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. 2024 Jan 25;19(1):e0296815.
doi: 10.1371/journal.pone.0296815. eCollection 2024.

Enhanced glucose utilization of skeletal muscle after 4 weeks of intermittent hypoxia in a mouse model of type 2 diabetes

Yuqi Zhao  1   2 , Chaoqun Li  3 , Shi Zhou  4 , Youyu He  1 , Yun Wang  4 , Yuan Zhang  4 , Li Wen  1   2
Affiliations

Enhanced glucose utilization of skeletal muscle after 4 weeks of intermittent hypoxia in a mouse model of type 2 diabetes

Yuqi Zhao et al. PLoS One. .

Abstract

Background: Intermittent hypoxia intervention (IHI) has been shown to reduces blood glucose and improves insulin resistance in type 2 diabetes (T2D) and has been suggested as a complementary or alternative intervention to exercise for individuals with limited mobility. Previous research on IHI has assessed cellular glucose uptake rather than utilization. The purpose of this study was to determine the effect of a 4-week IHI, with or without an aerobic exercise, on skeletal muscle glucose utilization as indicated by the changes in pyruvate, lactate, NAD+, and NADH, using a mouse model of diet-induced T2D. In addition, the effects of one exposure to hypoxia (acute) and of a 4-week IHI (chronic) were compared to explore their relationship.

Methods: C57BL/6J mice were randomly assigned to normal control and high-fat-diet groups, and the mice that developed diet-induced diabetes were assigned to diabetes control, and intervention groups with 1 hour (acute) or 4 weeks (1 hour/day, 6 days/week) exposure to a hypoxic envrionment (0.15 FiO2), exercise (treadmill run) in normoxia, and exercise in hypoxia, respectively, with N = 7 in each group. The effects of the interventions on concentrations of fasting blood glucose, muscle glucose, GLUT4, lactate, pyruvate, nicotinamide adenine dinucleotide (NAD+), and NADH were measured, and statistically compared between the groups.

Results: Compared with diabetes control group, the mice treated in the hypoxic environment for 4 weeks showed a significantly higher pyruvate levels and lower lactate/pyruvate ratios in the quadriceps muscle, and the mice exposed to hypoxia without or with aerobic exercise for either for 4 weeks or just 1 hour showed higher NAD+ levels and lower NADH/NAD+ ratios.

Conclusions: Exposure to moderate hypoxia for either one bout or 4 weeks significantly increased the body's mitochondrial NAD cyclethe in diabetic mice even in the absence of aerobic exercise. The hypoxia and exercise interventions exhibited synergistic effects on glycolysis. These findings provide mechanistic insights into the effects of IHI in respect of the management of hyperglycemia.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Fasting blood glucose (FBG) in skeletal muscle after the intervention.
The error bars represent SD. * p < 0.05. NC represents control mice, sedentary in normoxic environment; DC, diabetic control mice, sedentary in normoxic environment; DE, diabetic mice, 4 weeks of exercise in normoxic environment; DH, diabetic mice, sedentary for 4 weeks in hypoxic environment; and DHE, diabetic mice, 4 weeks of exercise in hypoxic environment; DE1, diabetic mice, one hour exposure to exercise in normoxic environment; DH1, diabetic mice, one hour exposure to exercise in hypoxic environment; and DHE1, diabetic mice, one hour exposure to exercise in hypoxic environment. N = 7 in each group.
Fig 2
Fig 2. Expression of GLUT4 in muscle plasma membrane and after the intervention.
The error bars represent SD. * p < 0.05. & Indicates that there is a significant difference as compared with all other groups. NC represents control mice, sedentary in normoxic environment; DC, diabetic control mice, sedentary in normoxic environment; DE, diabetic mice, 4 weeks of exercise in normoxic environment; DH, diabetic mice, sedentary for 4 weeks in hypoxic environment; and DHE, diabetic mice, 4 weeks of exercise in hypoxic environment; DE1, diabetic mice, one hour exposure to exercise in normoxic environment; DH1, diabetic mice, one hour exposure to exercise in hypoxic environment; and DHE1, diabetic mice, one hour exposure to exercise in hypoxic environment. N = 7 in each group.
Fig 3
Fig 3. Muscle glucose concentration after the intervention.
The error bars represent SD. NC represents control mice, sedentary in normoxic environment; DC, diabetic control mice, sedentary in normoxic environment; DE, diabetic mice, 4 weeks of exercise in normoxic environment; DH, diabetic mice, sedentary for 4 weeks in hypoxic environment; and DHE, diabetic mice, 4 weeks of exercise in hypoxic environment; DE1, diabetic mice, one hour exposure to exercise in normoxic environment; DH1, diabetic mice, one hour exposure to exercise in hypoxic environment; and DHE1, diabetic mice, one hour exposure to exercise in hypoxic environment. N = 7 in each group.
Fig 4
Fig 4
Lactate (a) and Pyruvate (b) concentrations and the ratio of lactate/pyruvate (c) in skeletal muscle after the intervention. The error bars represent SD. * p < 0.05. NC represents control mice, sedentary in normoxic environment; DC, diabetic control mice, sedentary in normoxic environment; DE, diabetic mice, 4 weeks of exercise in normoxic environment; DH, diabetic mice, sedentary for 4 weeks in hypoxic environment; and DHE, diabetic mice, 4 weeks of exercise in hypoxic environment; DE1, diabetic mice, one hour exposure to exercise in normoxic environment; DH1, diabetic mice, one hour exposure to exercise in hypoxic environment; and DHE1, diabetic mice, one hour exposure to exercise in hypoxic environment. N = 7 in each group.
Fig 5
Fig 5
NAD+ (a) and NADH (b) concentrations, and the ratio of NADH/NAD+ (c) in skeletal muscle after the intervention. The error bars represent SD. * p < 0.05. NC represents control mice, sedentary in normoxic environment; DC, diabetic control mice, sedentary in normoxic environment; DE, diabetic mice, 4 weeks of exercise in normoxic environment; DH, diabetic mice, sedentary for 4 weeks in hypoxic environment; and DHE, diabetic mice, 4 weeks of exercise in hypoxic environment; DE1, diabetic mice, one hour exposure to exercise in normoxic environment; DH1, diabetic mice, one hour exposure to exercise in hypoxic environment; and DHE1, diabetic mice, one hour exposure to exercise in hypoxic environment. N = 7 in each group.
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Grants and funding

This study was financially supported by the National Natural Science Foundation of China in the form of a grant (31271275) received by LW. This study was also financially supported by the National Natural Science Youth Fund Project in the form of a grant (32000839) received by YZ. No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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