IRS1 and metabolic disease: Over the past decade, a large body of evidence has shown that MG53 is a double-edged sword, involved in regulating both cell protection and energy metabolism.33 For cell protection, MG53 is an integral component of membrane repair machinery17 and involved in the activation of reperfusion injury salvage kinase signaling pathway in the heart in response to various insulting stimuli.18,19 However, MG53 also functions as an E3 ligase that catalyzes the ubiquitination of its substrates, such as IR, IRS1, and AMPKα,20,21,34,35 thereby leading to metabolic disorders when upregulated.