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.

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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.

Cystic fibrosis-related diabetes mellitus (CFRD) is the most common non-pulmonary co-morbidity in cystic fibrosis (CF). CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene ( CFTR), which leads to aberrant luminal fluid secretions in organs such as the lungs and pancreas. How dysfunctional CFTR leads to CFRD is still under debate. Both intrinsic effects of dysfunctional CFTR in hormone secreting cells of the islets and effects of exocrine damage have been proposed. In the current review, we discuss these non-mutually exclusive hypotheses with a special focus on how dysfunctional CFTR in endocrine cells may contribute to an altered glucose homeostasis. We outline the proposed role of CFTR in the molecular pathways of β-cell insulin secretion and α-cell glucagon secretion, and touch upon the importance of the exocrine pancreas and intra-pancreatic crosstalk for proper islet function.