. Type 2 diabetes currently affects >25.8 million Americans, creating an economic burden totaling over $245 billion dollars per year. It is a progressive metabolic disease characterized by hyperglycemia, hyper- insulinemia, and insulin resistance in skeletal muscle, the primary site of insulin-mediated glucose disposal. Importantly, while insulin-induced muscle glucose uptake is impaired in type 2 diabetes, the ability of insulin- independent stimuli such as exercise to increase muscle glucose uptake and lower blood glucose levels remains functional. Thus, increasing muscle glucose uptake via an exercise-dependent mechanism(s) is an effective strategy to treat hyperglycemia in type 2 diabetes. Unfortunately, those mechanisms are not well understood. Glucose transporter 4 (GLUT4) is the glucose transporter responsible for increasing skeletal muscle glucose uptake in response to both insulin and acute muscle contraction. Surprisingly, results from our lab have now found that chronic muscle loading, a model of resistance exercise training, increases muscle glucose uptake independent of both insulin and GLUT4. Thus, chronic muscle loading increases glucose uptake via a unique/alternative mechanism, and one which could represent a novel intracellular target for enhancing muscle glucose uptake in type 2 diabetes. Unfortunately, that mechanism is currently not known. Preliminary data from our lab indicate that glucose transporter 1 (GLUT1) and the Ca2+-activated, serine/threonine kinase, Ca2+/ calmodulin-dependent protein kinase kinase ? (CaMKK?) could be important proteins connecting chronic muscle loading to increased skeletal muscle glucose uptake. Thus, the specific objectives of this proposal are to determine if expression of GLUT1 in skeletal muscle is necessary for the regulation of basal or overload-induced muscle glucose uptake and/or growth (AIM 1), and to determine if CaMKK? regulates muscle glucose uptake in a GLUT4-dependent or independent manner (AIM 2). To achieve these objectives, a combination of innovative and state-of-the-art approaches and methodologies will be utilized including the newly created chemical GLUT1 inhibitor, BAY-876; generation of an inducible muscle-specific GLUT1 knockout mouse; in vivo muscle gene transfer/electroporation to allow for the rapid, transient expression of genes in mouse muscle; cultured mouse muscle cells that stably express exofacially labeled GLUT4; and a cell membrane impermeant bis-glucose photolabel, BIO-LC-ATB-BGPA, to examine cell surface GLUT4 localization in adult mouse skeletal muscle. It is anticipated that the proposed research will identify the glucose transporters responsible for chronic muscle loading/overload-induced and constitutively active CaMKK?-induced skeletal muscle glucose uptake. The significance of this research is that it represents a critical first step towards the development of new type 2 diabetes therapies designed to enhance insulin-independent skeletal muscle glucose uptake.
. The proposed research is relevant to public health as it expands our understanding of the intracellular mechanism(s) regulating resistance exercise training-induced skeletal muscle glucose uptake. This is a crucial first step towards the development of new pharmaceutical treatments for type 2 diabetes that target muscle independent of insulin. This research is relevant to the mission of NIH because we are pursuing knowledge of the mechanisms modulating skeletal muscle glucose metabolism with the purpose of improving the health of individuals with type 2 diabetes.
