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Efraim Westholm

Research student

ludc web

Human Islet MicroRNA-200c Is Elevated in Type 2 Diabetes and Targets the Transcription Factor ETV5 to Reduce Insulin Secretion

Author

  • Jones Ofori
  • Alexandros Karagiannopoulos
  • Mototsugu Nagao
  • Efraim Westholm
  • Shaima Ramadan
  • Anna Wendt
  • Jonathan LS Esguerra
  • Lena Eliasson

Summary, in English

MicroRNAs (miRNAs) are part of deregulated insulin secretion in type 2 diabetes (T2D) development. Rodent models have suggested miR-200c to be involved, but the role and potential as therapeutic target of this miRNA in human islets are not clear. Here we report increased expression of miR-200c in islets from T2D as compared with nondiabetic (ND) donors and display results showing reduced glucose-stimulated insulin secretion in EndoC-βH1 cells overexpressing miR-200c. We identify transcription factor ETV5 as the top rank target of miR-200c in human islets using TargetScan in combination with Pearson correlation analysis of miR-200c and mRNA expression data from the same human donors. Among other targets were JAZF1, as earlier shown in miR-200 knockout mice. Accordingly, linear model analysis of ETV5 and JAZF1 gene expression showed reduced expression of both genes in islets from human T2D donors. Western blot analysis confirmed the reduced expression of ETV5 on the protein level in EndoC-βH1 cells overexpressing miR-200c, and luciferase assay validated ETV5 as a direct target of miR-200c. Finally, LNA knockdown of miR-200c increased glucose-stimulated insulin secretion in islets from T2D donors approximately threefold. Our data reveal a vital role of the miR-200c–ETV5 axis in β-cell dysfunction and pathophysiology of T2D.

Department/s

  • Diabetes - Epigenetics
  • EXODIAB: Excellence of Diabetes Research in Sweden
  • Diabetes - Islet Cell Exocytosis

Publishing year

2022

Language

English

Pages

275-284

Publication/Series

Diabetes

Volume

71

Issue

2

Document type

Journal article

Publisher

American Diabetes Association Inc.

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • Diabetes - Epigenetics
  • Diabetes - Islet Cell Exocytosis

ISBN/ISSN/Other

  • ISSN: 1939-327X