The rapid increase in the worldwide prevalence of type 2 diabetes (T2D) and metabolic diseases has led to a high demand for identifying new and more effective treatments. Skeletal muscle insulin resistance, a hallmark of T2D and metabolic syndrome, has been primarily studied for the identification of novel therapeutic targets and the development of cost-effective drugs. Our previous results have established a novel link between extracellular matrix (ECM) remodeling around muscle fibers and endothelial dysfunction which culminates in muscle insulin resistance. This concept is groundbreaking as the field of insulin resistance has been traditionally focused on intracellular insulin signaling. The main goal of this project is to define the role of hyaluronan, a major ECM constitute and its interaction with CD44, main cell surface receptor for hyaluronan in the pathogenesis of muscle insulin resistance. Results from my own work have shown that an increase in muscle hyaluronan contributes to muscle insulin resistance in high fat-fed obese mice and normalization of hyaluronan by long-acting pegylated human recombinant PH-20 hyaluronidase (PEGPH20) reverses muscle insulin resistance. As the underlying mechanisms are still unknown, studies of CD44 null mice combined with high fat diet intervention and pharmacological treatment with PEGPH20 by the state-of-the-art technique “hyperinsulinemic-euglycemic clamp” coupled with isotopic tracers, the gold-standard for in vivo measurement of insulin sensitivity will methodically and quantitatively reveal the role of hyaluronan-CD44 interaction in insulin resistance. Furthermore, the coupling of vascular endothelial dysfunction in these processes will also be assessed by cutting-edge techniques including laser Doppler imaging. These studies are important in providing mechanistic insight into the role of ECM remodeling in muscle insulin resistance and will open doors for new treatments for insulin resistance.