ABC | Volume 113, Nº6, December 2019

Review Article Ferrari et al. Exercise-mediated glucose uptake Arq Bras Cardiol. 2019; 113(6):1139-1148 In addition, there is evidence suggesting that activation of AMPK in skeletal muscle can increase lipid oxidation, and thereby glycogen resynthesis can adapt to PE (by sparing muscle glycogen) by stimulation of muscle contraction. 48 Some myokines, including interleukin-15 (IL-15) and interleukin-6 (IL-6), increase the expression of GLUT4 in adipose tissue, which can potentiate PE-induced glucose uptake, 49 and also activate AMPK and GLUT4 translocation to the cell surface. 50 Activation of AMPK is also important since as it promotes the phosphorylation of TBC1D1 and TBC1D4. Studies have shown that both acute and chronic exercise increase the expression of AMPK, TBC1D1, TBC1D4 and GLUT4 in skeletal muscles in humans. 51,52 It was also reported that in contracted epitrochlearis muscles of rats, TBC1D4 phosphorylation was increased, and this effect persisted for 3-4 hours after the animals swam for four 30‑min bouts with a 5-min rest between bouts. 53 Kjøbsted et al. 54 corroborated this hypothesis in a recent study showing that increased phosphorylation of TBC1D4 stimulated by insulin in exercised muscles improves insulin sensitivity. Another important event associated with PE and AMPK activation is the activation of the of peroxisome proliferator- activated receptor gamma coactivator 1-alpha (PGC-1 α ), 55 mediated p38 MAPK and histone deacetylase-5 (HDAC5). 56 In addition, phosphorylation of Ca2+/calmodulin-dependent protein kinase (CaMKK) followed by activation of PGC-1 α , can be induced by low-intensity, resisted exercise, suggesting that PE-induced GLUT4 translocation can be achieved by several modalities. 57 On the other hand, other important proteins, as the case of Pac1, 34,35 do not require activation of the AMPK pathway to promote PE-induced glucose uptake in skeletal muscle. 34,35 Studies have indicated that muscle elongation contributes to activation of Rac1. 58,59 Silow et al. 58 have shown that Rac1 signaling is impaired in muscles resistant to insulin in rats and humans. The importance of Rac1 in this context is attributed to its effects on actin cytoskeleton. Thus, dysregulation of Rac1 and actin cytoskeleton in the skeletal muscle can be newmolecular candidates that contribute to the phenotype of IR and DM2. 58 More recent data have supported these findings, suggesting that Rac1 essentially contributes to PE-stimulated glucose uptake. 60,61 However, it is important to mention that previous studies have shown that short exercise completely restored insulin sensitivity in Rac1-deficient muscle containing RI. 62 Therefore, although Rac1 is essential for regulation of glucose transport stimulated by PE, it is dispensable for the insulin sensitizing effect of exercise. This is important since Rac1 is dysfunctional in insulin-resistant muscle. 63 These findings indicate that other pathways different from the Rac1 pathway, can exhibit more pronounced effects of insulin sensitization during PE. 64 A schematic illustration of GLUT4 translocation mediated by insulin and by muscle contraction is presented in Figure 1. Other important and complex mechanisms related to the AMPK pathway need to be mentioned. For example, its relationship with autophagy, a process involved with glucose metabolism and insulin sensitivity. Autophagy is a self‑degradative process that occurs via lysossomal pathway that plays a role in the removal of malformed or aggregated proteins, eliminating damaged organelles, similarly to mitochondria and sarcoplasmic reticulum. Autophagy is generally considered a survival mechanism, although its dysregulation has been associated with non-apoptotic cell death. 65,66 The relationship between autophagy, PE and metabolic regulation is still a little explored area. However, there is increasing evidence that the autophagic process is strongly induced during physical training, 67,68 and seems to play an important role in the metabolism of skeletal muscle. 69 In this regard, autophagy can regulate the homeostasis of muscle glucose and contribute to the reduction of RI in response to PE. 70 These data are corroborated by He et al., 71 in an experiment conducted with mice, showing that mice with induced allelic loss of Beclin 1 , an autophagy-related gene that promotes a decrease in autophagy in the skeletal muscle, had impaired exercise-induced GLUT4 plasma membrane localization. These data suggest an important role of autophagy and Beclin 1 in improving glucose uptake in response to PE. For example, a single bout of running for 90 minutes on a treadmill was sufficient to induce autophagy in the skeletal muscle and in the brain of mice. 68 One of the hypotheses that may explain the mechanisms involved in this scenario is that PE can increase the concentrations of proteins of the sestrins (SESNs) induced by stress, such as SESN1 and SESN3, which not only increase the autophagic activity, but also interact with AMPK, and stimulate its activation. 72,73 The induction of SESNs inhibits the mechanistic target of rapamycin complex 1 (mTORC1) activity by stimulation of AMPK. 73 Thus, the interaction between sestrin and AMPK induced by PE may be involved in the beneficial metabolic effect of training, activating autophagy. This interaction provides a molecular mechanism that is a potential target in metabolic syndromes. Obesity, inflammation and insulin resistance IR develops silently and may lead to pancreatic failure, starting with a resistance to insulin activity in the target-tissues, followed by an increase in pancreatic insulin production in response to such IR, and ultimately with incapacity of the pancreas to continue insulin production. This fact opens the door to DM2, characterized by an acquired chronic hyperglycemia associated with other diseases including hypertension and dyslipidemia. The main factors that cause this syndrome are obesity, sedentary lifestyle and genetic factors. 74 IR is characterized by pathological changes in several steps of insulin metabolic pathway, 75 with simultaneous increase in endogenous production of hepatic glucose, leading to chronic hyperglycemia. 76 Today, obesity, especially visceral obesity, is recognized as one of the main risk factors of IR. 77 Several mechanisms are involved in the etiopathogenesis of obesity-related IR, characterized by changes in several steps of insulin signaling, with reduction in IR concentration and kinase activity, in IRS-1 and IRS-2 78 phosphorylation into tyrosine, and in PI3K activity. 79 In addition, a significant increase in abdominal adipose tissue induces the delivery of free fatty to the liver through the portal vein, aggravating hepatic insulin resistance, 80 thereby increasing the release of proinflammatory cytokines through the portal vein, which acts as a feedback to the process. 81 The role of chronic inflammation in this scenario cannot be excluded. IR is related to obesity-induced inflammation, 1141