Diabetes mellitus is characterized by insulin secretion from pancreatic β cells that is insufficient to maintain blood glucose homeostasis. Autoimmune destruction of β cells results in type 1 diabetes mellitus, whereas conditions that reduce insulin sensitivity and negatively affect β-cell activities result in type 2 diabetes mellitus. Without proper management, patients with diabetes mellitus develop serious complications that reduce their quality of life and life expectancy. Biomarkers for early detection of the disease and identification of individuals at risk of developing complications would greatly improve the care of these patients. Small non-coding RNAs called microRNAs (miRNAs) control gene expression and participate in many physiopathological processes. Hundreds of miRNAs are actively or passively released in the circulation and can be used to evaluate health status and disease progression. Both type 1 diabetes mellitus and type 2 diabetes mellitus are associated with distinct modifications in the profile of miRNAs in the blood, which are sometimes detectable several years before the disease manifests. Moreover, circulating levels of certain miRNAs seem to be predictive of long-term complications. Technical and scientific obstacles still exist that need to be overcome, but circulating miRNAs might soon become part of the diagnostic arsenal to identify individuals at risk of developing diabetes mellitus and its devastating complications.

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.

Diabetes mellitus is a complex disease resulting in altered glucose homeostasis. In both type 1 and type 2 diabetes mellitus, pancreatic β cells cannot secrete appropriate amounts of insulin to regulate blood glucose level. Moreover, in type 2 diabetes mellitus, altered insulin secretion is combined with a resistance of insulin-target tissues, mainly liver, adipose tissue, and skeletal muscle. Both environmental and genetic factors are known to contribute to the development of the disease. Growing evidence indicates that microRNAs (miRNAs), a class of small noncoding RNA molecules, are involved in the pathogenesis of diabetes. miRNAs function as translational repressors and are emerging as important regulators of key biological processes. Here, we review recent studies reporting changes in miRNA expression in tissues isolated from different diabetic animal models. We also describe the role of several miRNAs in pancreatic β cells and insulin-target tissues. Finally, we discuss the possible use of miRNAs as blood biomarkers to prevent diabetes development and as tools for gene-based therapy to treat both type 1 and type 2 diabetes mellitus.

ObjectiveThere is strong evidence for an involvement of different classes of non-coding RNAs, including microRNAs and long non-coding RNAs, in the regulation of β-cell activities and in diabetes development. Circular RNAs were recently discovered to constitute a substantial fraction of the mammalian transcriptome but the contribution of these non-coding RNAs in physiological and disease processes remains largely unknown. The goal of this study was to identify the circular RNAs expressed in pancreatic islets and to elucidate their possible role in the control of β-cells functions.MethodsWe used a microarray approach to identify circular RNAs expressed in human islets and searched their orthologues in RNA sequencing data from mouse islets. We then measured the level of four selected circular RNAs in the islets of different Type 1 and Type 2 diabetes models and analyzed the role of these circular transcripts in the regulation of insulin secretion, β-cell proliferation, and apoptosis.ResultsWe identified thousands of circular RNAs expressed in human pancreatic islets, 497 of which were conserved in mouse islets. The level of two of these circular transcripts, circHIPK3 and ciRS-7/CDR1as, was found to be reduced in the islets of diabetic db/db mice. Mimicking this decrease in the islets of wild type animals resulted in impaired insulin secretion, reduced β-cell proliferation, and survival. ciRS-7/CDR1as has been previously proposed to function by blocking miR-7. Transcriptomic analysis revealed that circHIPK3 acts by sequestering a group of microRNAs, including miR-124-3p and miR-338-3p, and by regulating the expression of key β-cell genes, such as Slc2a2, Akt1, and Mtpn.ConclusionsOur findings point to circular RNAs as novel regulators of β-cell activities and suggest an involvement of this novel class of non-coding RNAs in β-cell dysfunction under diabetic conditions.

