title: 1, 25(OH)2D3 protects β cell against high glucose-induced apoptosis through mTOR suppressing.
abstract: Diabetes mellitus is a leading cause of death and disability worldwide, which presents a serious public health crisis in China nowadays. It has been well recognized that excessive β-cell apoptosis is the key pathogenesis of diabetes, of which the mammalian target of rapamycin (mTOR) serves as the critical signaling pathway. Emerging evidence indicates that vitamin D deficiency acts as a potential risk factor for diabetes. The present study aims to test the hypothesis that 1 alpha, 25-dihydroxyvitamin D(3) [1, 25(OH)2D3] can inhibit β-cell apoptosis via the suppression of mTOR signaling pathway. β-cells (INS-1) were cultured in the context of normal glucose or high glucose media with or without 1, 25(OH)2D3 treatment. β-cell apoptosis was evaluated by inverted fluorescence microscope, flow cytometry and electron microscope, respectively. Quantitative RT-PCR and Western blotting were performed to assess the possible perturbations in mTOR signaling pathway. High glucose significantly increased β-cell apoptosis. Of importance, RT-PCR and Western blotting demonstrated that high glucose inhibited DNA-damage-inducible transcript 4 (DDIT4) and TSC1/TSC2, up-regulated Rheb/mTOR/p70S6K and enhanced expression of the apoptosis regulating proteins, such as phospho-Bcl-2, cytochrome C and cleaved caspase. Interestingly, 1, 25(OH)2D3 treatment reversed high glucose induced pathological changes in mTOR signaling pathway, restored expression of DDIT4 and TSC1/TSC2, blocked aberrant up-regulation of Rheb/mTOR/p70S6K and the apoptosis regulating proteins, and effectively inhibited β-cell apoptosis. Therefore, 1, 25(OH)2D3 treatment can effectively protects β cell against high glucose-induced apoptosis mainly via the suppression of mTOR signaling pathway, which may be considered as a potential therapy for patients with diabetes.
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, PR China.
authors.forename: Zesong
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, PR China.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, PR China.
authors.forename: Hua
authors.initials: H
authors.lastname: Qu
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, PR China.
authors.forename: Hang
authors.initials: H
authors.lastname: Wang
authors.affiliation: Laboratory of Lipid and Glucose Metabolism, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, PR China.
authors.forename: Xiaoqiu
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, PR China. Electronic address: huacong_deng@163.com.
authors.forename: Huacong
authors.initials: H
authors.lastname: Deng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002117:Calcitriol / Q000494:pharmacology*; D002460:Cell Line; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000009:adverse effects*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014815:Vitamins / Q000494:pharmacology*
chemical_list: D014815:Vitamins; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D002117:Calcitriol; D005947:Glucose
keywords: 1, 25-Dihydroxyvitamin D3; Diabetes mellitus; mTOR; β-Cell apoptosis