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Type 2 diabetes (T2D), a chronic metabolic disease, has attained the status of a global epidemic with steadily increasing incidence worldwide. Improved diagnosis, stratification and prognosis of T2D patients and the development of more effective treatments are needed. In this era of personalized medicine, the discovery and evaluation of innovative circulating biomarkers can be an effective tool for better stratification, prognosis and therapeutic selection/management of T2D patients. MicroRNAs (miRNAs), a class of small non-coding RNAs that modulate gene expression, have been investigated as potential circulating biomarkers in T2D. Several studies have investigated the expression of circulating miRNAs in T2D patients from various biological fluids, including plasma and serum, and have demonstrated their potential as diagnostic and prognostic biomarkers, as well as biomarkers of response to therapy. In this review, we provide an overview of the current state of knowledge, focusing on circulating miRNAs that have been consistently expressed in at least two independent studies, in order to identify a set of consistent biomarker candidates in T2D. The expression levels of miRNAs, correlation with clinical parameters, functional roles of miRNAs and their potential as biomarkers are reported. A systematic literature search and assessment of studies led to the selection and review of 10 miRNAs (miR-126-3p, miR-223-3p, miR-21-5p, miR-15a-5p, miR-24-3p, miR-34a-5p, miR-146a-5p, miR-148a-3p, miR-30d-5p and miR-30c-5p). We also present technical challenges and our thoughts on the potential validation of circulating miRNAs and their application as biomarkers in the context of T2D., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Diabetes mellitus is a group of heterogeneous metabolic disorders characterized by chronic hyperglycaemia mainly due to pancreatic β cell death and/or dysfunction, caused by several types of stress such as glucotoxicity, lipotoxicity and inflammation. Different patho-physiological mechanisms driving β cell response to these stresses are tightly regulated by microRNAs (miRNAs), a class of negative regulators of gene expression, involved in pathogenic mechanisms occurring in diabetes and in its complications. In this review, we aim to shed light on the most important miRNAs regulating the maintenance and the robustness of β cell identity, as well as on those miRNAs involved in the pathogenesis of the two main forms of diabetes mellitus, i.e., type 1 and type 2 diabetes. Additionally, we acknowledge that the understanding of miRNAs-regulated molecular mechanisms is fundamental in order to develop specific and effective strategies based on miRNAs as therapeutic targets, employing innovative molecules.

We identified and compared secreted microRNA (miRNA) expression in aqueous humor (AH) and plasma samples among patients with: type 2 diabetes mellitus (T2D) complicated by non-proliferative diabetic retinopathy (DR) associated with diabetic macular edema (DME) (DME group: 12 patients); T2D patients without DR (D group: 8 patients); and non-diabetic patients (CTR group: 10 patients). Individual patient AH samples from five subjects in each group were profiled on TaqMan Low Density MicroRNA Array Cards. Differentially expressed miRNAs identified from profiling were then validated in single assay for all subjects. The miRNAs validated in AH were then evaluated in single assay in plasma. Gene Ontology (GO) analysis was conducted. From AH profiling, 119 mature miRNAs were detected: 86 in the DME group, 113 in the D group and 107 in the CTR group. miRNA underexpression in the DME group was confirmed in single assay for let-7c-5p, miR-200b-3p, miR-199a-3p and miR-365-3p. Of these four, miR-199a-3p and miR-365-3p were downregulated also in the plasma of the DME group. GO highlighted 54 validated target genes of miR-199a-3p, miR-200b-3p and miR-365-3p potentially implied in DME pathogenesis. Although more studies are needed, miR-200b-3p, let-7c-5p, miR-365-3p and miR-199a-3p represent interesting molecules in the study of DME pathogenesis., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Diabetes mellitus is a group of heterogeneous metabolic disorders characterized by chronic hyperglycaemia as a consequence of pancreatic β cell loss and/or dysfunction, also caused by oxidative stress. The molecular mechanisms involved inβ cell dysfunction and in response to oxidative stress are also regulated by microRNAs (miRNAs). miRNAs are a class of negative gene regulators, which modulate pathologic mechanisms occurring in diabetes and its complications. Although several pharmacological therapies specifically targeting miRNAs have already been developed and brought to the clinic, most previous miRNA-based drug delivery methods were unable to target a specific miRNA in a single cell type or tissue, leading to important off-target effects. In order to overcome these issues, aptamers and nanoparticles have been described as non-cytotoxic vehicles for miRNA-based drug delivery. These approaches could represent an innovative way to specifically target and modulate miRNAs involved in oxidative stress in diabetes and its complications. Therefore, the aims of this review are: (i) to report the role of miRNAs involved in oxidative stress in diabetes as promising therapeutic targets; (ii) to shed light onto the new delivery strategies developed to modulate the expression of miRNAs in diseases.

