Biochemical and Molecular Mechanisms of Glucose Uptake Stimulated by Physical Exercise in Insulin Resistance State: Role of Inflammation

Abstract Obesity associated with 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-Jun N-terminal kinase (JNK), nuclear factor-kappa B (NF-κB) 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-1α), 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.

摘要 与全身性炎症相关的肥胖可诱导胰岛素抵抗（insulin resistance, IR），进而引发慢性高血糖。该过程涉及一系列级联反应：促炎细胞因子释放增加，c-Jun氨基末端激酶（c-Jun N-terminal kinase, JNK）、核因子-κB（nuclear factor-kappa B, NF-κB）以及toll样受体4（toll-like receptor 4, TLR4）受体被激活。当前可用的治疗手段中，体育运动（physical exercise, PE）已被证实具有明确的降糖效应，其背后涉及复杂的分子机制：包括增加胰岛素受体磷酸化水平、增强AMP活化蛋白激酶（AMP-activated protein kinase, AMPK）活性、激活Ca2+/钙调蛋白依赖性蛋白激酶激酶（Ca2+/calmodulin-dependent protein kinase kinase, CaMKK）通路，进而激活过氧化物酶体增殖物激活受体γ辅激活因子1-α（peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PGC-1α）、Rac1、TBC1域家族成员1与4（TBC1 domain family member 1 and 4, TBC1D1和TBC1D4），此外还涉及多种信号分子，例如GTP酶、Rab蛋白以及可溶性N-乙基马来酰亚胺敏感因子附着蛋白受体（soluble N-ethylmaleimide-sensitive factor attached protein receptor, SNARE）家族蛋白。上述通路可促进葡萄糖转运蛋白4（GLUT4）的转位增强，进而使骨骼肌摄取更多葡萄糖。磷脂酰肌醇依赖性激酶（phosphoinositide-dependent kinase, PDK）、非典型蛋白激酶C（atypical protein kinase C, aPKC）及其部分亚型（如PKC-ι/λ）似乎也在葡萄糖转运过程中发挥关键作用。在此背景下，自噬与运动的关联也被证实对肌肉葡萄糖摄取具有重要意义。而胰岛素则通过磷脂酰肌醇3-激酶（phosphoinositide 3-kinase, PI3K）依赖的机制发挥作用，运动信号则可通过肌浆网释放钙离子来触发。本综述旨在阐明胰岛素抵抗的主要分子机制，以及体育运动与葡萄糖摄取之间的关联。