title: Transcription factor Ets-1 links glucotoxicity to pancreatic beta cell dysfunction through inhibiting PDX-1 expression in rodent models.
abstract: OBJECTIVE
  'Glucotoxicity' is a term used to convey the negative effect of hyperglycaemia on beta cell function; however, the underlying molecular mechanisms that impair insulin secretion and gene expression are poorly defined. Our objective was to define the role of transcription factor v-ets avian erythroblastosis virus E26 oncogene homologue 1 (Ets-1) in beta cell glucotoxicity.
  
  
  METHODS
  Primary islets and Min6 cells were exposed to high glucose and Ets-1 expression was measured. Recombinant adenovirus and transgenic mice were used to upregulate Ets-1 expression in beta cells in vitro and in vivo, and insulin secretion was assessed. The binding activity of H3/H4 histone on the Ets-1 promoter, and that of forkhead box (FOX)A2, FOXO1 and Ets-1 on the Pdx-1 promoter was measured by chromatin immunoprecipitation and quantitative real-time PCR assay.
  
  
  RESULTS
  High glucose induced upregulation of Ets-1 expression and hyperacetylation of histone H3 and H4 at the Ets-1 gene promoter in beta cells. Ets-1 overexpression dramatically suppressed insulin secretion and biosynthesis both in vivo and in vitro. Besides, Ets-1 overexpression increased the activity of FOXO1 but decreased that of FOXA2 binding to the pancreatic and duodenal homeobox 1 (PDX-1) homology region 2 (PH2), resulting in inhibition of Pdx-1 promoter activity and downregulation of PDX-1 expression and activity. In addition, high glucose promoted the interaction of Ets-1 and FOXO1, and the activity of Ets-1 binding to the Pdx-1 promoter. Importantly, PDX-1 overexpression reversed the defect in pancreatic beta cells induced by Ets-1 excess, while knockdown of Ets-1 prevented hyperglycaemia-induced dysfunction of pancreatic beta cells.
  
  
  CONCLUSIONS
  Our observations suggest that Ets-1 links glucotoxicity to pancreatic beta cell dysfunction through inhibiting PDX-1 expression in type 2 diabetes.
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, People's Republic of China.
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Sha
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, People's Republic of China.
authors.forename: Yanyang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, People's Republic of China.
authors.forename: Tijun
authors.initials: T
authors.lastname: Wu
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Shan
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, People's Republic of China.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, People's Republic of China.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, People's Republic of China.
authors.forename: Yunxia
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, People's Republic of China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Yuguang
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Rutgers New Jersey Medical School, Newark, NJ, USA.
authors.forename: David
authors.initials: D
authors.lastname: Bleich
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, People's Republic of China. hanxiao@njmu.edu.cn.
authors.forename: Xiao
authors.initials: X
authors.lastname: Han
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000502:physiology; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006943:Hyperglycemia / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050784:Proto-Oncogene Protein c-ets-1 / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D018398:Homeodomain Proteins; D050784:Proto-Oncogene Protein c-ets-1; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein
keywords: Beta cell; Dysfunction; Ets-1; Glucotoxicity; PDX-1