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, Sep 30, 2015
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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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    ABSTRACT: Diabetes is associated with hyperglycemia and increased thrombin production. However, it is unknown whether a combination of high glucose and thrombin can modulate the expression of NAPDH oxidase (Nox) subtypes in human aortic endothelial cells (HAECs). Moreover, we investigated the role of a diabetes-associated microRNA (miR-146a) in a diabetic atherothrombosis model. We showed that high glucose (HG) exerted a synergistic effect with thrombin to induce a 10.69-fold increase in Nox4 mRNA level in HAECs. Increased Nox4 mRNA expression was associated with increased Nox4 protein expression and ROS production. Inflammatory cytokine kit identified that the treatment increased IL-8 and IL-6 levels. Moreover, HG/thrombin treatment caused an 11.43-fold increase of THP-1 adhesion to HAECs. In silico analysis identified the homology between miR-146a and the 3'-untranslated region of the Nox4 mRNA, and a luciferase reporter assay confirmed that the miR-146a mimic bound to this Nox4 regulatory region. Additionally, miR-146a expression was decreased to 58% of that in the control, indicating impaired feedback restraint of HG/thrombin-induced endothelial inflammation. In contrast, miR-146a mimic transfection attenuated HG/thrombin-induced upregulation of Nox4 expression, ROS generation, and inflammatory phenotypes. In conclusion, miR-146a is involved in the regulation of endothelial inflammation via modulation of Nox4 expression in a diabetic atherothrombosis model.
    Mediators of Inflammation 09/2014; 2014:379537. DOI:10.1155/2014/379537 · 3.24 Impact Factor
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    • "These results suggest that a change in the level of these c-miRNAs may be useful as a biomarker for the clinical diagnosis of rhabdomyosarcoma in the future, for which there is no serum biomarker currently known. Furthermore, Karolina et al. (2011) found that the level of circulating miR-144 increased in type 2 diabetic animals and humans and that this elevation is negatively correlated with insulin receptor substrate 1 in insulin-responding tissues, including skeletal muscle. Thus, the elevation of miR-144 in circulation may be associated with the development of insulin resistance in skeletal muscle. "
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    ABSTRACT: MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation. Recently, growing evidence has shown that miRNAs are taken in by intracellular exosomes, secreted into circulation, and taken up by other cells. Circulating levels of several miRNAs are changed in diseases such as cancer, diabetes, and cardiovascular diseases; therefore, they are suggested to regulate functions of the recipient cells by modulating protein expression. Circulating miRNAs (c-miRNAs) may also modulate skeletal muscle function in physiological and pathological conditions. It has been suggested that acute and chronic exercise transiently or adaptively changes the level of c-miRNAs, thus post-transcriptionally regulating proteins associated with energy metabolism, myogenesis, and angiogenesis. Circulating levels of several miRNAs that are enriched in muscle are altered in muscle disorders and may be involved in their development and progression. In addition, such c-miRNAs may be useful as biomarkers to determine various interactions between tissues and also to reflect athletic performance, physical fatigue, incidence risk, and development of diseases.
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    • "Another gene with altered expression in blood of pre-diabetes, type 2 diabetes and Parkinson's disease patients is APP. Interestingly, the expression of app mRNA in blood is significantly upregulated in pre-diabetes [25] and Parkinson's disease patients [21]. These results suggest that elevated levels of APP in blood of type 2 diabetes may be an indicator of neurodegeneration. "
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    ABSTRACT: Shared dysregulated pathways may contribute to Parkinson's disease and type 2 diabetes, chronic diseases that afflict millions of people worldwide. Despite the evidence provided by epidemiological and gene profiling studies, the molecular and functional networks implicated in both diseases, have not been fully explored. In this study, we used an integrated network approach to investigate the extent to which Parkinson's disease and type 2 diabetes are linked at the molecular level. Using a random walk algorithm within the human functional linkage network we identified a molecular cluster of 478 neighboring genes closely associated with confirmed Parkinson's disease and type 2 diabetes genes. Biological and functional analysis identified the protein serine-threonine kinase activity, MAPK cascade, activation of the immune response, and insulin receptor and lipid signaling as convergent pathways. Integration of results from microarrays studies identified a blood signature comprising seven genes whose expression is dysregulated in Parkinson's disease and type 2 diabetes. Among this group of genes, is the amyloid precursor protein (APP), previously associated with neurodegeneration and insulin regulation. Quantification of RNA from whole blood of 192 samples from two independent clinical trials, the Harvard Biomarker Study (HBS) and the Prognostic Biomarker Study (PROBE), revealed that expression of APP is significantly upregulated in Parkinson's disease patients compared to healthy controls. Assessment of biomarker performance revealed that expression of APP could distinguish Parkinson's disease from healthy individuals with a diagnostic accuracy of 80% in both cohorts of patients. These results provide the first evidence that Parkinson's disease and diabetes are strongly linked at the molecular level and that shared molecular networks provide an additional source for identifying highly sensitive biomarkers. Further, these results suggest for the first time that increased expression of APP in blood may modulate the neurodegenerative phenotype in type 2 diabetes patients.
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