulin; D017382:Reactive Oxygen Species; C502443:Trib3 protein, rat; D019284:Thapsigargin; D014969:Xanthine Oxidase; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D053148:Caspase 3; D005947:Glucose