Graphical Abstract Highlights d T lymphocytes release exosomes containing specific microRNAs d T lymphocyte exosomes can transfer microRNAs to rodent and human pancreatic b cells d The transferred microRNAs trigger chemokine expression and apoptosis of b cells d Blockade of microRNAs transferred in b cells decreases diabetes incidence in NOD mice In Brief Guay et al. show that T cells release exosomes containing specific microRNAs that trigger chemokine expression and apoptosis in recipient pancreatic b cells in type 1 diabetes. Inactivation of miR-142-3p/-5p and miR-155 in b cells results in higher insulin levels, lower insulitis scores, and reduced inflammation and protects NOD mice from diabetes development.

Glucose-induced insulin secretion is an essential function of pancreatic β-cells that is partially lost in individuals affected by Type 2 diabetes. This unique property of β-cells is acquired through a poorly understood postnatal maturation process involving major modifications in gene expression programs. Here we show that β-cell maturation is associated with changes in microRNA expression induced by the nutritional transition that occurs at weaning. When mimicked in newborn islet cells, modifications in the level of specific microRNAs result in a switch in the expression of metabolic enzymes and cause the acquisition of glucose-induced insulin release. Our data suggest microRNAs have a central role in postnatal β-cell maturation and in the determination of adult functional β-cell mass. A better understanding of the events governing β-cell maturation may help understand why some individuals are predisposed to developing diabetes and could lead to new strategies for the treatment of this common metabolic disease.

Blood glucose homeostasis requires a constant communication between insulin-secreting and insulin-sensitive cells. A wide variety of circulating factors, including hormones, cytokines and chemokines work together to orchestrate the systemic response of metabolic organs to changes in the nutritional state. Failure in the coordination between these organs can lead to a rise in blood glucose levels and to the appearance of metabolic disorders such as diabetes mellitus. Exosomes are small extracellular vesicles (EVs) that are produced via the endosomal pathway and are released from the cells upon fusion of multivesicular bodies with the plasma membrane. There is emerging evidence indicating that these EVs play a central role in cell-to-cell communication. The interest in exosomes exploded when they were found to transport bioactive proteins, messenger RNA (mRNAs) and microRNA (miRNAs) that can be transferred in active form to adjacent cells or to distant organs. In this review, we will first outline the mechanisms governing the biogenesis, the cargo upload and the release of exosomes by donor cells as well as the uptake by recipient cells. We will then summarize the studies that support the novel concept that miRNAs and other exosomal cargo components are new important vehicles for metabolic organ cross-talk.cell-to-cell communication, diabetes, exosomes, metabolism, miRNAs | INTRODUCTIONIn modern societies, the combination of sedentary lifestyles with excessive caloric intake has resulted in a dramatic rise in the incidence of chronic metabolic diseases and in the associated premature deaths. Thus, it is becoming urgent to find novel strategies to cure or prevent the development of these diseases and to stop their epidemic progression. To achieve this goal, we need to improve our basic knowledge of the biological mechanisms governing the maintenance of glucose homeostasis.Several organs contribute to the regulation of blood glucose levels and the communication between them is vital to achieve this and were first thought to participate in the selective removal of unwanted cell components. However, the interest in these EVs exploded in the last decade, when they were found to transport bioactive molecules, including proteins and nucleic acids, which can be transferred in active form to recipient cells. 5,6 Exosomes are now seen as vehicles of a new cell-to-cell signalling pathway whose rules and limitations remain to be completely established. Also, a consensus is still lacking about the nomenclature and the most appropriate isolation method of exosomes and other types of microvesicles released by the cells. Typically, the term "exosome" is used to designate EVs with a diameters of 50 to 150 nm that originate from the The most common strategy used to isolate exosomes remains differential centrifugation. Therefore, unless specified, in this review we will focus mainly on studies on exosomes (also called exosome-like microvesicles or small EVs) that were isolated by high speed ultra-centrifugation. | Exosome biogenesis...

Our data suggest that muscle ELVs might have an endocrine effect and could participate in adaptations in beta cell mass during insulin resistance.