The Circulatory and Metabolic Responses to Hypoxia in Humans - With Special Reference to Adipose Tissue Physiology and Obesity

Adipose tissue metabolism and circulation play an important role in human health. It is well-known that adipose tissue mass is increased in response to excess caloric intake leading to obesity and further to local hypoxia and inflammatory signaling. Acute exercise increases blood supply to adipose tissue and mobilization of fat stores for energy. However, acute exercise during systemic hypoxia reduces subcutaneous blood flow in healthy young subjects, but the response in overweight or obese subjects remains to be investigated. Emerging evidence also indicates that exercise training during hypoxic exposure may provide additive benefits with respect to many traditional cardiovascular risk factors as compared to exercise performed in normoxia, but unfavorable effects of hypoxia have also been documented. These topics will be covered in this brief review dealing with hypoxia and adipose tissue physiology

Muscle Free Fatty-Acid Uptake Associates to Mechanical Efficiency During Exercise in Humans

Intrinsic factors related to muscle metabolism may explain the differences in mechanical efficiency (ME) during exercise. Therefore, this study aimed to investigate the relationship between muscle metabolism and ME. Totally 17 healthy recreationally active male participants were recruited and divided into efficient (EF; n = 8) and inefficient (IE; n = 9) groups, which were matched for age (mean +/- SD 24 +/- 2 vs. 23 +/- 2 years), BMI (23 +/- 1 vs. 23 +/- 2 kg m(-2)), physical activity levels (3.4 +/- 1.0 vs. 4.1 +/- 1.0 sessions/week), and (V)over dotO(2)peak (53 +/- 3 vs. 52 +/- 3 mL kg(-1) min(-1)), respectively, but differed for ME at 45% of (V)over dotO(2)peak intensity during submaximal bicycle ergometer test (EF 20.5 +/- 3.5 vs. IE 15.4 +/- 0.8%, P < 0.001). Using positron emission tomography, muscle blood flow (BF) and uptakes of oxygen (m(V)over dotO(2)), fatty acids (FAU) and glucose (GU) were measured during dynamic submaximal knee-extension exercise. Workload-normalized BF (EF 35 +/- 14 vs. IE 34 +/- 11 mL 100 g(-1) min(-1), P = 0.896), m(V)over dotO(2) (EF 4.1 +/- 1.2 vs. IE 3.9 +/- 1.2 mL 100 g(-1) min(-1), P = 0.808), and GU (EF 3.1 +/- 1.8 vs. IE 2.6 +/- 2.3 m mol 100 g(-1) min(-1), P = 0.641) as well as the delivery of oxygen, glucose, and FAU, as well as respiratory quotient were not different between the groups. However, FAU was significantly higher in EF than IE (3.1 +/- 1.7 vs. 1.7 +/- 0.6 m mol 100 g(-1) min(-1), P = 0.047) and it also correlated with ME (r = 0.56, P = 0.024) in the entire study group. EF group also demonstrated higher use of plasma FAU than IE, but no differences in use of plasma glucose and intramuscular energy sources were observed between the groups. These findings suggest that the effective use of plasma FAU is an important determinant of ME during exercise

Different Predictors of Right and Left Ventricular Metabolism in Healthy Middle-Aged Men

Dysfunction of the right ventricle (RV) plays a crucial role in the outcome of various cardiovascular diseases. Previous studies on RV metabolism are sparse although evidence implies it may differ from left ventricular (LV) metabolism. Therefore, the aims of this study were (1) to determine predictors of RV glucose uptake (GU) and free fatty acid uptake (FFAU) and (2) to compare them to predictors of LV metabolism in healthy middle-aged men. Altogether 28 healthy, sedentary, middle-aged (40-55 years) men were studied. Insulin-stimulated GU and fasting FFAU were measured by positron emission tomography and RV and LV structural and functional parameters by cardiac magnetic resonance. Several parameters related to whole-body health were also measured. Predictors of RV and LV metabolism were determined by pairwise correlation analysis, lasso regression models, and variable clustering using heatmap. RVGU was most strongly predicted by age and moderately by RV ejection fraction (EF). The strongest determinants of RVFFAU were exercise capacity (peak oxygen uptake), resting heart rate, LVEF, and whole body insulin stimulated glucose uptake rate. When considering LV metabolism, age and RVEF were associated also with LVGU. In addition, LVGU was strongly, and negatively, influenced by whole-body insulin-stimulated glucose uptake rate. LVFFAU was predicted only by LVEF. This study shows that while RV and LV metabolism have shared characteristics, they also have unique properties. Age of the subject should be taken into account when measuring myocardial glucose utilization. Ejection fraction is related to myocardial metabolism, and even so that RVEF may be more closely related to GU of both ventricles and LVEF to FFAU of both ventricles, a finding supporting the ventricular interdependence. However, only RV fatty acid utilization associates with exercise capacity so that better physical fitness in a relatively sedentary population is related with decreased RV fat metabolism. To conclude, this study highlights the need for further study designed specifically on less known RV as the results on LV metabolism and physiology may not be directly applicable to the RV.</p

