ABC | Volume 113, Nº6, December 2019

Review Article Biochemical and Molecular Mechanisms of Glucose Uptake Stimulated by Physical Exercise in Insulin Resistance State: Role of Inflammation Filipe Ferrari, 1, 2 P atrícia Martins Bock, 3,4, 5 Marcelo Trotte Motta, 6 Lucas Helal 1, 3 Programa de Pós-graduação em Cardiologia e Ciências Cardiovasculares - Faculdade de Medicina - Hospital de Clínicas de Porto Alegre (HCPA) - Universidade Federal do Rio Grande do Sul, 1 Porto Alegre, RS – Brazil Grupo de Pesquisa em Cardiologia do Exercício - CardioEx (HCPA/UFRGS), 2 Porto Alegre, RS – Brazil Laboratório de Fisiopatologia do Exercício (LaFiEx), (HCPA/UFRGS), 3 Porto Alegre, RS – Brazil Instituto de Avaliação de Tecnologias em Saúde (IATS), Hospital de Clínicas de Porto Alegre, 4 Porto Alegre, RS – Brazil Faculdades Integradas de Taquara, 5 Taquara, RS – Brazil Departamento de Ciências Biológicas, Universidade Estadual de Feira de Santana (UEFS), 6 Feira de Santana, BA – Brazil Keywords Exercise; Insulin Resistance; Chronic Inflammation; Glucose Metabolism Disorders; Anti-Inflammatoty Agents; Glucose Transporter Type 4. Mailing Address: Lucas Helal • Programa de Pós-graduação em Cardiologia e Ciências Cardiovasculares, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre – Brasil Laboratório de Fisiopatologia do Exercício, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brasil - Rua Ramiro Barcelos, 2350. Postal Code 90035-003, Santa Cecília, Porto Alegre, RS – Brazil E-mail: lucas.helal@ufrgs.br , lhelal@hcpa.edu.br Manuscript received November 18, 2018, revised manuscript March 26, 2019, accepted May 15, 2019 DOI: 10.5935/abc.20190224 Abstract Obesity associatedwith systemic inflammation induces insulin resistance (IR), with consequent chronic hyperglycemia. A series of reactions are involved in this process, including increased release of proinflammatory cytokines, and activation of c-JunN-terminal kinase (JNK), nuclear factor-kappa B (NF- κ B) and toll-like receptor 4 (TLR4) receptors. Among the therapeutic tools available nowadays, physical exercise (PE) has a known hypoglycemic effect explained by complex molecular mechanisms, including an increase in insulin receptor phosphorylation, in AMP-activated protein kinase (AMPK) activity, in the Ca2+/calmodulin- dependent protein kinase kinase (CaMKK) pathway, with subsequent activation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 α ), Rac1, TBC1 domain family member 1 and 4 (TBC1D1 and TBC1D4), in addition to a variety of signaling molecules, such as GTPases, Rab and soluble N-ethylmaleimide-sensitive factor attached protein receptor (SNARE) proteins. These pathways promote greater translocation of GLUT4 and consequent glucose uptake by the skeletal muscle. Phosphoinositide-dependent kinase (PDK), atypical protein kinase C (aPKC) and some of its isoforms, such as PKC-iota/lambda also seem to play a fundamental role in the transport of glucose. In this sense, the association between autophagy and exercise has also demonstrated a relevant role in the uptake of muscle glucose. Insulin, in turn, uses a phosphoinositide 3-kinase (PI3K)-dependent mechanism, while exercise signal may be triggered by the release of calcium from the sarcoplasmic reticulum. The objective of this review is to describe the main molecular mechanisms of IR and the relationship between PE and glucose uptake. Introduction Insulin resistance (IR) at target tissues is directly related to chronic subclinical inflammation. When inadequately controlled, IR cause a permanent hyperglycemic status, characterizing the pathophysiology of type 2 diabetes mellitus (DM2). 1 Cardiovascular diseases are the main cause of morbidity and mortality in DM2 patients, 2 leading to annual costs per year of nearly 40 billion. 3 Hyperglycemia, per se , is a devastating condition for the cardiovascular system. Among the complications caused by chronic hyperglycemia in patients with DM2, there is a reduction in endothelial vasodilator capacity (by reduced nitric oxide availability), increase in advanced glycation end products, in addition to increased oxidative stress, which leads to endothelial dysfunction and atherogenesis in long term, and increased cardiovascular risk. 4,5 Physical exercise (PE), combined with pharmacologic therapy, is an effective strategy in the approach of DM2 patients, with direct effect on glycemic ontrol, 6,7 due to its capacity in reducing blood glucose concentrations 8 and its anti-inflammatory effect in long term, 9 with potential positive effect in reducing cardiovascular complications in these patients. Muscle contraction acutely increases trigger biochemical reactions that culminate in increased glucose uptake by the muscle. This is caused by two important mechanisms – increase in insulin sensitivity 10 and translocation of the type 4 glucose transporter (GLUT4) to the cell surface independent of insulin use. 11 In addition, PE chronically increases intramuscular GLUT4 content 12 and reduces the inflammatory state, especially by the release of anti-inflammatory cytokines 13 and reduction in total lipid content. 14 The objective of this review is to provide an overview of the regulation of glucose uptake in IR and chronic subclinical inflammation, and the role of PE in this situation. First, we present a discussion about biochemical and molecular mechanisms of the hypoglycemic effect of PE, with special attention to the increase in insulin sensitivity and translocation of de GLUT4 independent of insulin; then, we present evidence of the role of PE as an anti-inflammatory strategy and its association with IR. Signaling of insulin and glucose uptake by skeletal muscle Insulin is a peptide hormone released by the pancreas, specifically by beta cells of the pancreatic islets. 15 Intracellular signaling of insulin in insulin-sensitive tissues requires 1139