Involvement of MicroRNAs in the Cytotoxic Effects Exerted by Proinflammatory Cytokines on Pancreatic β-Cells

Abstract

OBJECTIVEPancreatic β-cells exposed to proinflammatory cytokines display alterations in gene expression resulting in defective insulin secretion and apoptosis. MicroRNAs are small noncoding RNAs emerging as key regulators of gene expression. Here, we evaluated the contribution of microRNAs to cytokine-mediated β-cell cytotoxicity.RESEARCH DESIGN AND METHODSWe used global microarray profiling and real-time PCR analysis to detect changes in microRNA expression in β-cells exposed to cytokines and in islets of pre-diabetic NOD mice. We assessed the involvement of the microRNAs affected in cytokine-mediated β-cell failure by modifying their expression in insulin-secreting MIN6 cells.RESULTSWe found that IL-1β and TNF-α induce the expression of miR-21, miR-34a, and miR-146a both in MIN6 cells and human pancreatic islets. We further show an increase of these microRNAs in islets of NOD mice during development of pre-diabetic insulitis. Blocking miR-21, miR-34a, or miR-146a function using antisense molecules did not restore insulin-promoter activity but prevented the reduction in glucose-induced insulin secretion observed upon IL-1β exposure. Moreover, anti–miR-34a and anti–miR-146a treatment protected MIN6 cells from cytokine-triggered cell death.CONCLUSIONSOur data identify miR-21, miR-34a, and miR-146a as novel players in β-cell failure elicited in vitro and in vivo by proinflammatory cytokines, notably during the development of peri-insulitis that precedes overt diabetes in NOD mice.

Elevated circulating stearic acid leads to a major lipotoxic effect on mouse pancreatic beta cells in hyperlipidaemia via a miR-34a-5p-mediated PERK/p53-dependent pathway

“…The mechanistic pathways responsible for HSD-induced lipotoxicity in pancreatic beta cells are not fully understood. Recent evidence has provided new clues that miRNAs are involved in the regulation of beta cell failure and type 2 diabetes [32][33][34]. In our study, we selected 19 miRNAs that are differentially expressed in islets of HSD mice relative to HPD and normal mice, based on gene-chip microarray analysis.…”

“…Chronic exposure to inflammatory conditions leads to beta cell dysfunction and apoptosis [32,44,45]. A recent investigation has revealed that the level of miR-34a increased concomitantly in cytokinetreated MIN6 cells and human pancreatic islets, and contributed to beta cell dysfunction [32].…”

Clinical relevance of epigenetics in the onset and management of type 2 diabetes mellitus

“…This effect might link obesity-induced inflammation and miRNA expression in b-cells, which, in turn, can influence functionality, insulin exocytosis, and apoptosis of the same cells. [47][48][49] Since miR-21, miR-34a, and miR-146a are involved in such events, they could represent novel biomarkers for b-cell failure elicited by proinflammatory cytokines, thus providing a valuable opportunity for translational application. 50 Additional clinical relevance is attributed to miR-30d as novel potential epigenetic drug for diabetes because it preserves mouse b-cells against TNFa-induced suppression of insulin expression and signaling.…”

Impaired Biomechanical Properties of Diabetic Skin

“…36 Alternatively, studies have demonstrated that lack of microRNA production can permit uncontrolled cellular proliferation in the setting of leukemia 37 and breast cancer. 38 Recently, Roggli et al 39 demonstrated in a mouse diabetic model that inflammatory cytokines elicit production of microRNA species that may be involved in the development of pancreatic ␤-cell failure, whereas the direct connection between increased production of microRNA targeting collagen gene expression and diabetes is still unclear. This pathophysiology can certainly explain our findings, but of course, more investigation is necessary of to further evaluate the role microRNA species play in the development of diabetes.…”