Respiratory function in uncomplicated type 1 diabetes: Blunted during exercise even though normal at rest!

AIMS: Type 1 diabetes is associated with a substantially increased risk of impaired lung function, which may impair aerobic fitness. We therefore aimed to examine the ventilatory response during maximal exercise and the pulmonary diffusion capacity function at rest in individuals with uncomplicated type 1 diabetes. METHODS: In all, 17 adults with type 1 diabetes free from micro-macrovascular complications (glycated haemoglobin: 8.0 ± 1.3%), and 17 non-diabetic adults, carefully matched to the type 1 diabetes group according to gender, age, level of physical activity and body composition, participated in our study. Lung function was assessed by spirometry and measurements of the combined diffusing capacity for nitric oxide (DLNO) and carbon monoxide (DLCO) at rest. Subjects performed a maximal exercise test during which the respiratory parameters were measured. RESULTS: At rest, DLCO (30.4 ± 6.1 ml min-1  mmHg-1 vs. 31.4 ± 5.7 ml min-1 mmHg-1 , respectively, p = 0.2), its determinants Dm (membrane diffusion capacity) and Vc (pulmonary capillary volume) were comparable among type 1 diabetes and control groups, respectively. Nevertheless, spirometry parameters (forced vital capacity = 4.9 ± 1.0 L vs. 5.5 ± 1.0 L, p < 0.05; forced expiratory volume 1 = 4.0 ± 0.7 L vs. 4.3 ± 0.7 L, p < 0.05) were lower in individuals with type 1 diabetes, although in the predicted normal range. During exercise, ventilatory response to exercise was different between the two groups: tidal volume was lower in type 1 diabetes vs. individuals without diabetes (p < 0.05). Type 1 diabetes showed a reduced VO2max (34.7 ± 6.8 vs. 37.9 ± 6.3, respectively, p = 0.04) in comparison to healthy subjects. CONCLUSIONS: Individuals with uncomplicated type 1 diabetes display normal alveolar-capillary diffusion capacity and at rest, while their forced vital capacity, tidal volumes and VO2 are reduced during maximal exercise.

Oxygen supplementation to limit hypoxia-induced muscle atrophy in C2C12 myotubes: comparison with amino acid supplement and electrical stimulation.

In skeletal muscle, chronic oxygen depletion induces a disturbance leading to muscle atrophy. Mechanical stress (physical exercise) and nutritional supplement therapy are commonly used against loss of muscle mass and undernutrition in hypoxia, while oxygenation therapy is preferentially used to counteract muscle fatigue and exercise intolerance. However, the impact of oxygenation on skeletal muscle cells remains poorly understood, in particular on signalling pathways regulating protein balance. Thus, we investigated the effects of each separated treatment (mechanical stress, nutritional supplementation and oxygenation therapy) on intracellular pathways involved in protein synthesis and degradation that are imbalanced in skeletal muscle cells atrophy resulting from hypoxia. Myotubes under hypoxia were treated by electrical stimulation, amino acids supplement or oxygenation period. Signalling pathways involved in protein synthesis (PI3K-Akt-mTOR) and degradation (FoxO1 and FoxO3a) were investigated, so as autophagy, ubiquitin-proteasome system and myotube morphology. Electrical stimulation and oxygenation treatment resulted in higher myotube diameter, myogenic fusion index and myotubes density until 48 h post-treatment compared to untreated hypoxic myotubes. Both treatments also induced inhibition of FoxO3a and decreased activity of ubiquitin-proteasome system; however, their impact on protein synthesis pathway was specific for each one. Indeed, electrical stimulation impacted upstream proteins to mTOR (i.e., Akt) while oxygenation treatment activated downstream targets of mTOR (i.e., 4E-BP1 and P70S6K). In contrast, amino acid supplementation had very few effects on myotube morphology nor on protein homeostasis. This study demonstrated that electrical stimulation or oxygenation period are two effective treatments to fight against hypoxia-induced muscle atrophy, acting through different molecular adaptations.

Circulating biomarkers of nitric oxide bioactivity and impaired muscle vasoreactivity to exercise in adults with uncomplicated type 1 diabetes.

