Secreted MG53 From Striated Muscle Impairs Systemic Insulin Sensitivity

Abstract

Diabetes mellitus is 1 of the most prevalent health challenges worldwide, affecting >422 million people. In the United States alone, >30 million people were diagnosed with diabetes mellitus in 2015, and this number is predicted to double by 2030.1 More than 1 of every 3 adults in the United States has prediabetes, indicated by elevated blood glucose levels but below those of full-blown diabetes mellitus. Prediabetic patients are generally insulin-resistant, meaning that their muscle, fat, and liver cells are resistant to glucose uptake from the blood. Despite decades of research, we still do not fully understand the underlying causes of insulin resistance and prediabetes. Skeletal muscle is the major site of glucose uptake in humans.2 Maintaining the integrity of the insulin signaling pathway is essential for normal insulin-mediated glucose uptake in muscle. Skeletal muscle participates in systemic metabolism not only by taking up glucose, but also by sending messengers, such as secreted myokines, to communicate with other tissues. Like skeletal muscle, the heart also secretes myokines, called cardiokines.3 Secretome analysis of exercised muscle in humans and rodents previously led to the discovery of a number of myokines that were shown to have beneficial effects on body metabolism.4 Indeed, many of the identified myokines have been shown to be involved in various processes of exercise adaptation, muscle growth, and regulation of wholebody glucose/lipid metabolism. The existence of myokines and cardiokines has enhanced our understanding of how muscles communicate with other tissues such as adipose tissue, liver, bone, and brain to regulate whole-body metabolism. The list of new myokines is continuously increasing, and some are promising targets for the treatment of metabolic disorders, although their physiological actions remain largely unexplored. Skeletal muscle insulin resistance is recognized as the primary defect in patients with type 2 diabetes mellitus (T2D).5 However, the etiologic factors causing muscle insulin resistance remain unclear. It is also unknown whether diabetic muscle communicates with other tissues to promote systemic metabolic disorders. It is plausible that myokines or cardiokines secreted by diseased muscle might contribute to the systemic diabetic state. Similar to exercise-induced myokines that elicit a beneficial effect, myokines secreted by diabetic muscle may drive the pathogenesis of the disease, thereby impairing systemic metabolism. Understanding both the beneficial and deleterious functions of myokines in regulating systemic metabolism may help identify druggable targets for future treatment of insulin resistance and T2D. In this issue of Circulation, Wu et al6 report the discovery of a novel myokine, mitsugumin 53 (MG53), which impairs whole-body insulin sensitivity, further supThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.