Serum CD5L as potential biomarker of thyroid hormone status during pregnancy.

The thyroid hormone (TH) status is routinely assessed by thyrotropin (TSH) and thyroxine (T4). Both biomarkers are mainly regulated by TH receptor beta, whereas many peripheral organs employ the alpha receptor. Serum cluster of differentiation 5-like molecule (CD5L) is a liver-derived protein under control of both TH receptor isoforms. However, clinical data on its relation to TH status are sparse. An additional biomarker of TH status is needed in particular during pregnancy, where the routine biomarkers become dynamically disturbed. This study aimed to determine possible covariates regulating serum CD5L and to test its potential suitability as additional TH biomarker during pregnancy. A sandwich ELISA for serum CD5L was established using newly raised antibodies. Circadian effects and the impact of liver disease on serum CD5L concentrations were assessed. Serum samples from pregnant women with well-characterized TH and trace element status were analyzed, and CD5L concentrations were correlated with other indicators of TH status including TSH, fT4, fT3, copper, and selenium concentrations. The new quantitative assay for CD5L showed high accuracy. Serum CD5L was stable in dilution and refreezing experiments and did not show strong circadian variance or dependency on liver disease. In serum of pregnant women, CD5L correlated positively to fT3, but not to fT4 or TSH. Significant positive correlations of CD5L were observed with serum levels of the TH-responsive trace elements selenium and copper. The data support the potential suitability of serum CD5L as an additional marker of TH status, with potential value for pregnancy and thyroid disease.

[Consequences of chronodisruption on body weight regulation and metabolism]. / Konsequenzen von Chronodisruption auf Körpergewichtsregulation und Stoffwechsel.

INTRODUCTION: The prevalence of overweight and obesity has increased dramatically. At the same time, lack of sleep has become a part of the modern lifestyle, as well as shift and night work. As a result, chronodisruption, i. e. a change in physiological processes that are controlled by the internal clock, becomes commonplace. Epidemiological data show that too short but also too long sleep are associated with an increased risk of obesity, also seen for night shift work. Overweight and obesity are associated with metabolic syndrome and data likewise report an increased risk by both short and long sleep. It has not yet been conclusively clarified how chronodisruption influences the metabolic risks. Clinical experimental studies report on neuroendocrine and circadian mechanisms and it has been shown that lack of sleep increases the hunger-promoting hormone ghrelin as well as subjective feelings of hunger and increases leptin levels. Lack of sleep also increases hedonic hunger and food-related reward signals. Through preventive measures, chronodisruption and thus, the risk of obesity can be counteracted. The extent to which smartwatches and fitness trackers, which according to the manufacturer can measure and analyze sleep, provide an objective picture of sleep has not been sufficiently investigated. However, smartwatches and fitness trackers can - probably - increase awareness of sleep in the modern society.

Metabolic Effects of Brown Adipose Tissue Activity Due to Cold Exposure in Humans: A Systematic Review and Meta-Analysis of RCTs and Non-RCTs.

Brown adipose tissue (BAT), specialized in thermoregulation in mammals, has been linked to improved glucose and lipid homeostasis when activated by cold exposure (CE). This systematic review and meta-analysis assessed the metabolic effects of CE-induced BAT activation in healthy humans, examining changes in glucose and lipid metabolism compared to thermoneutrality (TN). A literature search was conducted, identifying relevant human studies, including randomized controlled trials (RCTs) and non-RCTs, based on predefined inclusion criteria. Seven studies (a total of 85 participants) fully met the criteria. Data on plasma glucose, insulin, triglycerides (TGs), and free fatty acids (FFAs) were extracted for meta-analysis. When comparing TN and CE under fasting conditions, there were no significant changes in glucose, insulin, or TG concentrations (all p > 0.36). In contrast, CE significantly increased FFA concentrations (p = 0.002; n = 38). Bias was absent for all parameters, but heterogeneity was observed for insulin (I2 = 74.8%). CE primarily affects FFA concentration, likely reflecting cold-induced BAT activity. This suggests that circulating FFAs, serving as the primary fuel for thermogenesis, could indicate BAT activation. However, understanding the effects of BAT activation on overall metabolism requires a broader approach beyond fasting glucose and lipid concentration measurements.

Levodopa Impairs the Energy Metabolism of the Basal Ganglia In Vivo.

