MicroRNA miR-124a, a negative regulator of insulin secretion, is hyperexpressed in human pancreatic islets of type 2 diabetic patients

Abstract

MicroRNAs are a class of negative regulators of gene expression, which have been demonstrated to be involved in the development of endocrine pancreas and in the regulation of insulin secretion. Type 2 Diabetes (T2D) is a metabolic disease characterized by insulin-resistance in target tissues and by the functional alteration of pancreatic insulin-secreting beta-cells. Recently, we characterized the expression levels of microRNAs miR-124a and miR-375, both involved in the control of beta cell function, in human pancreatic islets obtained from T2D and from age-matched non-diabetic organ donors. We observed the hyperexpression of miR-124a in human pancreatic islets obtained from T2D patients vs non-diabetic subjects, while miR-375 did not result differentially expressed. Moreover, we demonstrated that miR-124a overexpression in MIN6-pseudoislets reduced glucose-stimulated insulin secretion. Among predicted miR-124a target genes we focused on Foxa2 and Mtpn, which are both involved in the regulation of insulin secretion and of glucose sensing. Indeed, using luciferase assay, we validated miR-124a targeting Foxa2 and Mtpn 3’UTR sequences. Accordingly, upon miR-124a inhibition in MIN6 pseudoislets, we detected the upregulation of Foxa2 and Mtpn and of other selected miR-124a predicted target genes such as Akt3, Flot2, Sirt1, and NeuroD1, indicating a possible role for such a microRNA in the control of several beta-cell functions. In conclusion, we uncovered a major hyperexpression of miR-124a in T2D islets, whose silencing resulted in increased expression of target genes of major importance for beta cell function and whose overexpression impaired glucose stimulated insulin secretion, leading to the hypothesis that an altered miR-124a expression may contribute to beta cell dysfunction in type 2 diabetes