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

Ofori, Jones LU ; Karagiannopoulos, Alexandros LU orcid ; Nagao, Mototsugu LU ; Westholm, Efraim LU ; Ramadan, Shaima LU orcid ; Wendt, Anna LU ; Esguerra, Jonathan LS LU orcid and Eliasson, Lena LU orcid (2022) In Diabetes 71(2). p.275-284
Abstract
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... (More)
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. (Less)
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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetes
volume
71
issue
2
pages
275 - 284
publisher
American Diabetes Association Inc.
external identifiers
  • pmid:34753799
  • scopus:85123508755
ISSN
1939-327X
DOI
10.2337/db21-0077
language
English
LU publication?
yes
id
96d0480a-bb35-4e63-9227-f825b86a4c2a
date added to LUP
2022-01-24 13:45:43
date last changed
2022-10-17 20:22:17
@article{96d0480a-bb35-4e63-9227-f825b86a4c2a,
  abstract     = {{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.}},
  author       = {{Ofori, Jones and Karagiannopoulos, Alexandros and Nagao, Mototsugu and Westholm, Efraim and Ramadan, Shaima and Wendt, Anna and Esguerra, Jonathan LS and Eliasson, Lena}},
  issn         = {{1939-327X}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{275--284}},
  publisher    = {{American Diabetes Association Inc.}},
  series       = {{Diabetes}},
  title        = {{Human Islet MicroRNA-200c Is Elevated in Type 2 Diabetes and Targets the Transcription Factor ETV5 to Reduce Insulin Secretion}},
  url          = {{http://dx.doi.org/10.2337/db21-0077}},
  doi          = {{10.2337/db21-0077}},
  volume       = {{71}},
  year         = {{2022}},
}