OBJECTIVE: One proposed mechanism of disease progression in Parkinson's disease includes the interplay of endogenous dopamine toxicity and mitochondrial dysfunction. However, the in-vivo effects of exogenous dopamine administration on cerebral bioenergetics are unknown. METHODS: We performed a double-blinded, cross-over, placebo-controlled trial. Participants received either 200/50 mg levodopa/benserazide or a placebo and vice versa on the second study visit. Clinical assessments and multimodal neuroimaging were performed, including 31phosphorus magnetic resonance spectroscopy of the basal ganglia and the midbrain. RESULTS: In total, 20 (6 female) patients with Parkinson's disease and 22 sex- and age-matched healthy controls (10 female) were enrolled. Treatment with levodopa/benserazide but not with placebo resulted in a substantial reduction of high-energy phosphorus-containing metabolites in the basal ganglia (patients with Parkinson's disease: -40%; healthy controls: -39%) but not in the midbrain. There were no differences in high-energy phosphorus-containing metabolites for patients with Parkinson's disease compared to healthy controls in the OFF state and treatment response. INTERPRETATION: Exogenously administered levodopa/benserazide strongly interferes with basal ganglia high-energy phosphorus-containing metabolite levels in both groups. The lack of effects on midbrain levels suggests that the observed changes are limited to the site of dopamine action. ANN NEUROL 2024;95:849-857.

Mechanisms and consequences of weight gain after deep brain stimulation of the subthalamic nucleus in patients with Parkinson's disease.

Body weight gain in combination with metabolic alterations has been observed after deep brain stimulation (DBS) of subthalamic nucleus (STN) in patients with Parkinson's disease (PD), which potentially counteracts the positive effects of motor improvement. We aimed to identify stimulation-dependent effects on motor activities, body weight, body composition, energy metabolism, and metabolic blood parameters and to determine if these alterations are associated with the local impact of DBS on different STN parcellations. We assessed 14 PD patients who underwent STN DBS (PD-DBS) before as well as 6- and 12-months post-surgery. For control purposes, 18 PD patients under best medical treatment (PD-CON) and 25 healthy controls (H-CON) were also enrolled. Wrist actigraphy, body composition, hormones, and energy expenditure measurements were applied. Electrode placement in the STN was localized, and the local impact of STN DBS was estimated. We found that STN DBS improved motor function by ~ 40% (DBS ON, Med ON). Weight and fat mass increased by ~ 3 kg and ~ 3% in PD-DBS (all P ≤ 0.005). fT3 (P = 0.001) and insulin levels (P = 0.048) increased solely in PD-DBS, whereas growth hormone levels (P = 0.001), daily physical activity, and VO2 during walking were decreased in PD-DBS (all P ≤ 0.002). DBS of the limbic part of the STN was associated with changes in weight and body composition, sedentary activity, insulin levels (all P ≤ 0.040; all r ≥ 0.56), and inversely related to HOMA-IR (P = 0.033; r = - 0.62). Daily physical activity is decreased after STN DBS, which can contribute to weight gain and an unfavorable metabolic profile. We recommend actigraphy devices to provide feedback on daily activities to achieve pre-defined activity goals.

Late, but Not Early, Night Sleep Loss Compromises Neuroendocrine Appetite Regulation and the Desire for Food.

OBJECTIVE: There is evidence that reduced sleep duration increases hunger, appetite, and food intake, leading to metabolic diseases, such as type 2 diabetes and obesity. However, the impact of sleep timing, irrespective of its duration and on the regulation of hunger and appetite, is less clear. We aimed to evaluate the impact of sleep loss during the late vs. early part of the night on the regulation of hunger, appetite, and desire for food. METHODS: Fifteen normal-weight ([mean ± SEM] body-mass index: 23.3 ± 0.4 kg/m2) healthy men were studied in a randomized, balanced, crossover design, including two conditions of sleep loss, i.e., 4 h sleep during the first night-half ('late-night sleep loss'), 4 h sleep during the second night-half ('early-night sleep loss'), and a control condition with 8h sleep ('regular sleep'), respectively. Feelings of hunger and appetite were assessed through visual analogue scales, and plasma ghrelin and leptin were measured from blood samples taken before, during, and after night-time sleep. RESULTS: Ghrelin and feelings of hunger and appetite, as well as the desire for food, were increased after 'late-night sleep loss', but not 'early-night sleep loss', whereas leptin remained unaffected by the timing of sleep loss. CONCLUSIONS: Our data indicate that timing of sleep restriction modulates the effects of acute sleep loss on ghrelin and appetite regulation in healthy men. 'Late-night sleep loss' might be a risk factor for metabolic diseases, such as obesity and type 2 diabetes. Thereby, our findings highlight the metabolic relevance of chronobiological sleep timing.

