These results indicate that, under the pathological conditions of T2D, GSK3β-MG53-IR/IRS1 signaling axis forms a vicious cycle where insulin resistance relieves insulin induced-repression of GSK3β, resulting in enhanced phosphorylation of MG53 at S255 and subsequently promoting the degradation of both IR and IRS1, thus exacerbating insulin resistance in the heart and skeletal muscle. Here, IRS1 is linked to Insulin resistance.