MicroRNA 144 Impairs Insulin Signaling by Inhibiting the Expression of Insulin Receptor Substrate 1 in Type 2 Diabetes Mellitus

University of Barcelona, Spain
PLoS ONE (Impact Factor: 3.23). 08/2011; 6(8):e22839. DOI: 10.1371/journal.pone.0022839
Source: PubMed


Dysregulation of microRNA (miRNA) expression in various tissues and body fluids has been demonstrated to be associated with several diseases, including Type 2 Diabetes mellitus (T2D). Here, we compare miRNA expression profiles in different tissues (pancreas, liver, adipose and skeletal muscle) as well as in blood samples from T2D rat model and highlight the potential of circulating miRNAs as biomarkers of T2D. In parallel, we have examined the expression profiles of miRNAs in blood samples from Impaired Fasting Glucose (IFG) and T2D male patients.
Employing miRNA microarray and stem-loop real-time RT-PCR, we identify four novel miRNAs, miR-144, miR-146a, miR-150 and miR-182 in addition to four previously reported diabetes-related miRNAs, miR-192, miR-29a, miR-30d and miR-320a, as potential signature miRNAs that distinguished IFG and T2D. Of these microRNAs, miR-144 that promotes erythropoiesis has been found to be highly up-regulated. Increased circulating level of miR-144 has been found to correlate with down-regulation of its predicted target, insulin receptor substrate 1 (IRS1) at both mRNA and protein levels. We could also experimentally demonstrate that IRS1 is indeed the target of miR-144.
We demonstrate that peripheral blood microRNAs can be developed as unique biomarkers that are reflective and predictive of metabolic health and disorder. We have also identified signature miRNAs which could possibly explain the pathogenesis of T2D and the significance of miR-144 in insulin signaling.

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Available from: Subramaniam Tavintharan
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    • "Generally, an increased level of cellular miR-146a that exerts a negative feedback effect on NF-κB signaling is observed during multiple stresses (e.g., TNF-α, LPS, interleukin- (IL-) 1β, PMA, and ox-LDL) [6, 8–11]. However, decreased cellular miR-146a levels have been reported in multiple diabetes-related studies, including in high glucose- (HG-) stimulated endothelial cells and diabetic rats [12, 13], in diabetic mouse wounds [14], in glycated albumin-stimulated endothelial cells [15], and in type 2 diabetes patients with subclinical inflammation and insulin resistance [16]. All of the above in vitro and in vivo evidences indicate that impaired miR-146a expression contributes to the proinflammatory state in diabetes. "
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