When should I run-the role of exercise timing in metabolic health.

The prevalence of type 2 diabetes is reaching epidemic proportions. First line therapy approaches are lifestyle interventions including exercise. Although a vast amount of studies reports on beneficial effects of exercise on metabolism in humans per se, overall data are contradictory which makes it difficult to optimize interventions. Innovative exercise strategies and its underlying mechanism are needed to elucidate in order to close this therapeutic gap. The skeletal muscle produces and secretes myokines and microRNAs in response to exercise and both are discussed as mechanisms linking exercise and metabolic adaptation. Aspects of chronophysiology such as diurnal variation in insulin sensitivity or exercise as a signal to reset dysregulated peripheral clocks are of growing interest in the context of impaired metabolism. Deep insight of how exercise timing determines metabolic adaptations is required to optimize exercise interventions. This review aims to summarize the current state of research on the interaction between timing of exercise and metabolism in humans, providing insights into proposed mechanistic concepts focusing on myokines and microRNAs. First evidence points to an impact of timing of exercise on health outcome, although data are inconclusive. Underlying mechanisms remain elusive. It is currently unknown if the timed release of mykokines depends on time of day when exercise is performed. microRNAs have been found as an important mediator of processes associated with exercise adaptation. Further research is needed to evaluate their full relevance. In conclusion, it seems to be too early to provide concrete recommendations on timing of exercise to maximize beneficial effects.

Sleep deprivation prevents counterregulatory adaptation to recurrent hypoglycaemia.

AIMS/HYPOTHESIS: Attenuated counterregulation after recurrent hypoglycaemia is a major complication of diabetes treatment. As there is previous evidence for the relevance of sleep in metabolic control, we assessed the acute contribution of sleep to the counterregulatory adaptation to recurrent hypoglycaemia. METHODS: Within a balanced crossover design, 15 healthy, normal-weight male participants aged 18-35 years underwent three hyperinsulinaemic-hypoglycaemic clamps with a glucose nadir of 2.5 mmol/l, under two experimental conditions, sleep and sleep deprivation. Participants were exposed to two hypoglycaemic episodes, followed by a third hypoglycaemic clamp after one night of regular 8 h sleep vs sleep deprivation. The counterregulatory response of relevant hormones (glucagon, growth hormone [GH], ACTH, cortisol, adrenaline [epinephrine] and noradrenaline [norepinephrine]) was measured, and autonomic and neuroglycopenic symptoms were assessed. RESULTS: Sleep deprivation compared with sleep dampened the adaptation to recurrent hypoglycaemia for adrenaline (p=0.004), and this pattern also emerged in an overall analysis including adrenaline, GH and glucagon (p=0.064). After regular sleep, the counterregulatory responses of adrenaline (p=0.005), GH (p=0.029) and glucagon (p=0.009) were attenuated during the 3rd clamp compared with the 1st clamp, but were preserved after sleep deprivation (all p>0.225). Neuroglycopenic and autonomic symptoms during the 3rd clamp compared with the 1st clamp were likewise reduced after sleep (p=0.005 and p=0.019, respectively). In sleep deprivation, neuroglycopenic symptoms increased (p=0.014) and autonomic symptoms were unchanged (p=0.859). CONCLUSIONS/INTERPRETATION: The counterregulatory adaptation to recurrent hypoglycaemia is compromised by sleep deprivation between hypoglycaemic episodes, indicating that sleep is essential for the formation of a neurometabolic memory, and may be a potential target of interventions to treat hypoglycaemia unawareness syndrome.

Metabolic Status Modulates Choroidal Thickness - A Possible Early Indicator for Diabetic Eye Complications?

