Distributed Control of Muscle Glucose Uptake: A Tribute to the Late Dr. David H. Wasserman by Revisiting a 2004...

The control of muscle glucose uptake (MGU) is distributed across delivery, transport, and phosphorylation of glucose. These steps have been defined as control points of MGU in vivo due to the application of isotopic tracer techniques to transgenic mouse models. Using these techniques in a classic study published in Diabetes, Fueger et al. demonstrated that overexpression in skeletal muscle of hexokinase II (HKII), the enzyme responsible for intracellular glucose phosphorylation, enhanced MGU in insulin-sensitive but not in insulin-resistant mice. Conversely, HKII overexpression enhanced MGU in insulin-resistant mice in response to exercise. Since exercise reduces barriers of glucose delivery and transport, this suggested that these two processes contribute to the dysregulation of MGU in insulin-resistant states. These fundamental findings have spurred subsequent studies highlighting the contribution of glucose delivery and transport to the regulation of MGU in health and disease.