Affective Adaptation to Repeated SIT and MICT Protocols in Insulin-Resistant Subjects

Introduction The aim of this study was to investigate affective responses to repeated sessions of sprint interval training (SIT) in comparison with moderate-intensity continuous training (MICT) in insulin-resistant subjects.Methods Twenty-six insulin-resistant adults (age, 49 (4) yr; 10 women) were randomized into SIT (n = 13) or MICT (n = 13) groups. Subjects completed six supervised training sessions within 2 wk (SIT session, 4-6 x 30 s all-out cycling/4-min recovery; MICT session, 40-60 min at 60% peak work load). Perceived exertion, stress, and affective state were assessed with questionnaires before, during and after each training session.Results Perceived exertion, displeasure, and arousal were higher during the SIT compared with MICT sessions (all P 0.05).Conclusions The perceptual and affective responses are more negative both during and acutely after SIT compared with MICT in untrained insulin-resistant adults. These responses, however, show significant improvements already within six training sessions, indicating rapid positive affective and physiological adaptations to continual exercise training, both SIT and MICT. These findings suggest that even very intense SIT is mentally tolerable alternative for untrained people with insulin resistance

Bone Marrow Metabolism Is Impaired in Insulin Resistance and Improves After Exercise Training

Context: Exercise training improves bone mineral density, but little is known about the effects of training on bone marrow (BM) metabolism. BM insulin sensitivity has been suggested to play an important role in bone health and whole-body insulin sensitivity.Objective: To study the effects of exercise training on BM metabolism.Design: Randomized controlled trial.Setting: Clinical research center.Participants: Sedentary healthy (n = 28, 40-55 years, all males) and insulin resistant (IR) subjects (n = 26, 43-55 years, males/females 16/10).Intervention: Two weeks of sprint interval training or moderate-intensity continuous training.Main outcome measures: We measured femoral, lumbar, and thoracic BM insulin-stimulated glucose uptake (GU) and fasting free fatty acid uptake (FFAU) using positron-emission tomography and bone turnover markers from plasma.Results: At baseline, GU was highest in lumbar, followed by thoracic, and lowest in femoral BM (all Ps Conclusions: BM metabolism differs regarding anatomical location. Short-term training improves BM GU and FFAU in healthy and IR subjects. Bone turnover rate is decreased in insulin resistance and associates positively with BM metabolism and glycemic control.</p

Sprint interval training decreases left-ventricular glucose uptake compared to moderate-intensity continuous training in subjects with type 2 diabetes or prediabetes

Type 2 diabetes mellitus (T2DM) is associated with reduced myocardial glucose uptake (GU) and increased free fatty acid uptake (FFAU). Sprint interval training (SIT) improves physical exercise capacity and metabolic biomarkers, but effects of SIT on cardiac function and energy substrate metabolism in diabetic subjects are unknown. We tested the hypothesis that SIT is more effective than moderate-intensity continuous training (MICT) on adaptations in left and right ventricle (LV and RV) glucose and fatty acid metabolism in diabetic subjects. Twenty-six untrained men and women with T2DM or prediabetes were randomized into two-week-long SIT (n = 13) and MICT (n = 13) interventions. Insulin-stimulated myocardial GU and fasted state FFAU were measured by positron emission tomography and changes in LV and RV structure and function by cardiac magnetic resonance. In contrast to our hypothesis, SIT significantly decreased GU compared to MICT in LV. FFAU of both ventricles remained unchanged by training. RV end-diastolic volume (EDV) and RV mass increased only after MICT, whereas LV EDV, LV mass, and RV and LV end-systolic volumes increased similarly after both training modes. As SIT decreases myocardial insulin-stimulated GU compared to MICT which may already be reduced in T2DM, SIT may be metabolically less beneficial than MICT for a diabetic heart

Intramyocellular lipid accumulation after sprint interval and moderate-intensity continuous training in healthy and diabetic subjects

The effects of sprint interval training (SIT) on intramyocellular (IMCL) and extramyocellular (EMCL) lipid accumulation are unclear. We tested the effects of SIT and moderate-intensity continuous training (MICT) on IMCL and EMCL accumulation in a randomized controlled setting in two different study populations; healthy untrained men (n 28) and subjects with type 2 diabetes (T2D) or prediabetes (n 26). Proton magnetic resonance spectroscopy (H-1 MRS) was used to determine IMCL and EMCL in the Tibialis anterior muscle (TA) before and after a 2-week exercise period. The exercise period comprised six sessions of SIT or MICT cycling on a cycle ergometer. IMCL increased after SIT compared to MICT (P = 0.042) in both healthy and T2D/prediabetic subjects. On EMCL the training intervention had no significant effect. In conclusion, IMCL serves as an important energy depot during exercise and can be extended by high intensity exercise. The effects of high intensity interval exercise on IMCL seem to be similar regardless of insulin sensitivity or the presence of T2D

Effects of Different Exercise Training Protocols on Gene Expression of Rac1 and PAK1 in Healthy Rat Fast- and Slow-Type Muscles