AIMS/HYPOTHESIS: Early compromised endothelial function challenges the ability of individuals with type 1 diabetes to perform normal physical exercise. The exact mechanisms underlying this vascular limitation remain unknown, but may involve either formation or metabolism of nitric oxide (NO), a major vasodilator, whose activity is known to be compromised by oxidative stress. METHODS: Muscle microvascular reactivity (near-infrared spectroscopy) to an incremental exhaustive bout of exercise was assessed in 22 adults with uncomplicated type 1 diabetes (HbA1c 64.5 ± 15.7 mmol/mol; 8.0 ± 1.4%) and in 21 healthy individuals (18-40 years of age). NO-related substrates/metabolites were also measured in the blood along with other vasoactive compounds and oxidative stress markers; measurements were taken at rest, at peak exercise and after 15 min of recovery. Demographic characteristics, body composition, smoking status and diet were comparable in both groups. RESULTS: Maximal oxygen uptake was impaired in individuals with type 1 diabetes compared with in healthy participants (35.6 ± 7.7 vs 39.6 ± 6.8 ml min-1 kg-1, p < 0.01) despite comparable levels of habitual physical activity (moderate to vigorous physical activity by accelerometery, 234.9 ± 160.0 vs 280.1 ± 114.9 min/week). Compared with non-diabetic participants, individuals with type 1 diabetes also displayed a blunted exercise-induced vasoreactivity (muscle blood volume at peak exercise as reflected by ∆ total haemoglobin, 2.03 ± 5.82 vs 5.33 ± 5.54 µmol/l; interaction 'exercise' × 'group', p < 0.05); this was accompanied by lower K+ concentration (p < 0.05), reduced plasma L-arginine (p < 0.05)-in particular when HbA1c was high (mean estimation: -4.0, p < 0.05)-and lower plasma urate levels (p < 0.01). Nonetheless, exhaustive exercise did not worsen lipid peroxidation or other oxidative stress biomarkers, and erythrocytic enzymatic antioxidant resources were mobilised to a comparable extent in both groups. Nitrite and total nitrosation products, which are potential alternative NO sources, were similarly unaltered. Graphical abstract CONCLUSIONS/INTERPRETATION: Participants with uncomplicated type 1 diabetes displayed reduced availability of L-arginine, the essential substrate for enzymatic nitric oxide synthesis, as well as lower levels of the major plasma antioxidant, urate. Lower urate levels may reflect a defect in the activity of xanthine oxidase, an enzyme capable of producing NO from nitrite under hypoxic conditions. Thus, both canonical and non-canonical NO production may be reduced. However, neither of these changes exacerbated exercise-induced oxidative stress. TRIAL REGISTRATION: clinicaltrials.gov NCT02051504.

Early Endothelial Dysfunction in Type 1 Diabetes Is Accompanied by an Impairment of Vascular Smooth Muscle Function: A Meta-Analysis.

Background: A large yet heterogeneous body of literature exists suggesting that endothelial dysfunction appears early in type 1 diabetes, due to hyperglycemia-induced oxidative stress. The latter may also affect vascular smooth muscles (VSM) function, a layer albeit less frequently considered in that pathology. This meta-analysis aims at evaluating the extent, and the contributing risk factors, of early endothelial dysfunction, and of the possible concomitant VSM dysfunction, in type 1 diabetes. Methods: PubMed, Web of Sciences, Cochrane Library databases were screened from their respective inceptions until October 2019. We included studies comparing vasodilatory capacity depending or not on endothelium (i.e., endothelial function or VSM function, respectively) in patients with uncomplicated type 1 diabetes and healthy controls. Results: Fifty-eight articles studying endothelium-dependent function, among which 21 studies also assessed VSM, were included. Global analyses revealed an impairment of standardized mean difference (SMD) (Cohen's d) of endothelial function: -0.61 (95% CI: -0.79, -0.44) but also of VSM SMD: -0.32 (95% CI: -0.57, -0.07). The type of stimuli used (i.e., exercise, occlusion-reperfusion, pharmacological substances, heat) did not influence the impairment of the vasodilatory capacity. Endothelial dysfunction appeared more pronounced within macrovascular than microvascular beds. The latter was particularly altered in cases of poor glycemic control [HbA1c > 67 mmol/mol (8.3%)]. Conclusions: This meta-analysis not only corroborates the presence of an early impairment of endothelial function, even in response to physiological stimuli like exercise, but also highlights a VSM dysfunction in children and adults with type 1 diabetes. Endothelial dysfunction seems to be more pronounced in large than small vessels, fostering the debate on their relative temporal appearance.

Beetroot Juice Does Not Enhance Supramaximal Intermittent Exercise Performance in Elite Endurance Athletes.

