The skeletal muscle is the largest organ in the body, by mass. It is also the regulator of glucose homeostasis, responsible for 80% of postprandial glucose uptake from the circulation. Skeletal muscle is essential for metabolism, both for its role in glucose uptake and its importance in exercise and metabolic disease. In this article, we give an overview of the importance of skeletal muscle in metabolism, describing its role in glucose uptake and the diseases that are associated with skeletal muscle metabolic dysregulation. We focus on the role of skeletal muscle in peripheral insulin resistance and the potential for skeletal muscle-targeted therapeutics to combat insulin resistance and diabetes, as well as other metabolic diseases like aging and obesity. In particular, we outline the possibilities and pitfalls of the quest for exercise mimetics, which are intended to target the molecular mechanisms underlying the beneficial effects of exercise on metabolic disease. We also provide a description of the molecular mechanisms that regulate skeletal muscle glucose uptake, including a focus on the SNARE proteins, which are essential regulators of glucose transport into the skeletal muscle. © 2020 American Physiological Society. Compr Physiol 10:785-809, 2020.
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