OBJECTIVE: To investigate the impact of metabolic status on choroidal thickness (ChT) in healthy subjects, patients with obesity, and type 2 diabetes. DESIGN AND METHODS: Fasting blood glucose, insulin, insulin-like growth factor-1 (IGF-1), and ChT measured by optical coherence tomography were assessed in healthy normal-weight (n=17), obese participants (n=20), and obese participants with T2D (n=16). RESULTS: ChT increased in obese participants and obese participants with T2D as compared to healthy normal-weight participants (P<0.0001). A negative correlation was observed between IGF1 and ChT (r=-0.268, P=0.050) for all cohorts. Furthermore, body mass index (BMI; R2=0.209; P=0.002; beta=0.388) and model assessment-estimated insulin resistance (HOMA-IR; R2=0.074; P=0.015; beta=0.305) were independent variables of ChT, explaining 20.9 and 7.4% of its variance (both p<0.016), whereas age, sex, and IGF-1 were not significant confounders of ChT (p>0.975). CONCLUSION: ChT is associated with metabolic characteristics, i. e., BMI and HOMA-IR. Due to the key role of choroidal function in retinal physiology, future studies are needed to evaluate whether metabolic traits, ChT, and potential metabolic eye complications are mechanistically linked.

Meal Timing and Macronutrient Composition Modulate Human Metabolism and Reward-Related Drive to Eat.

The 'time-of-day' modifies the metabolic response to meals, but less data exist on the diurnal variations in the hedonic drive to eat. In the present paper, we evaluate the effects of meal timing and macronutrient composition on metabolic responses and the homeostatic vs. hedonic regulation of appetite. In study 1, 84 young, healthy adults completed an online computer-based task assessing the homeostatic and hedonic drive to eat in the morning and evening. In study 2, 24 healthy, young men received 2 identical (850 kcal each) meals in the morning (8:45 h) and evening (18:00 h), of 2 experimental conditions: (i) regular carbohydrate (CH) meals (regular-CH), and (ii) high carbohydrate (high-CH) meals, containing 50 and 80% of energy from CHs, respectively. Serial blood samples were obtained, and the postprandial feelings of hunger, satiety, wanting and liking were assessed. Study 1 revealed a higher hedonic drive to eat in the evening compared to the morning. Study 2 confirmed this diurnal pattern of hedonic appetite regulation and, moreover, showed increased glucose and insulin responses to the evening meal. Postprandial ghrelin and leptin as well as feelings of hunger and satiety were not different between the mealtimes nor between the macronutrient conditions. In line with this, the homeostatic drive to eat was neither affected by the mealtime nor macronutrient composition. Increased the hedonic drive to eat in the evening may represent a vulnerability to palatable food and, thus, energy overconsumption. Together with lower evening glucose tolerance, these findings reflect an adverse metabolic constellation at the end of the day, especially after the ingestion of CH-rich foods.

Acute mild dim light at night slightly modifies sleep but does not affect glucose homeostasis in healthy men.

OBJECTIVE: We evaluated the effect of acute mild light exposure at night on sleep architecture and glucose homeostasis. PATIENTS/METHODS: Twenty healthy normal-weight men took part in two conditions of a randomized, controlled, balanced cross-over experimental study: i) two-consecutive nights with 8-h of sleep under dLAN (<5 lux) or ii) total darkness (CON). Sleep was evaluated by polysomnography. In the morning following 'night2', glucose homeostasis was assessed by an intravenous glucose tolerance test (ivGTT) with consecutive measures of glucose, insulin, and c-peptide. Plasma cortisol was measured at night before sleep, after morning awakening, and during mid-afternoon hours. RESULTS: There was no significant difference in total sleep time, sleep efficiency, and sleep latency between conditions (all p > 0.66). However, NREM sleep stage N3 latency was prolonged after dLAN (p = 0.02) and NREM sleep stage 2 was decreased after two nights with dLAN (p = 0.04). During the first sleep hour, power in slow-oscillations, slow-waves, and delta bands diminished after dLAN (all p < 0.04). Glucose, insulin, and c-peptide were not altered by dLAN (all p > 0.14). Cortisol was reduced in the afternoon after 'night1' and in the morning after 'night2' (both p < 0.03). CONCLUSIONS: dLAN slightly disturbed sleep architecture and quality without impairment of glucose homeostasis. Longer exposure to chronic dLAN might be needed to unmask its hypothesized metabolic consequences.

Eating to dare - Nutrition impacts human risky decision and related brain function.

