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Transcription factor Ets-1 links glucotoxicity to pancreatic beta cell dysfunction through inhibiting PDX-1

Fang Chen1, Min Sha1, Yanyang Wang1

  • 1Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, People's Republic of China.

Diabetologia
|November 14, 2015
PubMed
Abstract

Insights

High glucose harms pancreatic beta cells by increasing Ets-1. This factor suppresses insulin, linking glucotoxicity to type 2 diabetes dysfunction via PDX-1 inhibition.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Diabetes Research

Background:

  • Glucotoxicity, a consequence of hyperglycemia, impairs pancreatic beta cell function.
  • The precise molecular mechanisms underlying glucotoxicity-induced defects in insulin secretion and gene expression remain unclear.

Purpose of the Study:

  • To elucidate the role of the transcription factor v-ets avian erythroblastosis virus E26 oncogene homologue 1 (Ets-1) in pancreatic beta cell glucotoxicity.

Main Methods:

  • Primary islets and Min6 cells were exposed to high glucose to assess Ets-1 expression.
  • Recombinant adenovirus and transgenic mice models were employed to manipulate Ets-1 levels in beta cells.
  • Chromatin immunoprecipitation and quantitative real-time PCR were utilized to measure promoter binding activities.

Main Results:

  • High glucose upregulated Ets-1 and histone acetylation at the Ets-1 promoter, suppressing insulin secretion and biosynthesis.
  • Ets-1 overexpression altered FOXO1 and FOXA2 binding to the PDX-1 promoter, inhibiting PDX-1 expression.
  • PDX-1 overexpression rescued Ets-1-induced defects, while Ets-1 knockdown prevented hyperglycemia-induced beta cell dysfunction.

Conclusions:

  • Ets-1 acts as a crucial link between glucotoxicity and pancreatic beta cell dysfunction in type 2 diabetes.
  • Inhibition of PDX-1 expression by Ets-1 is a key mechanism contributing to beta cell failure under hyperglycemic conditions.
Keywords:
Beta cellDysfunctionEts-1GlucotoxicityPDX-1

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