Statin-induced miR-33a and miR-27b up-regulation contributes to the development of new-onset type 2 diabetes

Background and Aims: Although Statin effectiveness and safety has been widely demonstrated, increasing evidence suggest that long-term statin treatment could be responsible for an increased risk of new-onset type 2 diabetes mellitus (T2DM) by 10-12 %. Although the mechanism by which statin treatment induces T2DM remains not fully understood, some studies support the hypothesis that statins may disrupt glucose homeostasis through both mpaired insulin secretion and diminished insulin sensitivit. In this study we sought to unravel the molecular mechanism by which statin treatment induces T2DM through studying miRNAs implicated in β-cell insulin and glucose homeostasis. Methods: EndoC-βh cells were treated with statins and expression levels of miR-33a and miR-27b along with their target genes were studied. To confirm that the effects of statin treatment on insulin and glucose homeostasis were due to the overexpression of miR-27b and miR-33a, levels of the target genes were studied in mimic- and antagoMIR-transfected EndoC-βh cells. Ca2+ mobilization and insulin secretion was studied in all the conditions. Results: Statin treatment negatively affects insulin sensitivity, release of Ca2+ from the endoplasmic reticulum and, insulin secretion by causing the overexpression of miR-27b, which targets several genes involved in the aforementioned processes. This miR-27b overexpression occurs upon statin -induced miR-33a upregulation. Conclusions: The increased incidence of de novo T2DM in patients treated with statins could be due to a deregulation of the microRNAs miR-27b and miR-33a caused by the treatment, which leads to a downregulation of some key target-genes involved in insulin and glucose homeostasis.