Fang Chen1, Min Sha1, Yanyang Wang1, Tijun Wu1, Wei Shan1, Jia Liu1, Wenbo Zhou1, Yunxia Zhu1, Yujie Sun1, Yuguang Shi2, David Bleich3, Xiao Han4. 1. Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, People's Republic of China. 2. Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, TX, USA. 3. Rutgers New Jersey Medical School, Newark, NJ, USA. 4. 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.
Abstract
AIMS/HYPOTHESIS: '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/ INTERPRETATION: Our observations suggest that Ets-1 links glucotoxicity to pancreatic beta cell dysfunction through inhibiting PDX-1 expression in type 2 diabetes.
AIMS/HYPOTHESIS: '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/ INTERPRETATION: Our observations suggest that Ets-1links glucotoxicity to pancreatic beta cell dysfunction through inhibiting PDX-1 expression in type 2 diabetes.
Authors: Y Kajimoto; T Matsuoka; H Kaneto; H Watada; Y Fujitani; M Kishimoto; K Sakamoto; M Matsuhisa; R Kawamori; Y Yamasaki; M Hori Journal: Diabetologia Date: 1999-12 Impact factor: 10.122
Authors: H Watada; Y Kajimoto; Y Umayahara; T Matsuoka; H Kaneto; Y Fujitani; T Kamada; R Kawamori; Y Yamasaki Journal: Diabetes Date: 1996-11 Impact factor: 9.461
Authors: J C Jonas; A Sharma; W Hasenkamp; H Ilkova; G Patanè; R Laybutt; S Bonner-Weir; G C Weir Journal: J Biol Chem Date: 1999-05-14 Impact factor: 5.157
Authors: Z X Meng; J Nie; J J Ling; J X Sun; Y X Zhu; L Gao; J H Lv; D Y Zhu; Y J Sun; X Han Journal: Diabetologia Date: 2008-10-24 Impact factor: 10.122
Authors: Fang Fang Zhang; Yu Hong Liu; Dan Wei Wang; Ting Sheng Liu; Yue Yang; Jia Min Guo; Yi Pan; Yan Feng Zhang; Hong Du; Ling Li; Liang Jin Journal: Diabetologia Date: 2020-02-01 Impact factor: 10.122
Authors: Aurora Merovci; Devjit Tripathy; Xi Chen; Ivan Valdez; Muhammad Abdul-Ghani; Carolina Solis-Herrera; Amalia Gastaldelli; Ralph A DeFronzo Journal: Diabetes Date: 2020-10-08 Impact factor: 9.461
Authors: Sara Andrade; Tiago Morais; Ionel Sandovici; Alexandre L Seabra; Miguel Constância; Mariana P Monteiro Journal: Front Endocrinol (Lausanne) Date: 2021-06-29 Impact factor: 5.555