posted on 2021-11-15, 17:42authored byJones K. Ofori, Alexandros Karagiannopoulos, Mototsugu Nagao, Efraim Westholm, Shaima Ramadan, Anna Wendt, Jonathan LS Esguerra, Lena Eliasson
(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 is not clear.
Here we report increased expression of
miR-200c in islets from T2D as compared with non-diabetic (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 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 (LNA200c) increased glucose-stimulated insulin
secretion in islets from T2D donors ~3-fold. Our data reveal a vital role of the
miR-200c-ETV5 axis in beta cell dysfunction and pathophysiology of T2D.
This work is supported by a grant from the Swedish Foundation for Strategic Research (IRC-LUDC) and the Swedish Research Council through an SRA grant SFO-EXODIAB. L.E. has support for this project through project grants from the Swedish Research Council, Region Skåne-ALF, the Swedish Diabetes Foundation, the Diabetes Wellness Network Sweden and EFSD-MSD. J.O is supported by the Royal Physiographic Society of Lund through Birgit and Hellmuth Hertz Foundation.