Objective: Nitrate (NO3-)-rich beetroot juice (BR) is recognized as an ergogenic supplement that improves exercise tolerance during submaximal to maximal intensity exercise in recreational and competitive athletes. A recent study has investigated the effectiveness of BR on exercise performance during supramaximal intensity intermittent exercise (SIE) in Olympic-level track cyclists, but studies conducted in elite endurance athletes are scarce. The present study aimed to determine whether BR supplementation enhances the tolerance to SIE in elite endurance athletes.Methods: Eleven elite endurance athletes (age: 21.7 ± 3.7 years, maximal oxygen uptake [Formula: see text] 71.1 ± 5.2 mL·kg-1·min-1) performed an SIE test until exhaustion following either a 3-day BR supplementation (340 mg/d) or a placebo (PL) supplementation (<2.5 mg/d) in a randomized, single blind, placebo-controlled, and crossover study. The exercise test consisted of 15-second cycling exercise bouts at 170% of the maximal aerobic power interspersed with 30-second passive recovery periods. Gas exchange was measured during SIE tests as local muscle O2 delivery and extraction were assessed by near infrared spectroscopy.Results: The number of repetitions completed was not significantly different between BR (13.9 ± 4.0 reps) and PL conditions (14.2 ± 4.5 reps). BR supplementation did not affect oxygen uptake ([Formula: see text]) during SIE tests (BR: 3378.5 ± 681.8 mL·min-1, PL: 3466.1 ± 505.3 mL·min-1). No significant change in the areas under curves was found for local muscle total hemoglobin (BR: 6816.9 ± 1463.1 arbitrary units (a.u.), PL: 6771.5 ± 3004.5 a.u.) and deoxygenated hemoglobin (BR: 6619.7 ± 875.8 a.u., PL: 6332.7 ± 1336.8 a.u.) during time-matched work + recovery periods from SIE tests following BR supplementation.Conclusions: BR supplementation does not enhance the tolerance to SIE in elite endurance athletes and affects neither [Formula: see text] nor local muscle O2 delivery and extraction.

Plasma asymmetric dimethylarginine concentrations are not related to differences in maximal oxygen uptake in endurance trained and untrained men.

NEW FINDINGS: What is the central question of this study? Is there an association of plasma concentration of asymmetric dimethylarginine, which is related to exercise capacity in patients with cardiovascular diseases, with oxygen delivery and subsequently exercise capacity in healthy subjects in the absence of the potentially confounding influence of inflammation and oxidative stress? What is the main finding and its importance? Plasma asymmetric dimethylarginine concentrations are not related to exercise capacity in healthy subjects, while O2 delivery in the working skeletal muscle during the maximal graded-exercise test is not associated with any of the l-arginine analogues. ADMA alone does not play a crucial role in local muscle perfusion and in maintaining exercise capacity. ABSTRACT: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthesis that could limit oxygen (O2 ) delivery in the working skeletal muscles by altering endothelium-dependent vasodilatation. Exercise capacity is associated with plasma ADMA concentrations in patients with cardiovascular diseases, but this issue has still not been investigated in healthy subjects. We aimed to determine whether plasma ADMA concentrations were negatively associated with exercise capacity in young healthy male subjects. Ten men with maximal oxygen uptake ( V ̇ O 2 max ) > 65 mL kg-1  min-1 were included in the high exercise capacity group (HI-FIT), and 10 men with V ̇ O 2 max  < 45 mL kg-1  min-1 were included in the low exercise capacity group (LO-FIT). Plasma ADMA and other l-arginine analogue concentrations were measured before and after a maximal graded-exercise test by liquid chromatography-tandem mass spectrometry. Microvascular O2 delivery during exercise was estimated through the pattern from the sigmoid model of muscle deoxygenation in the vastus lateralis measured by near infrared spectroscopy. V ̇ O 2 max was 60% higher in the HI-FIT group (median: 70.2 mL kg-1  min-1 ; IQR: 68.0-71.9 mL kg-1  min-1 ) than in the LO-FIT group (median: 43.8 mL kg-1  min-1 ; IQR: 34.8-45.3 mL kg-1  min-1 ). Plasma ADMA concentrations did not differ between the LO-FIT and HI-FIT groups before (0.50 ± 0.06 vs. 0.54 ± 0.07 µmol L-1 , respectively) and after the maximal incremental exercise test (0.49 ± 0.08 vs. 0.55 ± 0.03 µmol L-1 , respectively). There was no significant association of plasma ADMA concentrations with the pattern of local muscle deoxygenation and exercise capacity. Exercise capacity and microvascular O2 delivery are not related to plasma ADMA concentrations in young healthy male subjects. Our findings show that ADMA does not play a crucial role in local muscle perfusion and in maintaining exercise capacity without pathological conditions.