Macronutrient composition modulates plasma amino acids that are precursors of neurotransmitters and can impact brain function and decisions. Neurotransmitter serotonin has been shown to regulate not only food intake, but also economic decisions. We investigated whether an acute nutrition-manipulation inducing plasma tryptophan fluctuation affects brain function, thereby affecting risky decisions. Breakfasts differing in carbohydrate/protein ratios were offered to test changes in risky decision-making while metabolic and neural dynamics were tracked. We identified that a high-carbohydrate/protein breakfast increased plasma tryptophan/LNAA (large neutral amino acids) ratio which mapped to individual risk propensity changes. The nutrition-manipulation and tryptophan/LNAA fluctuation effects on risk propensity changes were further modulated by individual differences in body fat mass. Using fMRI, we further identified activation in the parietal lobule during risk-processing, of which activities 1) were sensitive to the tryptophan/LNAA fluctuation, 2) were modulated by individual's body fat mass, and 3) predicted the risk propensity changes in decision-making. Our results provide evidence for a personalized nutrition-driven modulation on human risky decision and its metabolic and neural mechanisms.

Evaluation of a near-infrared light ultrasound system as a non-invasive blood glucose monitoring device.

The aim of this study was to evaluate the newly developed non-invasive blood glucose system NIRLUS® (Near-Infra Red Light Ultra Sound; NIRLUS Engineering AG, Lübeck, Germany) under standardized conditions. Seventeen healthy men of normal weight (body mass index 22.4 ± 1.4 kg/m2 ), aged 18 to 45 years, were enrolled in this study. During an intravenous glucose tolerance test, blood glucose profiles were measured simultaneously using the NIRLUS system and a "gold standard" laboratory reference system. Correlation analysis revealed a strong association between NIRLUS and reference values (r = 0.934; P < 0.001). Subsequent Bland-Altman analysis showed a symmetric distribution (r = 0.047; P = 0.395), and 95.5% of the NIRLUS-reference pairs were within the difference (d) of d ± 2 SD. The median deviation of all paired NIRLUS-reference values was 0.5 mmol/L and the mean percent deviation was 11.5%. Error grid analysis showed that 93.6% of NIRLUS-reference pairs are located in the area A, and 6.4% in the area B. No data were allocated in the areas C to E. This proof-of-concept study demonstrates the reproducibility of accurate blood glucose measures obtained by NIRLUS as compared to a gold standard laboratory reference system. The technology of NIRLUS is an important step forward in the development of non-invasive glucose monitoring.

A systematic review of body mass gain after deep brain stimulation of the subthalamic nucleus in patients with Parkinson's disease.

This systematic review investigated the effects of deep brain stimulation of the subthalamic nucleus on extent and time course of body mass changes in patients with Parkinson's disease. A computerized search identified relevant articles using a priori defined inclusion and exclusion criteria. A descriptive analysis was calculated for the main outcome parameters body mass and BMI. Thirty-eight out of 206 studies fulfilled the inclusion criteria (979 patients aged 59.0±7.5 years). Considering the longest follow-up time for each study, body mass and BMI showed a mean increase across studies of +5.71kg (p < .0001; d = 0.64) and +1.8kg/m2 (p < .0001; d = 1.61). The time course of body mass gain revealed a continuous increase ranging from +3.25kg (d = 0.69) at 3 months, +3.88kg (d = 0.21) at 6 months, +6.35kg (d = 0.72) at 12 months, and +6.11kg (d = 1.02) greater than 12 months. Changes in BMI were associated with changes in disease severity (r = 0.502, p = .010) and pharmacological treatment (r = 0.440, p = .0231). Data suggest that body mass gain is one of the most common side effects of deep brain stimulation going beyond normalization of preoperative weight loss. Considering the negative health implications of overweight, we recommend the development of tailored therapies to prevent overweight and associated metabolic disorders following this treatment.

Chronobiological aspects of sleep restriction modulate subsequent spontaneous physical activity.

PURPOSE: First evidence suggests that chronobiological aspects of sleep restriction affect metabolic conditions. Our aim was to investigate whether spontaneous free-living physical activity likewise is affected by chronobiological timing of short sleep. METHODS: In an experimental randomized, balanced cross-over design, eleven healthy, normal-weight (BMI: 23.9 ± 0.4 kg/m2) men were evaluated. Physical activity was assessed by tri-axial wrist actigraphy after (i) four-hour sleep during the first night-half of the night ('late night sleep loss'), (ii) four-hour sleep during the second night-half ('early night sleep loss'), and (iii) eight-hour regular sleep ('regular sleep'), from 7:00 to 24:00 (17 h). Feelings of tiredness and activity were measured by semi-quantitative questionnaires. RESULTS: Physical activity differed between sleep conditions (P < 0.05) with the lowest physical activity after 'late night sleep loss'. Accordingly, less time was spent in high-intensity physical activity after 'late night sleep loss' as compared to the 'early night sleep loss' and 'regular sleep' conditions (both P < 0.05). Perceived feelings of tiredness were higher after both short sleep conditions as compared to 'regular sleep' (both P < 0.05). CONCLUSIONS: Sleep restriction during the second half of the night elicits stronger effects on spontaneous physical activity than sleep restriction during the first half of the night despite identical sleep duration, but the impact of longer period awake needs to be evaluated in further research. In sum, these data indicate that not only short sleep per se but also chronobiological aspects modulate physical activity pattern.

