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

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 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.

miRNAs provide mechanisms for integrated control of endocrine pancreas homeostasis and metabolic disease pathogenesis: a narrative review

“…miR-200c targets Etv5, a transcription factor that regulates the expression of insulin exocytosis genes, including Syt11, Aqp3 and Cbfb. The knockout of miR-200c in islets from T2D patients significantly improves GSIS (50). miR-7a is another miRNA highly expressed in human and mouse islet cells whose expression is initially downregulated in the islets of genetic and diet-induced obese mice at early stages, although its expression seems to increase in advanced stages (102).…”