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

Abstract

BackgroundDysregulation 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.Methodology/Principal FindingsEmploying 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.ConclusionWe 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.

MicroRNA-144 Is Regulated by Activator Protein-1 (AP-1) and Decreases Expression of Alzheimer Disease-related A Disintegrin and Metalloprotease 10 (ADAM10)

“…The impaired insulin and insulin-like growth factor signaling contributes to AD-associated neuronal loss, synaptic disconnection, hyperphosphorylation, and A␤ accumulation (55). Similarly, miR-144 is also increased and impairs insulin signaling through down-regulation of insulin receptor substrate 1 (56) in impaired fasting glucose and Type 2 diabetes mellitus patients. This suggests the importance and multiple implications of miR-144 in the pathogenesis of sporadic AD.…”

Application of microRNAs in diabetes mellitus

“…Importantly, a decrease in miR-15a, miR-29b, miR-126, and miR-223 and an increase in miR-28-3p levels in plasma indicated the manifestation of disease, indicating their value for predicting T2D. Karolina et al (2011) identified miR-144, miR-146a, miR-150, and miR-182 in the blood of T2D patients as the signature miRNAs for predicting of T2D. In addition, Pescador et al (2013) showed that three serum miRNAs (miR-138, miR-376a, and miR-15b) are potential biomarkers for distinguishing obese patients from obese-T2D and T2D patients; meanwhile, the combination of miR-503 and miR-138 can distinguish diabetic from obese-diabetic patients.…”

Hepatic miR-378 targets p110α and controls glucose and lipid homeostasis by modulating hepatic insulin signalling

“…In breast cancer, miR-378* upregulation results in an increase in cell proliferation and lactate production, and a repression of tricarboxylic acid cycle and oxygen consumption, indicating that miR-378* is able to mediate metabolic shift in cancer cells 20 . It has also been reported that hepatic miR-378/378* expression is dysregulated in a rat model of type 2 diabetes and obese mouse models, including genetic ob/ob mice and mice fed a high-fat diet 15,21,22 . However, whether and how miR-378 or miR-378* plays a regulatory role in hepatic glucose and lipid metabolism remains unclear.…”