ABC | Volume 113, Nº6, December 2019

Review Article Ferrari et al. Exercise-mediated glucose uptake Arq Bras Cardiol. 2019; 113(6):1139-1148 Figure 1 – Schematic representation of the main pathways that promote the translocation of GLUT4-containing vesicles to the membrane in the skeletal muscle induced by insulin (A) and insulin-independent pathways during physical exercise (B) P: Phosphorylation;ATP:Adenosine triphosphate;ADP:Adenosine diphosphate; IRS: insulin receptor substrate; PI3K: phosphoinositide 3-kinase; PI2P: phosphatidylinositol-4,5-bisphosphate; PI3P: phosphatidylinositol (3,4,5)-trisphosphate; PDK: phosphoinositide- dependent kinase; aPKC: atypical protein kinase C; DOC2b: double C2-like domain-containing protein; SNARE: soluble N-ethylmaleimide-sensitive factor attached protein receptor; TBC1D1: TBC1 domain family member 1; TBC1D4: TBC1 domain family member 4; GLUT4: glucose transporter type;Ca+: Calcium; eNOS: nitric oxide synthase; MAPK: mitogen-activated protein kinase; CaMK: Ca2+/calmodulin-dependent protein kinase; PKC: protein kinase C; AMPK: AMP-activated protein kinase. Insulin Plasma membrane Plasma membrane Insulin receptor Activation Activation Activation ATP ATP ADP ADP IRS IRS P P P P P P P P β PI2P PI3P PI3K PDK DOC2b aPKC Akt Rab Rab-GTP TBC1D1 TBC1D4 SNARE/Syntaxin-4 GLUT4-containing vesicles Glucose Glucose GLUT4 Glucose Glucose GLUT4 Dissociation GLUT4-containing vesicles Dissociation Muscle contraction Ca + Ca + Activation Sarcoplasmic reticulum AMPK TBC1D1 TBC1D4 Rab Rab-GTP eNOS MAPK CaMK PKC Hipóxia A B Insulin Plasma membrane Plasma membrane Insulin receptor Activation Activation Activation ATP ATP ADP ADP IRS IRS P P P P P P P P β PI2P PI3P PI3K PDK DOC2b aPKC Akt Rab Rab-GTP TBC1D1 TBC1D4 SNARE/Syntaxin-4 GLUT4-containing vesicles Glucose l GLUT4 Glucose Glucose GLUT4 Dissociation GLUT4-containing vesicles Dissociation Muscle contraction Ca + Ca + Activation Sarcoplasmic reticulum AMPK TBC1D1 TBC1D4 Rab Rab-GTP eNOS MAPK CaMK PKC Hipóxia A B process already described in the 90’s. In this decade, several studies evaluated the association of IR with traditional inflammatory markers, such as tumor necrosis factor-alpha (TNF- α ) and showed that adipocytes treated with TNF- α had impaired insulin signaling. This response was associated with reduced IRS-1 and GLUT-482 transcription. 82 Pro-inflammatory cytokines, such as the TNF- α , can lead to activation of c-Jun N-terminal kinase (JNK), a critical enzyme in inflammation associated with obesity and IR, 83 by activating serine or threonine kinase, thereby reducing insulin signaling by phosphorylation of proteins into serine or threonine residues. 84 Besides, activation of this enzyme is related with signaling pathways that activate nuclear factor-kappa B (NF-B) which, in turn, stimulates the production of pro-inflammatory cytokines. 85 The activation of JNK also promotes NF-Bactivation in pancreatic islets, and therefore, perpetuating a vicious cycle of β -cells 1142