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.
Highlights
Insulin resistance is a crucial feature and risk factor for Type 2 diabetes (T2D)
The defects of insulin signaling in classical peripheral target organs are associated with impaired insulin signaling in non-classical target organs, which contribute to molecular and biochemical consequences of insulin resistance [5]
The first report describing a role for miRNAs in the regulation of glucose homeostasis through the modulation of insulin signaling in peripheral target tissues, was published in 2006 and was referred to the function of a specific miRNA in Drosophila Melanogaster adipocytes [77]
Summary
Insulin resistance is a crucial feature and risk factor for Type 2 diabetes (T2D). Namely, it is defined as the failure of a given quantity of insulin to increase glucose uptake and utilization, and to facilitate survival and proliferation. Activated Akt is able to phosphorylate several specific substrates such as AS160, which promotes Glucose Transporter Type-4 (GLUT4) translocation and glucose uptake [13,14], Glycogen Synthase Kinase-3 (GSK-3), a serine/threonine kinase that inhibits glycogen synthase (GS) [15], and FOXOs, which modulate gluconeogenesis These components of insulin signaling pathway play pivotal roles through signaling machinery fine-tuning. Initially lower in subjects who will subsequently develop T2D, representing a potential key molecule in metabolic control of glucose homeostasis These data provide evidences that insulin signaling and/or IGF-1 signaling disruption at multiple levels may result into the alteration of insulin metabolic effects, contributing to insulin resistance and T2D. Among several molecules and factors controlling the expression and/or activity of insulin or IGF-1 signaling components, miRNAs have been identified as potent modulators of multiple genes composing such complex molecular signaling machinery
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