title: Involvement of the Ca2+-responsive transactivator in high glucose-induced β-cell apoptosis.
abstract: The calcium-regulated transcription coactivator, Ca(2)(+)-responsive transactivator (CREST) was expressed in pancreatic β-cells. Moreover, CREST expression became significantly increased in pancreatic islets isolated from hyperglycemic Goto-Kakizaki rats compared with normoglycemic Wistar controls. In addition, culture of β-cells in the presence of high glucose concentrations also increased CREST expression in vitro. To further investigate the role of this transactivator in the regulation of β-cell function, we established a stable β-cell line with inducible CREST expression. Hence, CREST overexpression mimicked the glucotoxic effects on insulin secretion and cell growth in β-cells. Moreover, high glucose-induced apoptosis was aggravated by upregulation of the transactivator but inhibited when CREST expression was partially silenced by siRNA technology. Further investigation found that upregulation of Bax and downregulation of Bcl2 was indeed induced by its expression, especially under high glucose conditions. In addition, as two causing factors leading to β-cell apoptosis under diabetic conditions, endoplasmic reticulum stress and high free fatty acid, mimicked the high glucose effects on CREST upregulation and generation of apoptosis in β-cells, and these effects were specifically offset by the siRNA knockdown of CREST. These results indicated that CREST is implicated in β-cell apoptosis induced by culture in high glucose and hence that CREST may become a potential pharmacological target for the prevention and treatment of type 2 diabetes mellitus.
authors.affiliation: Department of Pathophysiology, Hebei United University, Tangshan 063000, People's Republic of China.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Men
authors.forename: Liang
authors.initials: L
authors.lastname: Peng
authors.forename: Haiyan
authors.initials: H
authors.lastname: Wang
authors.forename: Wenjian
authors.initials: W
authors.lastname: Zhang
authors.forename: Shiqing
authors.initials: S
authors.lastname: Xu
authors.forename: Qing
authors.initials: Q
authors.lastname: Fang
authors.forename: Honglin
authors.initials: H
authors.lastname: Liu
authors.forename: Wenying
authors.initials: W
authors.lastname: Yang
authors.forename: Jinning
authors.initials: J
authors.lastname: Lou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D007328:Insulin; C481041:Ss18l1 protein, rat; D015534:Trans-Activators; D051028:bcl-2-Associated X Protein; D005947:Glucose