Wednesday, February 5, 2025
2/5/2025
PROJECT SUMMARY Nearly 1 in 10 Americans has type 2 diabetes mellitus (T2DM), and the incidence continues to rise as the US population both grows heavier and ages. T2DM is characterized by insulin resistance, where the insulin target tissues become under-responsive to insulin stimulation, leading to unregulated blood glucose and tissue damage. Despite multiple therapeutic approaches to increase insulin production and to enhance insulin receptor sensitivity, there are no drugs that directly ameliorate insulin resistance by targeting mechanisms that drive insulin resistance, in part because these mechanisms remain poorly defined. We have identified novel machinery that regulates S-nitrosylation of the insulin receptor (INSR) and its key downstream mediator, insulin receptor substrate 1 (IRS1), including the enzymes SCAN and SCoR, which catalyze S-nitrosylation and denitrosylation of INSRβ/IRS1 respectively. Under normal conditions, insulin-stimulated S-nitrosylation of INSRβ/IRS1 by SCAN transiently inhibits signaling to prevent hypoglycemia. In obesity, sustained and excessive S-nitrosylation of INSRβ/IRS1 by SCAN in skeletal muscle chronically inhibits insulin signaling, leading to insulin resistance. Excessive SCAN activity and consequent hypernitrosylation of INSRβ/IRS1 are also induced by aging and by glucocorticoid treatment, representing a widespread cause of insulin resistance. In human skeletal muscle and adipose tissue, SCAN expression increases with Body Mass Index and correlates with INSRβ S-nitrosylation, suggesting this mechanism is relevant to human insulin resistance. Our goal is to define the role of this novel pair of enzymes (SCAN and SCoR) in insulin signaling and to elucidate their clinical significance. We will 1) characterize a newly discovered S-nitrosylation-based feedback loop in insulin signaling; 2) define the pathological role of SCAN and SCoR in insulin resistance; 3) determine the clinical significance of SCAN in insulin resistance. Successful completion of these Aims will define the functional role of S-nitrosylation of INSRβ/IRS1 by SCAN and SCoR in both health and disease. More broadly, our work promises both new understanding of obesity-, aging-, and glucocorticoid therapy -associated T2DM and new therapeutic opportunities for treating metabolic disorders and T2DM.
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