MicroRNAs as Regulators of Insulin Signaling: Research Updates and Potential Therapeutic Perspectives in Type 2 Diabetes

Abstract

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.

Non-Coding RNAs in IGF-1R Signaling Regulation: The Underlying Pathophysiological Link between Diabetes and Cancer

“…The roles of the IR and IR/IGF-IR were reviewed, along with their association with ncRNAs in regulating DM and cancer [25,116]. We discussed a number of well-known miRNAs and lncRNAs that regulate IGF-1R signaling in DM and cancer, and further highlight the potential underlying molecular pathogenesis of their comorbidity.…”

“…The principal therapeutic approach is to restore miRNAs that target and downregulate the IGF-1R expression and/or signaling during the development of DM, which is extensively discussed in previous reviews [116,117]. Delivering miRNA directly or using exogenous recombinant viral vectors are two common therapeutic approaches under development.…”

Statin Treatment-Induced Development of Type 2 Diabetes: From Clinical Evidence to Mechanistic Insights

“…Direct inactivation of AKT is mediated by protein phosphatase 2a (PP2A) [162]. PP2A activity has been shown to be increased in primary rat hepatocytes in insulin resistance condition [163]. Interestingly, insulin resistant Zucker Diabetic Fatty rats, PP2A mRNA is increased in liver, muscle and adipose tissue, thus suggesting a role for the phosphatase in deregulating insulin signaling in T2DM [163].…”

Targeting microRNAs as a Therapeutic Strategy to Reduce Oxidative Stress in Diabetes

“…Multiple studies have shown that miRNAs are pivotal regulators of different aspects of glucose homeostasis, such as peripheral insulin signaling [4], β cells function [5], and phenotype maintenance [6,7].…”