Effect of dietary nitrate supplementation on metabolic rate during rest and exercise in human: A systematic review and a meta-analysis.

BACKGROUND: Recent randomized controlled trials have suggested that dietary nitrate (NO3(-)), found in beetroot and other vegetables, and inorganic NO3(-) salts decrease metabolic rate under resting and exercise conditions. OBJECTIVE: Our aim was therefore to determine from a systematic review and meta-analysis whether dietary NO3(-) supplementation significantly reduces metabolic rate, expressed as oxygen uptake (VO2), under resting and exercise conditions in healthy humans and those with cardiorespiratory diseases. DESIGN: A systematic article search was performed on electronic databases (PubMed, Scopus and Web of Science) from February to March 2015. The inclusion criteria included 1) randomized controlled trials; 2) studies reporting the effect of NO3(-) on VO2 under resting and/or exercise conditions; 3) comparison between dietary NO3(-) supplementation and placebo. Random-effects models were used to calculate the pooled effect size. RESULTS: Twenty nine randomized placebo-controlled trials were included in the systematic review, and 26 of which were included in the meta-analysis. Dietary NO3(-) supplementation significantly decreases VO2 during submaximal intensity exercise [-0.26 (95% IC: -0.38, -0.15), p < 0.01], but not in the sub-analysis of subjects with chronic diseases [-0.09 (95% IC: -0.50, 0.32), p = 0.67]. When data were separately analyzed by submaximal intensity domains, NO3(-) supplementation reduces VO2 during moderate [-0.29 (95% IC: -0.48,-0.10), p < 0.01] and heavy [-0.33 (95% IC: -0.54,-0.12), p < 0.01] intensity exercise. When the studies with the largest effects were excluded from the meta-analysis, there is a trend for a VO2 decrease under resting condition in dietary NO3(-) supplementation [-0.28 (95% IC: -0.62, 0.05), p = 0.10]. CONCLUSION: Dietary NO3(-) supplementation decreases VO2 during exercise performed in the moderate and heavy intensity domains in healthy subjects. The present meta-analysis did not show any significant effect of dietary NO3(-) supplementation on metabolic rate in subjects with chronic diseases, despite enhanced exercise tolerance.

Effect of dietary nitrate supplementation on tolerance to supramaximal intensity intermittent exercise.

Dietary nitrate (NO3(-)) supplementation has been shown to increase exercise tolerance and improve oxidative efficiency during aerobic exercise in healthy subjects. We tested the hypothesis that a 3-day supplementation in beetroot juice (BJ) rich in NO3(-) would improve the tolerance to supramaximal intensity intermittent exercise consisting of 15-s exercise periods at 170% of the maximal aerobic power interspersed with 30-s passive recovery periods. The number of repetitions completed before reaching volitional exhaustion was significantly higher in the BJ than in the placebo condition (26.1 ± 10.7 versus 21.8 ± 8.0 respectively, P < 0.05). In contrast to previous findings during exercise performed at intensity below the peak oxygen uptake (VO2peak), oxygen uptake (VO2) was unaffected (BJ: 2735 ± 345 mL kg(-1) min(-1) vs. placebo: 2787 ± 346 mL kg(-1) min(-1), NS). However, the Area Under the Curve for microvascular total hemoglobin (AUC-THb) in the vastus lateralis muscle assessed by near infrared spectroscopy during 3 time-matched repetitions was significantly increased with NO3(-) supplementation (BJ: 9662 ± 1228 a.u. vs. placebo:8178 ± 1589 a.u.; P < 0.05). Thus, increased NO3(-) (BJ: 421.5 ± 107.4 µM vs placebo:39.4 ± 18.0 µM) and NO2(-) (BJ: 441 ± 184 nM vs placebo: 212 ± 119 nM) plasma levels (P < 0.001 for both) are associated with improved muscle microvascular Red Blood Cell (RBC) concentration and O2 delivery during intense exercise, despite no effect on resting femoral artery blood flow, and vascular conductance. Maximal voluntary force during an isometric leg extensor exercise, and blood lactate levels were also unaffected by NO3(-) supplementation. To conclude, dietary NO3(-) supplementation enhances tolerance to exercise at supramaximal intensity, with increased microvascular total RBC concentration in the working muscle, in the absence of effect on contractile function and resting hemodynamic parameters.