Eight-week exercise training in humans with obesity: Marked improvements in insulin sensitivity and modest changes in gut microbiome.

OBJECTIVE: Obesity is associated with impaired gut microbiota diversity, which has been linked to the development of type 2 diabetes. This study aims to examine the effects of an 8-week aerobic exercise intervention on insulin sensitivity, visceral adiposity, and gut microbiota diversity and composition in participants with obesity. METHODS: Fourteen participants (mean [SD], age 51 [11] years; BMI 34.9 [4.9] kg/m2 ) performed an 8-week exercise intervention (2 to 4 times/week on 65% to 85% of heart rate reserve). Insulin sensitivity (hyperinsulemic euglycemic clamp), cardiorespiratory fitness (maximal oxygen uptake), visceral adiposity (dual-energy X-ray absorptiometry scan) and gut microbiota composition (16S rRNA gene sequencing) were measured before and after the intervention. RESULTS: Insulin sensitivity showed a significant increase (pre: 3.8 [1.9] mg/min/kg; post: 4.5 [1.7] mg/min/kg; p = 0.007) after training, whereas visceral adiposity decreased (pre: 959 [361] cm3 ; post: 897 [364] cm3 ; p = 0.02). No change in gut microbiota α- or ß-diversity was found. At the genus level, the abundance of Ruminococcus gauvreauii (p = 0.02); Lachnospiraceae FCS020 group (p = 0.04), and Anaerostipes (p = 0.04) significantly increased after exercise training. Significant positive correlations were present for M-value (R. gauvreauii) and VO2 max (R. gauvreauii and Anaerostipes). CONCLUSIONS: Eight-week exercise training in humans with obesity leads to marked improvements in insulin sensitivity and body composition and is accompanied by modest changes in 3 gut microbiome genera, all belonging to the Firmicutes phylum.

Favorable Anakinra Responses in Severe Covid-19 Patients with Secondary Hemophagocytic Lymphohistiocytosis.

Dysregulation of inflammation is hypothesized to play a crucial role in the severe complications of COVID-19, with the IL-1/IL-6 pathway being central. Here, we report on the treatment of eight severe COVID-19 pneumonia patients-seven hospitalized in intensive care units (ICUs) in Greece and one non-ICU patient in the Netherlands-with the interleukin-1 receptor antagonist Anakinra. All patients scored positive for the hemophagocytosis score (HScore) and were diagnosed with secondary hemophagocytic lymphohistocytosis (sHLH) characterized by pancytopenia, hyper-coagulation, acute kidney injury, and hepatobiliary dysfunction. At the end of treatment, ICU patients had less need for vasopressors, significantly improved respiratory function, and lower HScore. Although three patients died, the mortality was lower than historical series of patients with sHLH in sepsis. These data suggest that administration of Anakinra may be beneficial for treating severe COVID-19 patients with sHLH as determined by the HScore, and they support the need for larger clinical studies to validate this concept.

[Medicines: what has the last decade given us and what can we expect in the coming 10 years?] / Geneesmiddelen: 10 jaar terug en vooruitkijken.

Recent years have seen important changes in pharmacology. New techniques have been developed which are increasingly aimed at smaller groups of patients or even individual patients. In the past, thousands of chemical molecules were tested on a potential molecular target and the most effective molecules were selected. Nowadays a growing number of drugs are designed to aim at a specific molecular target, an example being monoclonal antibodies. There are developments that go fundamentally further and enable patients to be treated in an increasingly targeted and individual manner. These new therapies (i.e., Advanced Therapy Medicinal Products) are based on different principles than those of classical pharmacotherapy, and require different risk assessments as well as a different regulatory system. In this paper we discuss a selection of the developments in pharmacotherapy that have taken place during the past decade. In addition, we look into what sort of developments can be expected in the future.

Cytokine responses to repeated, prolonged walking in lean versus overweight/obese individuals.