The insulin signaling pathway is composed of a large number of molecules that positively or negatively modulate insulin specific signal transduction following its binding to the cognate receptor. Given the importance of the final effects of insulin signal transduction, it is conceivable that many regulators are needed in order to tightly control the metabolic or proliferative functional outputs. MicroRNAs (miRNAs) are small non-coding RNA molecules that negatively modulate gene expression through their specific binding within the 3'UTR sequence of messenger RNA (mRNA), thus causing mRNA decoy or translational inhibition. In the last decade, miRNAs have been addressed as pivotal cellular rheostats which control many fundamental signaling pathways, including insulin signal transduction. Several studies demonstrated that multiple alterations of miRNAs expression or function are relevant for the development of insulin resistance in type 2 diabetes (T2D); such alterations have been highlighted in multiple insulin target organs including liver, muscles, and adipose tissue. Indirectly, miRNAs have been identified as modulators of inflammation-derived insulin resistance, by controlling/tuning the activity of innate immune cells in insulin target tissues. Here, we review main findings on miRNA functions as modulators of insulin signaling in physiologic- or in T2D insulin resistance- status. Additionally, we report the latest hypotheses of prospective therapies involving miRNAs as potential targets for future drugs in T2D.

Autoimmune type 1 diabetes (T1D) is thought to be caused by a defective immune regulation with regulatory T (Treg) cells playing a fundamental role in this process. Tolerance mechanisms depend on tunable responses that are sensitive to minor perturbations in the expression of molecules that can be carried out by multiple epigenetic mechanisms, including regulation by microRNAs. In this study, microRNA expression profile was investigated in Treg cells isolated from peripheral blood (PB) and from pancreatic draining lymph nodes (PLN) of T1D patients and non-diabetic subjects. Among 72 microRNAs analyzed, miR-125a-5p resulted specifically hyper-expressed in Treg cells purified from PLN of T1D patients. TNFR2 and CCR2 were identified as miR-125a-5p target genes. Elevated miR-125a-5p was detected in Treg cells isolated from PLN but not from PB of donors with T1D and was associated with reduced CCR2 expression. A specific beta-cell expression of the CCR2-ligand (CCL2) was observed in the pancreata of cadaveric donors, suggesting that beta-cells are prone to attract CCR2 + Treg cells. These novel data propose a mechanism, occurring in PLNs of T1D patients, involving increased expression of miR-125a-5p on Treg cells which results into reduced expression of CCR2, thus limiting their migration and eventual function in the pancreas.

Aims: MicroRNAs are a class of small noncoding RNAs, which control gene expression by inhibition of mRNA translation. MicroRNAs are involved in the control of biological processes including cell differentiation. Here, we aim at characterizing microRNA expression profiles during differentiation of human induced pluripotent stem cells (hiPSCs) into insulin-producing cells., Methods: We differentiated hiPSCs toward endocrine pancreatic lineage following a 18-day protocol. We analyzed genes and microRNA expression levels using RT real-time PCR and TaqMan microRNA arrays followed by bioinformatic functional analysis., Results: MicroRNA expression profiles analysis of undifferentiated hiPSCs during pancreatic differentiation revealed that 347/768 microRNAs were expressed at least in one time point of all samples. We observed 18 microRNAs differentially expressed: 11 were upregulated (miR-9-5p, miR-9-3p, miR-10a, miR-99a-3p, miR-124a, miR-135a, miR-138, miR-149, miR-211, miR-342-3p and miR-375) and 7 downregulated (miR-31, miR-127, miR-143, miR-302c-3p, miR-373, miR-518b and miR-520c-3p) during differentiation into insulin-producing cells. Selected microRNAs were further evaluated during differentiation of Sendai-virus-reprogrammed hiPSCs using an improved endocrine pancreatic beta cell derivation protocol and, moreover, in differentiated NKX6.1 + sorted cells. Following Targetscan7.0 analysis of target genes of differentially expressed microRNAs and gene ontology classification, we found that such target genes belong to categories of major significance in pancreas organogenesis and development or exocytosis., Conclusions: We detected a specific hiPSCs microRNAs signature during differentiation into insulin-producing cells and demonstrated that differentially expressed microRNAs target several genes involved in pancreas organogenesis.

MicroRNAs are small noncoding RNA molecules that regulate gene expression in all cell types. Therefore, these tiny noncoding RNA molecules are involved in a wide range of biological processes, exerting functional effects at cellular, tissue, and organ level. In pancreatic islets of Langerhans, including beta-cells, microRNAs are involved in cell differentiation as well as in insulin secretion, while in immune cells they have been shown to play pivotal roles in development, activation, and response to antigens. Indeed, it is not surprising that microRNA alterations can lead to the development of several diseases, including type 1 diabetes (T1D). Type 1 diabetes is the result of a selective autoimmune destruction of insulin-producing beta-cells, characterized by islet inflammation (insulitis), which leads to chronic hyperglycemia. Given the growing importance of microRNA in the pathophysiology of T1D, the aim of this review is to summarize the most recent data on the potential involvement of microRNAs in autoimmune diabetes. Specifically, we will focus on three different aspects: (i) microRNAs as regulators of immune homeostasis in autoimmune diabetes; (ii) microRNA expression in pancreatic islet inflammation; (iii) microRNAs as players in the dialogue between the immune system and pancreatic endocrine cells.