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.

The skeletal muscle is the largest organ in the body and secretes circulating factors, including myokines, which are involved in various cellular signaling processes. Skeletal muscle is vital for metabolism and physiology and plays a crucial role in insulin-mediated glucose disposal. Myokines have autocrine, paracrine, and endocrine functions, serving as critical regulators of myogenic differentiation, fiber-type switching, and maintaining muscle mass. Myokines have profound effects on energy metabolism and inflammation, contributing to the pathophysiology of type 2 diabetes (T2D) and other metabolic diseases. Myokines have been shown to increase insulin sensitivity, thereby improving glucose disposal and regulating glucose and lipid metabolism. Many myokines have now been identified, and research on myokine signaling mechanisms and functions is rapidly emerging. This review summarizes the current state of the field regarding the role of myokines in tissue cross-talk, including their molecular mechanisms, and their potential as therapeutic targets for T2D.

Type 2 diabetes (T2D) is a heterogenous disease, and conventionally, peripheral insulin resistance (IR) was thought to precede islet β-cell dysfunction, promoting progression from prediabetes to T2D. New evidence suggests that T2D-lean individuals experience early β-cell dysfunction without significant IR. Regardless of the primary event (i.e., IR vs. β-cell dysfunction) that contributes to dysglycemia, significant early-onset oxidative damage and mitochondrial dysfunction in multiple metabolic tissues may be a driver of T2D onset and progression. Oxidative stress, defined as the generation of reactive oxygen species (ROS), is mediated by hyperglycemia alone or in combination with lipids. Physiological oxidative stress promotes inter-tissue communication, while pathological oxidative stress promotes inter-tissue mis-communication, and new evidence suggests that this is mediated via extracellular vesicles (EVs), including mitochondria containing EVs. Under metabolic-related stress conditions, EV-mediated cross-talk between β-cells and skeletal muscle likely trigger mitochondrial anomalies leading to prediabetes and T2D. This article reviews the underlying molecular mechanisms in ROS-related pathogenesis of prediabetes, including mitophagy and mitochondrial dynamics due to oxidative stress. Further, this review will describe the potential of various therapeutic avenues for attenuating oxidative damage, reversing prediabetes and preventing progression to T2D.

The World Health Organization estimates that diabetes prevalence has risen from 108 million in 1980 to 422 million in 2014, with type 2 diabetes accounting for more than 90% of these cases. Furthermore, the prevalence of prediabetes (impaired fasting glucose and/or impaired glucose tolerance) is more than 40% in some countries and is associated with a global rise in obesity. Therefore it is imperative that we develop new approaches to reduce the development of prediabetes and progression to type 2 diabetes. In this review, we explore the gains made over the past decade by focused efforts to improve insulin secretion by the beta cell or insulin sensitivity of target tissues. We also describe multitasking candidates, which could improve both beta cell dysfunction and peripheral insulin sensitivity. Moreover, we highlight provocative findings indicating that additional glucose regulatory tissues, such as the brain, may be key therapeutic targets. Taken together, the promise of these new multi-faceted approaches reinforces the importance of understanding and tackling type 2 diabetes pathogenesis from a multi-tissue perspective.