OBJECTIVES: Obesity is characterized by a pro-inflammatory state, which plays a role in the pathogenesis of metabolic and cardiovascular disease. An exercise bout causes a transient increase in pro-inflammatory cytokines, whilst training has anti-inflammatory effects. No previous study examined whether the exercise-induced increase in pro-inflammatory cytokines is altered with repeated prolonged exercise bouts and whether this response differs between lean and overweight/obese individuals. DESIGN: Lean (n=25, BMI 22.9±1.5kg/m2) and age-/sex-matched overweight/obese (n=25; BMI 27.9±2.4kg/m2) individuals performed walking exercise for 30, 40 or 50km per day on four consecutive days (distances similar between groups). METHODS: Circulating cytokines (IL-6, IL-10, TNF-α, IL-1ß and IL-8) were examined at baseline and <30min after the finish of each exercise day. RESULTS: At baseline, no differences in circulating cytokines were present between groups. In response to prolonged exercise, all cytokines increased on day 1 (IL-1ß: P=0.02; other cytokines: P<0.001). IL-6 remained significantly elevated during the 4 exercise days, when compared to baseline. IL-10, TNF-α, IL-1ß and IL-8 returned to baseline values from exercise day 2 (IL-10, IL-1ß, IL-8) or exercise day 3 (TNF-α) onward. No significant differences were found between groups for all cytokines, except IL-8 (Time*Group Interaction P=0.02). CONCLUSIONS: These data suggest the presence of early adaptive mechanisms in response to repeated prolonged walking, demonstrated by attenuated exercise-induced elevations in cytokines on consecutive days that occur similar in lean and overweight/obese individuals.

Improvements in fitness are not obligatory for exercise training-induced improvements in CV risk factors.

The purpose of this study was to assess whether changes in physical fitness relate to changes in cardiovascular risk factors following standardized, center-based and supervised exercise training programs in subjects with increased cardiovascular risk. We pooled data from exercise training studies of subjects with increased cardiovascular risk (n = 166) who underwent 8-52 weeks endurance training. We determined fitness (i.e., peak oxygen uptake) and traditional cardiovascular risk factors (body mass index, blood pressure, total cholesterol, high-density lipoprotein cholesterol), before and after training. We divided subjects into quartiles based on improvement in fitness, and examined whether these groups differed in terms of risk factors. Associations between changes in fitness and in cardiovascular risk factors were further tested using Pearson correlations. Significant heterogeneity was apparent in the improvement of fitness and individual risk factors, with nonresponder rates of 17% for fitness, 44% for body mass index, 33% for mean arterial pressure, 49% for total cholesterol, and 49% for high-density lipoprotein cholesterol. Neither the number, nor the magnitude, of change in cardiovascular risk factors differed significantly between quartiles of fitness change. Changes in fitness were not correlated with changes in cardiovascular risk factors (all P > 0.05). Our data suggest that significant heterogeneity exists in changes in peak oxygen uptake after training, while improvement in fitness did not relate to improvement in cardiovascular risk factors. In subjects with increased cardiovascular risk, improvements in fitness are not obligatory for training-induced improvements in cardiovascular risk factors.

Statins Affect Skeletal Muscle Performance: Evidence for Disturbances in Energy Metabolism.

Context: Statin myopathy is linked to disturbances in mitochondrial function and exercise intolerance. Objectives: To determine whether differences exist in exercise performance, muscle function, and muscle mitochondrial oxidative capacity and content between symptomatic and asymptomatic statin users, and control subjects. Design: Cross-sectional study. Setting: Department of Physiology, Radboud University Medical Center. Participants: Long-term symptomatic and asymptomatic statin users, and control subjects (n = 10 per group). Interventions: Maximal incremental cycling tests, involuntary electrically stimulated isometric quadriceps-muscle contractions, and biopsy of vastus lateralis muscle. Main Outcomes Measured: Maximal exercise capacity, substrate use during exercise, muscle function, and mitochondrial energy metabolism. Results: Peak oxygen uptake, maximal work load, and ventilatory efficiency were comparable between groups, but both statin groups had a depressed anaerobic threshold compared with the control group (P = 0.01). Muscle relaxation time was prolonged in both statin groups compared with the control group and rate of maximal force rise was decreased (Ptime×group < 0.001 for both measures). Mitochondrial activity of complexes II and IV was lower in symptomatic statin users than control subjects and tended to be lower for complex (C) III (CII: P = 0.03; CIII: P = 0.05; CIV: P = 0.04). Mitochondrial content tended to be lower in both statin groups than in control subjects. Conclusion: Statin use attenuated substrate use during maximal exercise performance, induced muscle fatigue during repeated muscle contractions, and decreased muscle mitochondrial oxidative capacity. This suggests disturbances in mitochondrial oxidative capacity occur with statin use even in patients without statin-induced muscle complaints.

