Identification of particular groups of microRNAs that positively or negatively impact on beta cell function in obese models of type 2 diabetes

Abstract

Aims/hypothesis MicroRNAs are key regulators of gene expression involved in health and disease. The goal of our study was to investigate the global changes in beta cell microRNA expression occurring in two models of obesityassociated type 2 diabetes and to assess their potential contribution to the development of the disease. Methods MicroRNA profiling of pancreatic islets isolated from prediabetic and diabetic db/db mice and from mice fed a high-fat diet was performed by microarray. The functional impact of the changes in microRNA expression was assessed by reproducing them in vitro in primary rat and human beta cells. Results MicroRNAs differentially expressed in both models of obesity-associated type 2 diabetes fall into two distinct categories. A group including miR-132, miR-184 and miR-338-3p displays expression changes occurring long before the onset of diabetes. Functional studies indicate that these expression changes have positive effects on beta cell activities and mass. In contrast, modifications in the levels of miR-34a, miR-146a, miR-199a-3p, miR-203, miR-210 and miR-383 primarily occur in diabetic mice and result in increased beta cell apoptosis. These results indicate that obesity and insulin resistance trigger adaptations in the levels of particular microRNAs to allow sustained beta cell function, and that additional microRNA deregulation negatively impacting on insulin-secreting cells may cause beta cell demise and diabetes manifestation. Conclusions/interpretation We propose that maintenance of blood glucose homeostasis or progression toward glucose intolerance and type 2 diabetes may be determined by the balance between expression changes of particular microRNAs.

The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

“…Moreover, alterations in the expression of several islet miRNAs have been reported in different models of diabetes [91,92]. As recently proposed by Nesca et al [93], obesity and insulin resistance trigger changes in the levels of miR-132, miR-184 and miR-338-3p, which promote beta cell mass compensation. However, the authors also suggest that compensation failure further modifies the expression of additional miRNAs (e.g.…”

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.…”

Role of islet microRNAs in diabetes: which model for which question?

“…The proliferative effect elicited by the downregulation of miR-184 has also been observed in dispersed islet cells in an independent in vitro study [21]. Moreover, blockade of this microRNA in rat and human islets protected the beta cells against apoptosis elicited by chronic exposure to proinflammatory cytokines or fatty acids (conditions typically associated with the diabetic state) [21]. Therefore, a reduction in miR-184 levels favours the replication and survival of insulin-secreting cells and expansion of the beta cell mass.…”

“…This is associated with improved insulin release in response to a glucose challenge [20]. The proliferative effect elicited by the downregulation of miR-184 has also been observed in dispersed islet cells in an independent in vitro study [21]. Moreover, blockade of this microRNA in rat and human islets protected the beta cells against apoptosis elicited by chronic exposure to proinflammatory cytokines or fatty acids (conditions typically associated with the diabetic state) [21].…”

“…A list of the microRNAs identified by these studies is provided in Table 2. Interestingly, a group of microRNAs including miR-34a, miR-132, miR-184, miR-199a-5p, miR-210, miR-212, miR-338-3p and miR-383 was found to be deregulated in different animal models of type 2 diabetes by independent research groups, and changes in their expression were confirmed by real-time PCR quantification [20,21,[29][30][31]. The functional role of some of these microRNAs in the regulation of beta cell function has been investigated in detail.…”