Increased expression of miR-187 in human islets from individuals with type 2 diabetes is associated with reduced glucose-stimulated insulin secretion

Abstract

Journal ArticleThis article is published with open access at Springerlink.com Electronic supplementary material. The online version of this article (doi:10.1007/s00125-013-3089-4) contains peer-reviewed but unedited supplementary material, which is available to authorised usersAims/hypothesis: Type 2 diabetes is characterised by progressive beta cell dysfunction, with changes in gene expression playing a crucial role in its development. MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression and therefore alterations in miRNA levels may be involved in the deterioration of beta cell function. Methods: Global TaqMan arrays and individual TaqMan assays were used to measure islet miRNA expression in discovery (n = 20) and replication (n = 20) cohorts from individuals with and without type 2 diabetes. The role of specific dysregulated miRNAs in regulating insulin secretion, content and apoptosis was subsequently investigated in primary rat islets and INS-1 cells. Identification of miRNA targets was assessed using luciferase assays and by measuring mRNA levels. Results: In the discovery and replication cohorts miR-187 expression was found to be significantly increased in islets from individuals with type 2 diabetes compared with matched controls. An inverse correlation between miR-187 levels and glucose-stimulated insulin secretion (GSIS) was observed in islets from normoglycaemic donors. This correlation paralleled findings in primary rat islets and INS-1 cells where overexpression of miR-187 markedly decreased GSIS without affecting insulin content or apoptotic index. Finally, the gene encoding homeodomain-interacting protein kinase-3 (HIPK3), a known regulator of insulin secretion, was identified as a direct target of miR-187 and displayed reduced expression in islets from individuals with type 2 diabetes. Conclusions/interpretation: Our findings suggest a role for miR-187 in the blunting of insulin secretion, potentially involving regulation of HIPK3, which occurs during the pathogenesis of type 2 diabetes. © 2013 The Author(s).This work was supported by the Wellcome Trust (project grant number 089845/Z/09/Z). GAR is the recipient of Royal Society Wolfson Research and Wellcome Trust Senior Investigator (WT098424AIA) Awards, and thanks the Medical Research Council (MRC) for Programme Grant MR/J0003042/1. GdSX and GAR were supported by a project grant from Diabetes UK (BDA 13/0004672) and HDR by MRC grant G1001644