A comparison of dicarbonyl stress and advanced glycation endproducts in lifelong endurance athletes vs. sedentary controls.

OBJECTIVES: Dicarbonyl stress and high concentrations of advanced glycation endproducts (AGEs) relate to an elevated risk for cardiovascular diseases (CVD). Exercise training lowers the risk for future CVD. We tested the hypothesis that lifelong endurance athletes have lower dicarbonyl stress and AGEs compared to sedentary controls and that these differences relate to a better cardiovascular health profile. DESIGN: Cross-sectional study. METHODS: We included 18 lifelong endurance athletes (ATH, 61±7years) and 18 sedentary controls (SED, 58±7years) and measured circulating glyoxal (GO), methylglyoxal (MGO) and 3-deoxyglucosone (3DG) as markers of dicarbonyl stress. Furthermore, we measured serum levels of protein-bound AGEs NƐ-(carboxymethyl)lysine (CML), NƐ-(carboxyethyl)lysine (CEL), methylglyoxal-derived hydroimidazolone-1 (MG-H1), and pentosidine. Additionally, we measured cardiorespiratory fitness (VO2peak) and cardiovascular health markers. RESULTS: ATH had lower concentrations of MGO (196 [180-246] vs. 242 [207-292] nmol/mmol lysine, p=0.043) and 3DG (927 [868-972] vs. 1061 [982-1114] nmol/mmol lysine, p<0.01), but no GO compared to SED. ATH demonstrated higher concentrations CML and CEL compared to SED. Pentosidine did not differ across groups and MG-H1 was significantly lower in ATH compared to SED. Concentrations of MGO en 3DG were inversely correlated with cardiovascular health markers, whereas CML and CEL were positively correlated with VO2peak and cardiovascular health markers. CONCLUSION: Lifelong exercise training relates to lower dicarbonyl stress (MGO and 3DG) and the AGE MG-H1. The underlying mechanism and (clinical) relevance of higher CML and CEL concentrations among lifelong athletes warrants future research, since it conflicts with the idea that higher AGE concentrations relate to poor cardiovascular health outcomes.

Exercise Improves Insulin Sensitivity in the Absence of Changes in Cytokines.

PURPOSE: The benefits of aerobic exercise training on insulin sensitivity in subjects with metabolic syndrome (MetS) are, at least in part, associated with changes in cytokines. Recent studies identified novel cytokines (e.g., fractalkine, omentin, and osteopontin) that are strongly involved in glucose homeostasis and therefore potentially contribute in the exercise-induced changes in insulin sensitivity. Therefore, we aim to examine changes in skeletal muscle RNA expression and plasma levels of novel cytokines after exercise training and correlate these changes to the exercise-induced changes in insulin sensitivity. METHODS: Women with metabolic syndrome (MetS, n = 11) and healthy women (n = 10) participated in a 6-month aerobic exercise training intervention (three times a week, 45 min per session at 65%-85% of individual heart rate reserve). Before and after training, we examined insulin sensitivity (M value during hyperinsulinemic euglycemic clamp) and circulating blood levels of cytokines (venous blood sample; leptin, adiponectin, omentin, fraktalkin, and osteopontin). The skeletal muscle RNA expression of these cytokines (muscle biopsy) was examined in two subgroups (MetS, n = 6; healthy women, n = 6). RESULTS: At baseline, plasma levels of omentin (85.8 ± 26.2 ng·mL) and adiponectin (5.0 ± 1.7 µg·mL) levels were significantly higher in controls compared with MetS (51.1 ± 27.1; 3.6 ± 1.1 respectively), and leptin levels were lower in controls (18.7 ± 11.5 vs 53.0 ± 23.5 ng·mL). M value was significantly higher in controls (8.1 ± 1.9 mg·kg·min) than in MetS (4.0 ± 1.7). Exercise training significantly improved M values in both groups (P < 0.01). Exercise training did not alter plasma and skeletal muscle RNA expression levels of cytokines, but no correlation was observed between changes in cytokine level/RNA expression and M values (P > 0.05). CONCLUSION: Although exercise training successfully improves insulin sensitivity in MetS and healthy women, we found no change in plasma and mRNA expression levels of novel cytokines.

