The Enhancement of Muscle Insulin Sensitivity After Exercise: A Rac1-Independent Handoff to Some Other Player?

Largely because of its relative mass, its oxidative capacity, and its capacity to store glycogen, skeletal muscle accounts for much of the body's insulin-mediated glucose clearance, even while at rest (1, 2). With muscular contractions (ie, physical activity, exercise), glucose uptake increases up to 50-fold (3, 4) without the need for insulin (5). Contraction-mediated glucose disposal disappears soon after the exercise ends (within minutes to hours), but increased insulin sensitivity of glucose disposal persists in recovery for up to 48 hours (6–10). This process appears linked, at least in part, to the restoration of muscle glycogen reserves (6) and provides an excellent “sink” for increased carbohydrate intake and nutrient distribution after exercise. Understanding the mechanisms behind the noninsulin-mediated glucose disposal during exercise, and the heightened insulin sensitivity that occurs in recovery from exercise, are important for a number of reasons. First, skeletal muscle insulin resistance is considered an early step in the development of pre diabetes, metabolic syndrome and type 2 diabetes mellitus (11). Restoring this defect early on in the disease process might delay not only diabetes development but also many of the clinical sequelae that accompany various diseases and disorders associated with muscle insulin resistance (cardiovascular disease, Cushing's, acquired immunodeficiency syndrome, some forms of cancer, etc). Indeed, understanding the physiological pathways that heighten muscle insulin signaling after exercise may be important for determining the therapeutic targets for pharmacological interventions and various lifestyle management strategies (eg, exercise prescriptions, neutraceuticals). Second, postexercise hypoglycemia, caused at least in part by heightened muscle insulin sensitivity, is a common manifestation of prolonged exercise in individuals with type 1 diabetes (12). A better understanding of the time course and mechanism of action of this process might be helpful in ameliorating this major barrier in clinical care (13). Third, recovery from exhaustive exercise in active individuals (ie, recreational or elite athletes) is tied to the restoration of muscular glycogen levels with carbohydrate feeding (14), which coincides with the enhancement of insulin sensitivity (15). A better understanding of the mechanism for glycogen repletion may help to facilitate new strategies for exercise recovery process and subsequent performance. Glucose uptake into skeletal muscle depends on many factors, including capillary blood flow, insulin concentrations, insulin binding and signaling, other endocrine and neural inputs, glucose transporter 4 (GLUT4) glucose transporter number and trafficking, and glucose metabolism (16). Insulin and exercise can independently increase glucose uptake via the redistribution of GLUT4 glucose transporters from the cell interior to cell surface membranes (17). Of late, much of the research attention has focused on the molecular regulation of the GLUT4 transporter translocation within muscle caused by acute and chronic exercise (16, 18, 19). A report in this issue of Endocrinology by Sylow et al (20) shows that the protein Ras-related C3 botulinum toxin substrate 1 (Rac1), which has been deemed a critical convergence point for both insulin- and exercise-stimulated glucose uptake in muscle, is not required for the enhancement of insulin sensitivity after exercise. Rac1, a small Rho family GTPase that is involved in membrane dynamics, cell adhesion and proliferation (21), has been shown to facilitate GLUT4 translocation to the sarcolemma upon stimulation with either insulin in resting muscle or in muscle that is subjected to stretch or contractions (22–24). Animal models of insulin resistance and humans with insulin resistance have reduced muscle Rac1 activation and muscle-specific Rac1 knockout (Rac1-mKO) lowers contraction-mediated glucose disposal (24). Yet, according to this well-executed work, the removal of Rac1 from the muscle does not attenuate the heightened insulin sensitivity that is observed after exercise. In other words, the insulin resistance of the Rac1-mKO mouse is overcome by a recent bout of exercise, suggesting that glucose transport is at least partially independent of Rac1-mediated actin remodeling (Figure 1). Simplified schematic of the regulation of muscle glucose uptake by insulin stimulation and acute exercise. Rac1 activation occurs with both acute