The effects of high intensity interval exercise in hypoxia on glucose regulation and insulin sensitivity in sedentary individuals with overweight and obesity

Jacky Soo

The global prevalence of type 2 diabetes has been increasing insidiously for decades. Evidence suggest that high intensity interval exercise (HIIE) is effective in improving glucose control and metabolic health. Furthermore, combining exercise with hypoxic exposure (i.e., reduced oxygen availability) may upregulate key molecular and adaptive responses, thereby enhancing the effects of exercise training. However, the current method of implementing hypoxia during HIIE – continuously throughout the exercise session – is likely to compromise absolute exercise intensity, which inadvertently blunts the exercise stimulus. In this regard, much less is known about the optimal pattern to enhance the hypoxia-induced exercise training response. Furthermore, whilst the metabolic benefits of hypoxia training are promising, limited studies have examined the longer-term effects of high intensity interval training in hypoxia on glucose metabolism and insulin sensitivity. Accordingly, the overarching aim of this PhD was to investigate the effects of normobaric hypoxia on the physiological responses and exercise performance of HIIE, and whether the addition of hypoxia enhances insulin sensitivity and glucose homeostasis. Chapter 3 and 4 examine if hypoxia implemented intermittently either during the work or recovery phase of a perceptually regulated HIIE may enhance the exercise-induced physiological and metabolic responses (e.g. lactate production) without compromising absolute exercise intensity in inactive individuals with overweight. Eighteen inactive men and women who were overweight completed a cycling HIIE protocol (6×1-min intervals with 4-min active recovery, maintaining a perceived rating of exertion of 16 and 10 during work and recovery, respectively, on the 6-20 Borg scale) in randomised conditions: normoxia (NN), normobaric hypoxia (inspired O2 fraction ≈ 0.14, corresponding to a simulated altitude of ~3000 m) during both work and recovery (HH), hypoxia during recovery (NH) and hypoxia during work only (HN). Intermittent hypoxia, applied either during work (HN) or recovery (NH) mitigated the declines in mechanical output observed when exercise is performed in continuous hypoxia (HH). Importantly, when hypoxia was implemented exclusively during recovery (NH), changes in exercise performance closely resembled that in normoxia. However, the addition of hypoxia, whether during the work or recovery phase, had minimal influence on measures of internal loads, including heart rate and blood lactate responses, when compared to HIIE in normoxia. Changes in blood lactate concentration, however, may not fully explain the underlying metabolic process associated with hypoxia and HIIE. As such, Chapter 4 used a multiplatform metabolomics approach to examine the plasma metabolome in response to HIIE and hypoxia (continuous and intermittent), with specific analyses on pyruvate and lipid metabolism due to their importance for aerobic and anaerobic metabolism. Similar increases in plasma concentration of lactate and pyruvate (and the lactate-to-pyruvate ratio) were observed in all conditions, indicating an upregulation of glycolysis. Additionally, increases in plasma concentration of alanine and citrate were observed whilst aspartate and the branched chained amino acids (valine, leucine, and isoleucine) were similarly reduced. These findings suggest an increased reliance on the tricarboxylic acid cycle; this was particularly relevant given that the total free fatty acid concentration was significantly increased following HIIE in all conditions, likely indicating that the contribution to skeletal muscle energetics was limited. Notably the addition of hypoxia – whether continuously or intermittently – had limited influence on the plasma metabolome. Consequently, it is likely that the use of intermittent hypoxia, whilst mitigating significant decline in exercise performance, does not enhance the acute metabolic responses beyond that in normoxia. Chapter 5 examined the effect of hypoxia during HIIE on glycaemic control and insulin sensitivity, within the context of a 10-week combined aerobic and resistance training intervention. Thirty sedentary individuals with overweight or obesity underwent a 10-week exercise intervention (3 sessions/week) starting with two weeks of standardised normoxic training, followed by eight weeks of HIIE training with (HYP) or without hypoxia (NOR). Glycaemic outcomes (haemoglobin A1c; HbA1c, fasting glucose and insulin, and homeostatic model assessment of insulin resistance; HOMA2-IR), peak oxygen consumption (V̇O2peak) and submaximal fat oxidation rate (Fatox) were assessed before and after training. Glycaemic outcomes (fasting glucose, HbA1c, and HOMA2-IR) did not change significantly in either group. This was likely due to the normoglycaemic status of the participants at baseline. V̇O2peak and Fatox increased similarly following training with no differences between groups. However, the total absolute workload across the 8-week hypoxia training was ~14 % lower compared to normoxia training. Taken together, 8 weeks of HIIE training under low oxygen conditions likely reduces mechanical loading without compromising training outcomes in sedentary individuals with overweight or obesity. In conclusion, findings in this thesis show that intermittent hypoxia applied during work or recovery during HIIE is effective in mitigating declines in exercise performance observed in continuous hypoxia. However, this does not enhance acute metabolic responses beyond that in normoxia. Hypoxia training, within the context of a 10-week combined aerobic and resistance training intervention, had minimal influence on glycaemic control. However, the improvement in cardiorespiratory fitness (V̇O2peak and Fatox) following HIIE training in hypoxia – achieved with ~14% lower workload compared to normoxia training – remains a relevant outcome that may contribute to reducing the risks of insulin resistant and type 2 diabetes.

The effects of high intensity interval exercise in hypoxia on glucose regulation and insulin sensitivity in sedentary individuals with overweight and obesity

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