Elevation in blood flow and shear rate prevents hyperglycemia-induced endothelial dysfunction in healthy subjects and those with type 2 diabetes.

Hyperglycemia, commonly present after a meal, causes transient impairment in endothelial function. We examined whether increases in blood flow (BF) protect against the hyperglycemia-mediated decrease in endothelial function in healthy subjects and patients with type 2 diabetes mellitus (T2DM). Ten healthy subjects and 10 age- and sex-matched patients with T2DM underwent simultaneous bilateral assessment of brachial artery endothelial function by means of flow-mediated dilation (FMD) using high-resolution echo-Doppler. FMD was examined before and 60, 120, and 150 min after a 75-g oral glucose challenge. We unilaterally manipulated BF by heating one arm between minute 30 and minute 60. Oral glucose administration caused a statistically significant, transient increase in blood glucose in both groups (P < 0.001). Forearm skin temperature, brachial artery BF, and shear rate significantly increased in the heated arm (P < 0.001), and to a greater extent compared with the nonheated arm in both groups (interaction effect P < 0.001). The glucose load caused a transient decrease in FMD% (P < 0.05), whereas heating significantly prevented the decline (interaction effect P < 0.01). Also, when correcting for changes in diameter and shear rate, we found that the hyperglycemia-induced decrease in FMD can be prevented by local heating (P < 0.05). These effects on FMD were observed in both groups. Our data indicate that nonmetabolically driven elevation in BF and shear rate can similarly prevent the hyperglycemia-induced decline in conduit artery endothelial function in healthy volunteers and in patients with type 2 diabetes. Additional research is warranted to confirm that other interventions that increase BF and shear rate equally protect the endothelium when challenged by hyperglycemia.

Entering a new era of body indices: the feasibility of a body shape index and body roundness index to identify cardiovascular health status.

BACKGROUND: The Body Mass Index (BMI) and Waist Circumference (WC) are well-used anthropometric predictors for cardiovascular diseases (CVD), but their validity is regularly questioned. Recently, A Body Shape Index (ABSI) and Body Roundness Index (BRI) were introduced as alternative anthropometric indices that may better reflect health status. OBJECTIVE: This study assessed the capacity of ABSI and BRI in identifying cardiovascular diseases and cardiovascular disease risk factors and determined whether they are superior to BMI and WC. DESIGN AND METHODS: 4627 Participants (54±12 years) of the Nijmegen Exercise Study completed an online questionnaire concerning CVD health status (defined as history of CVD or CVD risk factors) and anthropometric characteristics. Quintiles of ABSI, BRI, BMI, and WC were used regarding CVD prevalence. Odds ratios (OR), adjusted for age, sex, and smoking, were calculated per anthropometric index. RESULTS: 1332 participants (27.7%) reported presence of CVD or CVD risk factors. The prevalence of CVD increased across quintiles for BMI, ABSI, BRI, and WC. Comparing the lowest with the highest quintile, adjusted OR (95% CI) for CVD were significantly different for BRI 3.2 (1.4-7.2), BMI 2.4 (1.9-3.1), and WC 3.0 (1.6-5.6). The adjusted OR (95% CI) for CVD risk factors was for BRI 2.5 (2.0-3.3), BMI 3.3 (1.6-6.8), and WC 2.0 (1.6-2.5). No association was observed for ABSI in both groups. CONCLUSIONS: BRI, BMI, and WC are able to determine CVD presence, while ABSI is not capable. Nevertheless, the capacity of BRI as a novel body index to identify CVD was not superior compared to established anthropometric indices like BMI and WC.

Within-subject correlations between evening-related changes in body temperature and melatonin in the spinal cord injured.

