Chronic hyperinsulinemia induced miR-27b is linked to adipocyte insulin resistance by targeting insulin receptor

Defect in insulin signaling leads to the development of insulin resistance followed by type 2 diabetes. exploiting our previously developed physiological chronic hyperinsulinemia (ci)-mediated insulin resistance (ir) model, we wanted to understand how mirnas contribute to the development of ir. amongst the identified and validate mirnas, the expression of mir-27b was found to be highly upregulated during ci-induced ir in 3t3-l1 adipocytes. we also validated the expression of mir-27b in ci-induced ir in human mesenchymal stem cell (hmsc)-derived adipocytes and in vivo high fat diet (hfd)-induced ir mice model. bioinformatics target prediction softwares and luciferase reporter assay identified insulin receptor (insr) as one of a prime target of mir-27b. lentiviral mediated overexpression of mir-27b impairs insulin signaling by modulating insr expression that in turn led to decreased glucose uptake in both 3t3-l1 and hmsc-derived adipocytes. conversely, inhibition of mir-27b reversed ci-mediated suppression of target protein insr and improved phosphorylation of akt, a nodal protein of insulin signaling that is impaired by ci treatment. lentiviral mediated overexpression of mir-27b in in vivo c57bl/6 mice impaired whole body glucose tolerance and adipose tissue insulin sensitivity. furthermore, inhibition of mir-27b in hfd-induced insulin resistance mice model improved glucose tolerance and adipose tissue insulin sensitivity by increasing the expression of its target gene insr in ewat. thus, our results indicate that mir-27b functions as a prime modulator of ci-induced ir via regulating the expression of insr.