The post‐exercise paradox of reduced glucose tolerance and insulin sensitivity
2023-06-01

Exercise, in particular when performed on a regular basis, is widely accepted as the best non-pharmacological intervention to preserve glucose control in healthy subjects and to restore compromised glucose tolerance and insulin sensitivity in patients with prediabetes or type 2 diabetes. In contrast, in the study of Mikael Flockhart et al.1 the authors reported that in endurance athletes 3 h of prolonged continuous exercise on an ergometer at 65% of VO2max reduces glucose tolerance assessed by an OGTT at the following day. The results were compared with a resting condition, and the effect was also not observed after high-intensity interval training (HIIT; 5 × 4 min at approximately 95% VO2max). The prolonged ergometer exercise or HIIT did also not change glucose control in a group of healthy non-endurance-trained subjects. The endurance athletes were characterized by a higher capacity to oxidize fat due to a higher mitochondrial respiration and higher citrate synthase and 3-hydroxyacyl-CoA dehydrogenase activities per skeletal muscle weight. At the following morning after the prolonged continuous exercise, athletes had a twofold increase in 3-hydroxybutyrate concentration in serum compared with the resting condition, suggesting increased fat oxidation. Most importantly, during the OGTT, athletes had a pronounced shift from carbohydrate to fat oxidation compared to the OGTT without exercise the previous day. In view of the overwhelming literature consistently demonstrating the beneficial effects of regularly performed exercise on glucose tolerance and insulin sensitivity, the results of this study seem paradoxical. However, the study reported on the effects of one single bout of exercise on whole-body glucose control and insulin action, and here, the evidence is less clear. A substantial number of studies did not show enhanced glucose tolerance after acute exercise similar to the results of the non-endurance-trained group in the current study of Flockhart and co-authors. This is not surprising and should not be confused with the improved local insulin action on the exercised muscle frequently reported after one bout of exercise. The adaptations which are responsible for the exercise-induced improvement in whole-body glucose tolerance and insulin sensitivity are mediated by the cumulative effects of repeated bouts of exercise.2 Thus, regularly performed training is necessary to change the muscular phenotype toward increased capacity to uptake, utilize, and store glucose and fatty acids, which is an important contribution to increased glucose tolerance and insulin sensitivity on whole-body level.2 The remarkable finding in the current study is the worsening of glucose control after one single bout of prolonged endurance exercise. The data are in line with some previous studies also showing reduced glucose tolerance in the first hours or the following day after one exercise session or exercise training.3-5 Reported as post-marathon paradox, whole-body glucose disposal and glucose oxidation rate were decreased during a euglycemic-hyperinsulinemic clamp performed at the following morning after a marathon run.5 A similar observation was made in moderately trained subjects when glucose tolerance was assessed in an OGTT immediately after the last of five exercise sessions consisting of 45 min of endurance exercise at 75% VO2max which were performed over five consecutive days.4 In a recent study, Mikael Flockhart and co-authors analyzed glucose tolerance by OGTTs in healthy volunteers during 4 weeks of HIIT with increasing workload and found reduced glucose tolerance after the third week with the highest workload with only a partial recovery after the fourth week when HIIT was again performed at a moderate intensity.6 Even after a single bout of one-legged exercise to local exhaustion, whole-body insulin sensitivity assessed during a euglycemic-hyperinsulinemic clamp was lower compared with the clamp performed on a resting control day.7 To summarize, while one single bout of exercise clearly increases insulin sensitivity for glucose uptake in the exercised muscle, this is rarely reflected by an improvement of insulin sensitivity on whole-body level. In the first hours or the following day post-exercise, a reduced insulin sensitivity can even be observed. This reduction in glucose control was reported independent from assessment using OGTT or a euglycemic-hyperinsulinemic clamp and seems to occur more frequently after prolonged endurance exercise. This post-exercise paradox has previously received little attention. The recovery phase is considered as a glucose-sparing condition to direct glucose to the exercised muscles for glycogen storage, which is enabled by a switch in substrate oxidation from carbohydrates to fat. The data of the current study of Flockhart and co-authors suggest that an increasing capacity to mobilize and utilize fatty acids for oxidation in skeletal muscle which are characteristics of endurance-trained athletes favors high-fat oxidation in the early (first hours) and late recovery phase (following day) and this appears to mediate a resistance to insulin's inhibitory effect on fat oxidation during a glucose load. The mechanisms for this prolonged effect of a single bout of exercise to increase fat oxidation are not well understood. There is evidence that in the early recovery phase, increased mobilization of fatty acids is maintained by increased plasma concentrations of catecholamines and lower insulin levels and later on by the action of growth hormone.8 Enhanced lipoprotein lipase activity in skeletal muscle capillaries was reported in both the early and late recovery phase after exercise which can contribute to increased fatty acid supply by hydrolyzing VLDL-triglycerides.8 The endurance athletes in the study of Flockhart et al. had higher fasting plasma fatty acids at the following morning after the prolonged endurance exercise session compared with the resting condition, but the absolute fatty acid levels were not different from the group of non-endurance-trained subjects. While this is not a strong argument against increased mobilization of fatty acids in endurance athletes post-exercise, other mechanisms should be considered as well. Notably, skeletal muscle AMPK activity was found to be elevated for 5 days in the exercised leg after one single bout of one-legged exercise.9 This was accompanied by increased phosphorylation of the AMPK-target ACC2, which has been shown to promote fatty acid oxidation. Recent data also suggest that exercise can lead to a reduced insulin response of non-exercised muscles, which at least partially could account for the decreased whole-body glucose disposal.7 To which extend this observation can be translated to exercise performance involving many muscles of the body needs to be shown. To conclude, the post-exercise paradox of reduced glucose tolerance and insulin sensitivity should be considered as a potential consequence of a pronounced metabolic adaptation to regularly performed endurance exercise. It is a transient phenomenon which demonstrates the complexity of the coordination of insulin-dependent and insulin-independent glucose and fatty metabolism in skeletal muscle and serves more investigation to fully understand the underlying mechanisms and potential consequences. I have no conflict of interest to disclose.