BACKGROUND: Individuals with a spinal cord injury (SCI) demonstrate altered circadian variation in thermoregulatory control. Recently, we reported that tetraplegia is associated with a blunted release of melatonin in the evening. In order to examine whether this finding relates to circadian thermoregulation, we compared the correlations between evening changes in melatonin, core and skin temperature between thoracic and cervical SCI and able-bodied participants. METHODS: In 10 able-bodied, 9 paraplegic and 8 tetraplegic participants, we measured, between 1900 and 2300 h, core temperature, proximal skin temperature (above and below the level of the lesion) and physical activity. Salivary melatonin was also sampled during this period and analyzed using enzyme linked immunosorbant assay. RESULTS: Between 1900 and 2300 h, core and upper limb skin temperature gradually decreased in all groups (p = 0.01). A significant group × time interaction was evident in lower body skin temperature (p = 0.03). Lower body skin temperature was significantly higher in able-bodied controls compared with tetraplegics between 1900 and 2000 h (p < 0.05). In able-bodied and paraplegic participants, the changes in melatonin and core temperature were inversely correlated (r = -0.44 and -0.54, respectively, both p = 0.01). Melatonin and mean skin temperature changes were also inversely correlated (able-bodied controls: r = -0.24; p = 0.05 and paraplegics: r = -0.30; p= 0.02). CONCLUSION: The inverse correlation between evening changes in melatonin and thermoregulation is of a similar magnitude in paraplegic and able-bodied controls. In contrast, changes in skin temperature, below the level of the lesion, are unrelated to changes in melatonin in tetraplegics.

Impact of physical fitness and daily energy expenditure on sleep efficiency in young and older humans.

BACKGROUND: Physical activity is known to influence sleep efficiency. Relatively little is known about the relationship between physical activity and sleep efficiency in young and older humans and the impact of exercise training on sleep efficiency in healthy older individuals. OBJECTIVES: To determine the relationship between physical fitness and daily energy expenditure with sleep efficiency in young and older subjects, and assess the effect of 12-month exercise training on sleep efficiency in healthy older participants. METHODS: The relationship between physical fitness (maximal cycling test) and daily energy expenditure (accelerometry) with sleep efficiency (accelerometry) was examined cross-sectionally in 12 healthy young adults (27 ± 5 years) and 21 healthy older participants (69 ± 3 years). Subsequently, the effect of 12-month exercise training (n = 11) or control period (n = 10) on sleep efficiency in older participants was examined using a randomized controlled trial. RESULTS: Daily energy expenditure and sleep efficiency did not differ between young and older subjects. A significant correlation was found between energy expenditure and sleep efficiency (r = 0.627, p = 0.029) in young adults, but not in older participants (r = -0.158, p = 0.49). Physical fitness did not correlate with sleep efficiency in either group. Exercise training significantly improved physical fitness (15.0%, p < 0.001), but failed to alter sleep characteristics such as sleep efficiency, sleep onset latency and awakenings. CONCLUSIONS: We found that young adults with higher daily energy expenditure have greater sleep efficiency, whilst this relationship is diminished with advanced age. In contrast, we found no correlation between physical fitness and sleep characteristics in healthy young or older participants, which may explain the lack of improvement in sleep characteristics in older participants with 12-month exercise training. Exercise training may be more successful in subjects with existing sleep disturbances to improve sleep characteristics rather than in healthy older subjects.

Complete absence of evening melatonin increase in tetraplegics.

Individuals with a spinal cord injury (SCI), especially with tetraplegia, experience poor sleep quality, and this may be related to impaired control of circadian rhythmicity. Here, we examined the evening onset of melatonin secretion, an important hormone for the initiation of sleep, in people with a complete cervical (tetraplegia) and thoracic (paraplegia) SCI, and age- and sex-matched able-bodied control participants. Multiple samples of salivary melatonin were obtained during the evening hours and analyzed by ELISA methods in 10 control partcipants, 9 individuals with paraplegia, and 6 individuals with tetraplegia. Sleep quality was assessed using questionnaires. Interactive effects of group and time were found for melatonin levels (P=0.022). In the control and paraplegia groups, the mean melatonin level increased significantly from 2.59 ± 1.04 and 4.28 ± 3.28 pg/ml at 7 PM to 10.62 ± 4.59 and 13.10 ± 7.39 pg/ml at 11 PM, respectively (P<0.001). In the tetraplegia group, melatonin level was 5.25 ± 3.72 at 7 PM but only 2.41 ± 1.25 pg/ml at 11 PM (P>0.05). Decreased sleep quality was more prevalent in individuals with tetraplegia (83%) and paraplegia (75%) compared with controls (20%; P=0.02). Unlike in the control and paraplegia groups, the evening increase in melatonin concentration was completely absent in the tetraplegia group. This provides biological insight into sleep regulation in humans and provides better understanding of the poor sleep quality in people with tetraplegia.