MicroRNA-185 Targets SOCS3 to Inhibit Beta-Cell Dysfunction in Diabetes

Abstract

Diabetes is the most common and complex metabolic disorder, and one of the most important health threats now. MicroRNAs (miRNAs) are a group of small non-coding RNAs that have been suggested to play a vital role in a variety of physiological processes, including glucose homeostasis. In this study, we investigated the role of miR-185 in diabetes. MiR-185 was significantly downregulated in diabetic patients and mice, and the low level was correlated to blood glucose concentration. Overexpression of miR-185 enhanced insulin secretion of pancreatic β-cells, promoted cell proliferation and protected cells from apoptosis. Further experiments using in silico prediction, luciferase reporter assay and western blot assay demonstrated that miR-185 directly targeted SOCS3 by binding to its 3’-UTR. On the contrary to miR-185’s protective effects, SOCS3 significantly suppressed functions of β-cell and inactivated Stat3 pathway. When treating cells with miR-185 mimics in combination with SOCS3 overexpression plasmid, the inhibitory effects of SOCS3 were reversed. While combined treatment of miR-185 mimics and SOCS3 siRNA induced synergistically promotive effects compared to either miR-185 mimics or SOCS3 siRNA treatment alone. Moreover, we observed that miR-185 level was inversely correlated with SOCS3 expression in diabetes patients. In conclusion, this study revealed a functional and mechanistic link between miR-185 and SOCS3 in the pathogenesis of diabetes. MiR-185 plays an important role in the regulation of insulin secretion and β-cell growth in diabetes. Restoration of miR-185 expression may serve a potentially promising and efficient therapeutic approach for diabetes.

A Systematic Study of Dysregulated MicroRNA in Type 2 Diabetes Mellitus

“…The main characteristics extracted from various datasets are summarized in Table 1, which includes the number of patients investigated, the measurement platform, type of sample used and the identity of miRNAs in the study [23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81]. Comparing results from multiple tissues provides an overall view of the impact of miRNAs in T2DM pathology.…”

Retracted: MicroRNA‐30d preserves pancreatic islet β‐cell function through negative regulation of the JNK signaling pathway via SOCS3 in mice with streptozotocin‐induced diabetes mellitus

“…Additionaly, SOCS3 restoration by means of a demethylating agent in methylated pancreatic cells was found to markedly suppress cell proliferation and induce apoptosis of cells such as pancreatic cancer (PaC) (Wang et al, ). Interestingly, a previous study suggested that miR‐185 significantly induced pancreatic cell growth and insulin secretion, by regulating the activators of the transcription 3 (Stat3) pathway and signal transducers as well as by targeting SOCS3 (Bao et al, ).…”

MicroRNAs as regulators of beta‐cell function and dysfunction

“…By transfecting MIN6 cells with miR‐185 mimics or antagomirs, it was recently demonstrated that miR‐185 promotes proliferation and protects against spontaneous apoptosis by directly downregulating SOCS3, in turn reducing Stat3 proapoptotic signalling . Furthermore, plasma from diabetic patients contained reduced levels of miR‐185 and increased levels of SOCS3 compared with that from normal subjects, rendering this miR a potentially interesting therapeutic candidate .…”

“…Furthermore, glucose‐stimulated insulin release is improved by overexpression of miR‐132, which is predicted to target granuphilin . Other miRNAs (miR‐130a, miR‐185, miR‐200a and miR‐410) positively regulate insulin secretion, as knockdown of these miRNAs in MIN6‐cells reduces release of insulin . A predicted target of both miR‐130a and miR‐200a is thioredoxin‐interacting protein that inhibits thioredoxin, which protects against oxidative stress.…”