Exercise, GLUT4 and Skeletal Muscle Glucose Uptake: Advances and Emerging Directions

Abstract

Skeletal muscle is the principal site of postprandial glucose disposal, and its exercise-stimulated glucose uptake is a cornerstone of metabolic health. This process depends on the glucose transporter GLUT4, which is regulated by both insulin- and contraction-stimulated pathways. Understanding exercise-driven GLUT4 dynamics is crucial for combating insulin resistance and type 2 diabetes. Over the past decades, research has progressed from descriptive physiology to a mechanistic framework, identifying key insulin-independent regulators such as AMPK, Rab GTPases, SNAREs, Rac1, and redox mediators. Emerging methodologies, including high-resolution imaging, quantum dot tracking, and proteomics profiling, have provided insight into vesicle docking, fusion, and signalling convergence. Comparative exercise studies reveal modality-specific effects (e.g., HIIT) and that regulation varies by age, sex, and metabolic status, highlighting the need for population-specific approaches. Nevertheless, important questions remain: the kinetics of GLUT4 exocytosis and endocytosis in human muscle remain incompletely defined, and the integration of redox signalling with canonical kinases such as AMPK and CaMKII is poorly understood. Moreover, most mechanistic insights are derived from rodent models or young male subjects, limiting generalisability to elderly, female, or insulin-resistant populations. Addressing these gaps requires translational studies combining advanced imaging, CRISPR reporters, and molecular phenotyping with human exercise interventions. Integrating exercise with pharmacological or nutritional strategies may also unlock synergistic effects on glucose regulation. In conclusion, GLUT4 sits at the nexus of exercise biology and metabolic disease.  Elucidating its regulation across diverse populations is pivotal for advancing precision exercise medicine and developing targeted interventions for insulin resistance and type 2 diabetes.