Purpose Rac1 and its downstream target PAK1 are novel regulators of insulin and exercise-induced glucose uptake in skeletal muscle. However, it is not yet understood how different training intensities affect the expression of these proteins. Therefore, we studied the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on Rac1 and PAK1 expression in fast-type (gastrocnemius, GC) and slow-type (soleus, SOL) muscles in rats after HIIT and MICT swimming exercises. Methods The mRNA expression was determined using qPCR and protein expression levels with reverse-phase protein microarray (RPPA). Results HIIT significantly decreased Rac1 mRNA expression in GC compared to MICT (p = 0.003) and to the control group (CON) (p = 0.001). At the protein level Rac1 was increased in GC in both training groups, but only the difference between HIIT and CON was significant (p = 0.02). HIIT caused significant decrease of PAK1 mRNA expression in GC compared to MICT (p = 0.007) and to CON (p = 0.001). At the protein level, HIIT increased PAK1 expression in GC compared to MICT and CON (by similar to 17%), but the difference was not statistically significant (p = 0.3, p = 0.2, respectively). There were no significant differences in the Rac1 or PAK1 expression in SOL between the groups. Conclusion Our results indicate that HIIT, but not MICT, decreases Rac1 and PAK1 mRNA expression and increases the protein expression of especially Rac1 but only in fast-type muscle. These exercise training findings may reveal new therapeutic targets to treat patients with metabolic diseases

Decreased insulin-stimulated brown adipose tissue glucose uptake after short-term exercise training in healthy middle-aged men

Aims: To test the hypothesis that high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) improve brown adipose tissue (BAT) insulin sensitivity.Participants and methods: Healthy middle-aged men (n = 18, age 47 years [95% confidence interval {CI} 49, 43], body mass index 25.3 kg/m(2) [95% CI 24.1-26.3], peak oxygen uptake (VO2peak) 34.8 mL/kg/min [95% CI 32.1, 37.4]) were recruited and randomized into six HIIT or MICT sessions within 2 weeks. Insulin-stimulated glucose uptake was measured using 2-[F-18] flouro-2-deoxy-D-glucose positron-emission tomography in BAT, skeletal muscle, and abdominal and femoral subcutaneous and visceral white adipose tissue (WAT) depots before and after the training interventions.Results: Training improved VO2peak (P =.0005), insulin-stimulated glucose uptake into the quadriceps femoris muscle (P =.0009) and femoral subcutaneous WAT (P =.02) but not into BAT, with no difference between the training modes. Using pre-intervention BAT glucose uptake, we next stratified subjects into high BAT (> 2.9 mu mol/100 g/min; n = 6) or low BAT (< 2.9 mu mol/100 g/min; n = 12) groups. Interestingly, training decreased insulin-stimulated BAT glucose uptake in the high BAT group (4.0 [2.8, 5.5] vs 2.5 [1.7, 3.6]; training*BAT, P =.02), whereas there was no effect of training in the low BAT group (1.5 [1.2, 1.9] vs 1.6 [1.2, 2.0] mu mol/100 g/min). Participants in the high BAT group had lower levels of inflammatory markers compared with those in the low BAT group.Conclusions: Participants with functionally active BAT have an improved metabolic profile compared with those with low BAT activity. Short-term exercise training decreased insulin-stimulated BAT glucose uptake in participants with active BAT, suggesting that training does not work as a potent stimulus for BAT activation

Predicting Skeletal Muscle and Whole-Body Insulin Sensitivity Using NMR-Metabolomic Profiling

Purpose: Abnormal lipoprotein and amino acid profiles are associated with insulin resistance and may help to identify this condition. The aim of this study was to create models estimating skeletal muscle and whole-body insulin sensitivity using fasting metabolite profiles and common clinical and laboratory measures.Material and Methods: The cross-sectional study population included 259 subjects with normal or impaired fasting glucose or type 2 diabetes in whom skeletal muscle and whole-body insulin sensitivity (M-value) were measured during euglycemic hyperinsulinemic clamp. Muscle glucose uptake (GU) was measured directly using [F-18]FDG-PET. Serum metabolites were measured using nuclear magnetic resonance (NMR) spectroscopy. We used linear regression to build the models for the muscle GU (Muscle-insulin sensitivity index [ISI]) and M-value (whole-body [WB]-ISI). The models were created and tested using randomly selected training (n = 173) and test groups (n = 86). The models were compared to common fasting indices of insulin sensitivity, homeostatic model assessment-insulin resistance (HOMA-IR) and the revised quantitative insulin sensitivity check index (QUICKI).Results: WB-ISI had higher correlation with actual M-value than HOMA-IR or revised QUICKI (rho = 0.83 vs -0.67 and 0.66; P < 0.05 for both comparisons), whereas the correlation of Muscle-ISI with the actual skeletal muscle GU was not significantly stronger than HOMA-IR's or revised QUICKI's (rho = 0.67 vs -0.58 and 0.59; both nonsignificant) in the test dataset.Conclusion: Muscle-ISI and WB-ISI based on NMR-metabolomics and common laboratory measurements from fasting serum samples and basic anthropometrics are promising rapid and inexpensive tools for determining insulin sensitivity in at-risk individuals. (C) Endocrine Society 2020