Human Islet MicroRNA-200c Is Elevated in Type 2 Diabetes and Targets the Transcription Factor ETV5 to Reduce Insulin Secretion.
Animals
Cells, Cultured
DNA-Binding Proteins
/ genetics
Diabetes Mellitus, Type 2
/ genetics
Down-Regulation
/ genetics
Gene Expression Regulation
Glucose
/ pharmacology
Humans
Insulin
/ metabolism
Insulin Secretion
/ genetics
Insulin-Secreting Cells
/ drug effects
Islets of Langerhans
/ metabolism
Mice
MicroRNAs
/ genetics
Transcription Factors
/ genetics
Journal
Diabetes
ISSN: 1939-327X
Titre abrégé: Diabetes
Pays: United States
ID NLM: 0372763
Informations de publication
Date de publication:
01 02 2022
01 02 2022
Historique:
received:
01
02
2021
accepted:
29
10
2021
pubmed:
11
11
2021
medline:
24
2
2022
entrez:
10
11
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34753799
pii: db21-0077
doi: 10.2337/db21-0077
pmc: PMC8914283
doi:
Substances chimiques
DNA-Binding Proteins
0
ETV5 protein, human
0
Insulin
0
MIRN200 microRNA, human
0
MicroRNAs
0
Transcription Factors
0
Glucose
IY9XDZ35W2
Banques de données
figshare
['10.2337/figshare.16903927']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
275-284Informations de copyright
© 2022 by the American Diabetes Association.
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