Effects of four weeks intermittent hypoxia intervention on glucose homeostasis, insulin sensitivity, GLUT4 translocation, insulin receptor phosphorylation, and Akt activity in skeletal muscle of obese mice with type 2 diabetes

Abstract

AimsThe aims of this study were to determine the effects of four weeks of intermittent exposure to a moderate hypoxia environment (15% oxygen), and compare with the effects of exercise in normoxia or hypoxia, on glucose homeostasis, insulin sensitivity, GLUT4 translocation, insulin receptor phosphorylation, Akt-dependent GSK3 phosphorylation and Akt activity in skeletal muscle of obese mice with type 2 diabetes.MethodsC57BL/6J mice that developed type 2 diabetes with a high-fat-diet (55% fat) (fasting blood glucose, FBG = 13.9 ± 0.69 (SD) mmol/L) were randomly allocated into diabetic control (DC), rest in hypoxia (DH), exercise in normoxia (DE), and exercise in hypoxia (DHE) groups (n = 7, each), together with a normal-diet (4% fat) control group (NC, FBG = 9.1 ± 1.11 (SD) mmol/L). The exercise groups ran on a treadmill at intensities of 75–90% VO2max. The interventions were applied one hour per day, six days per week for four weeks. Venous blood samples were analysed for FBG, insulin (FBI) and insulin sensitivity (QUICKI) pre and post the intervention period. The quadriceps muscle samples were collected 72 hours post the last intervention session for analysis of GLUT4 translocation, insulin receptor phosphorylation, Akt expression and phosphorylated GSK3 fusion protein by western blot. Akt activity was determined by the ratio of the phosphorylated GSK3 fusion protein to the total Akt protein.ResultsThe FBG of the DH, DE and DHE groups returned to normal level (FBG = 9.4 ± 1.50, 8.86 ± 0.94 and 9.0 ± 1.13 (SD) mmol/L for DH, DE and DHE respectively, P < 0.05), with improved insulin sensitivity compared to DC (P < 0.05), after the four weeks treatment, while the NC and DC showed no significant changes, as analysed by general linear model with repeated measures. All three interventions resulted in a significant increase of GLUT4 translocation to cell membrane compared to the DC group (P < 0.05). The DE and DH showed a similar level of insulin receptor phosphorylation compared with NC that was significantly lower than the DC (P < 0.05) post intervention. The DH and DHE groups showed a significantly higher Akt activity compared to the DE, DC and NC (P < 0.05) post intervention, as analysed by one-way ANOVA.ConclusionsThis study produced new evidence that intermittent exposure to mild hypoxia (0.15 FiO2) for four weeks resulted in normalisation of FBG, improvement in whole body insulin sensitivity, and a significant increase of GLUT4 translocation in the skeletal muscle, that were similar to the effects of exercise intervention during the same time period, in mice with diet-induced type 2 diabetes. However, exercise in hypoxia for four weeks did not have additive effects on these responses. The outcomes of the research may contribute to the development of effective, alternative and complementary interventions for management of hyperglycaemia and type 2 diabetes, particularly for individuals with limitations in participation of physical activity.

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“…The plasma membrane of the skeletal muscle tissues was isolated as previously described (Wang et al 2018 ). Briefly, the skeletal muscle tissues were rinsed in Solution A containing 250 mmol/L Sucrose, 50 mmol/L Tris, 0.2 mmol/L EDTA, pH 7.4, followed by centrifugation at 120 g for 15 min at 4 °C.…”

Cellular adaptation to hypoxia through hypoxia inducible factors and beyond

“…Furthermore, HIF-1α was shown to increase the expression of RAB20 that promotes GLUT4 translocation to the plasma membrane and to negatively regulate TXNIP expression to promote AKT downstream signalling 183 . In a number of murine studies, longand short-term chronic intermittent hypoxia triggers AKT and AMPK pathway activation as well as changes in GLUT4 expression in skeletal muscle [184][185][186] . Hypoxia can support adaptation of cells to replenish ATP required for cell energetics -such as muscle contraction -by providing ample glucose.…”

Exercise as a Therapeutic Intervention in Gestational Diabetes Mellitus

“…Potential signals mediating this exercise-induced GLUT4 translocation include: (a) the release of Ca 2+ by the sarcoplasmic reticulum to be used for muscle contraction, which causes an increase in intracellular Ca 2+ concentration and activates the Ca 2+ /calmodulin-dependent protein kinase (CaMK), (b) the reduction in the ATP/ADP ratio and the activation of AMP-protein kinase (AMPK), and (c) the transient increase in oxidative stress [28,34,35]. Additional exercise-induced mechanisms that have been described include increased activity of endothelial nitric oxide, the activation of mitogen-activated protein kinase (MAPK), the activation of protein kinase C (PKC), bradykinin, hypoxia, and the increase in muscle temperature along with the mechanical deformation during muscle contraction [21,36,37]. The synergistic action of the above mechanisms stimulates an effective translocation of GLUT4 to the cell's membrane during muscle contraction and relaxation [28].…”