insulin stimulation and muscular contractions via independent signaling. Evidence presented by Sylow et al (20) indicates that after exercise, insulin sensitivity persists independent of Rac1, perhaps via AMPK activation or some other as yet to be identified signaling process. Upon insulin binding to its receptor, a conformational change occurs, causing autophosphorylation on tyrosine residues which then recruits insulin receptor substrate (IRS) proteins for additional phosphorylation on IRS tyrosine residues. Activated IRS is recognized by phosphatidylinositol-3-kinase (PI3K), which then diverges into at least 2 pathways, both of which ultimately result in glucose uptake after translocation of GLUT4 vesicles to the cell surface. One of these pathways involves PI3K-induced alterations of downstream signaling proteins, including Akt2 and the Rab-GTPases, TBC1D1 and TBC1D4 (25). Notably, a second pathway, which links PI3K to the Rho GTPase, Rac1, has more recently begun to be characterized. Previous studies have shown that Rac1 is important for insulin-, stretch-, and contraction-induced glucose transport into skeletal muscle of mice (22, 24, 26). However, no study to date had investigated the role of Rac1 in the improved insulin sensitivity that occurs after an acute bout of exercise. Rac1 acts as a regulator of cytoskeletal reorganization and GLUT4 vesicle traffic. More specifically, Rac1 activation induces cortical actin remodeling by its regulation of the actin-related protein complex 2/3, the serine/threonine p21-activated kinase, and the actin-binding protein, cofilin (27). The signaling underlying the activation of Rac1 is not yet fully understood, but it is thought to be through PI3K-dependent (27) and Akt2-independent (28) mechanisms. Exercise-stimulated glucose uptake into muscle depends on the activation of AMP-activated protein kinase (AMPK) and Rac1 (23), although other processes are likely in place (eg, protein kinase C, liver kinase B1, mechanical stretching, reactive oxygen species and nitric oxide) (29). Importantly, AMPK has also been shown to play a role in cortical actin remodeling and its targeted activation by AICAR recovers impaired insulin-induced GLUT4 regulation in insulin-resistant obese Zucker rats (30). Further, AICAR-induced glucose transport is not reduced in Rac1-mKO mice (22). Together, these data suggest that there is a yet to be determined mechanism that augments glucose uptake in exercise recovery, which is inducible by AMPK activation and is Rac1 independent. Thus, other signaling pathways, such as the sustained activation of AMPK by previous exercise, which can occur independent of Rac1 (24), may play an independent role on the actin cytoskeleton that facilitates GLUT4 translocation and insulin sensitivity after exercise. It would be surprising, however, if AMPK was the only molecular signal to explain the persistent insulin sensitivity after exercise (for up to 48 h), as several other molecular pathways appear to be “in play” with exercise (31). By highlighting the mechanistic differences in the action of acute exercise and insulin on postexercise insulin sensitization, this most recent study helps to clarify that the direct and lasting effects of exercise have inherently different molecular roots. Future studies should investigate the molecular basis of the postexercise sensitization to insulin stimulation. Is there still room for convergence of insulin action, exercise action and exercise-dependent insulin sensitization after exercise, aside from the involvement of Rac1? In summary, the article by Sylow et al has important clinical implications because it indicates that insulin resistance, which has been linked to impaired Rac1 activity (28) and reduced membrane-associated actin remodeling (30, 32), can be completely restored by an acute bout of exercise. Thus, even in insulin resistant individuals, exercise is capable of enhancing insulin-stimulated glucose uptake and whole-body insulin sensitivity. We thank Dr Amira Klip from the Cell Biology Program at The Hospital for Sick Children, Toronto, Canada, and Dr Erik Richter from the Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark, for their helpful comments on this News & Views. This work was funded by the Natural Sciences and Engineering Research Council of Canada (NSERC). Disclosure Summary: The authors have nothing to disclose. AMP-activated protein kinase glucose transporter 4 insulin receptor substrate phosphatidylinositol-3-kinase Ras-related C3 botulinum toxin substrate 1 Ras-related C3 botulinum toxin substrate 1 knockout.