Cardiorespiratory Fitness is Associated with Glycated Hemoglobin and Triglyceride Levels in Severely Obese Men: A Retrospective Clinical Data Analysis.

BACKGROUND: Even subjects with severe obesity show a wide range of metabolic health states, with some showing marked alterations in glucose and lipid metabolism whereas others do not. In severely obese women, we could recently show that the degree of cardiorespiratory fitness is, independently of body mass and age, associated with several markers of glucose and lipid metabolism. AIMS: In our retrospective study on a clinical data set, we questioned whether such an association also exists in severely obese men. METHODS: Cardiorespiratory fitness, i. e. workload (Wpeak) and oxygen uptake (V̇O2,peak) at peak exercise, was assessed by a bicycle spiroergometry in 133 severely obese men (all BMI>35 kg m-2). The following metabolic blood markers were also measured: Fasting serum glucose, insulin, triglycerides (TG), total, low-, high-density cholesterol (Chol, LDL, HDL), uric acid, and whole blood glycated hemoglobin (HbA1c). The Chol/HDL ratio and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) were also calculated. RESULTS: Multiple stepwise linear regression models including age, body mass, and smoking status as independent variables revealed that Wpeak and V̇O2,peak, explained 4.5 to 10.7% of variance in HbA1c and TG (all beta<- 0.22; all p<0.02). Including fat free mass instead of body mass in respective models revealed that both Wpeak and V̇O2,peak were predictors of HbA1c and TG (all beta<- 0.265; all p<0.013), respectively, while Wpeak also accounted for variance in glucose and Chol (both beta<- 0.259; both p<0.023). CONCLUSIONS: Similar to previous observations in women, our data indicate that cardiorespiratory fitness assessed by bicycle ergospirometry test is associated with glucose and lipid metabolism in severely obese men. The strength of the found associations suggest a mild to moderate influence of cardiorespiratory fitness on metabolic health in severe obesity.

The Use of Vitamin K2 in Patients With Parkinson's Disease and Mitochondrial Dysfunction (PD-K2): A Theranostic Pilot Study in a Placebo-Controlled Parallel Group Design.

Background: Despite rapid advances in research on Parkinson's disease (PD), in particular in the elucidation of genetic contributions, no disease-modifying therapy has become available to date. Objectives: In the proposed project, we aim to investigate the potential effects of vitamin K2 (long-chain menaquinone 7, MK-7) in genetically determined PD with mitochondrial dysfunction. Methods: A total of 130 study participants (26 biallelic Parkin/PINK1 mutation carriers, 52 sporadic PD patients, and 52 healthy controls) will receive the trial medication (MK-7 or placebo for 1 week). 31P-Magnetic resonance spectroscopy imaging of the forebrain and basal ganglia (31P-MRSI, primary endpoint) as well as other advanced neuroimaging methods, clinical assessment, including quantitative movement analysis, and biomarker sampling will be applied pre- and post-intervention. Innovation: The proposed project is highly translational as it builds on compelling mechanistic data from animal studies as well as on a small preliminary data set in humans. Patients are selected based on their mutation-related mitochondrial dysfunction and compared to disease and a healthy control group in a personalized medicine approach. We will further investigate how neuroimaging and blood-derived biomarkers can predict individual treatment response in sporadic PD. Clinical trial registration: This study was registered at the German Clinical Trial Registry (DRKS, DRKS00019932) on the 19th of December 2019.

Spiroergometric assessment of cardiorespiratory fitness in subjects with severe obesity: A challenge of reference.

BACKGROUND AND AIMS: Severe obesity is associated with poor physical performance but objective data are scarce. METHODS AND RESULTS: Bicycle spiroergometry data with focus on peak oxygen uptake (V˙O2,peak) and workload (Wpeak) from 476 subjects with severe obesity (BMI ≥ 35.0 kg/m2; 70% women) were analysed. In a first step, V˙O2,peak values were compared with reference values calculated upon different formulas (Wassermann; Riddle). Thereafter, multivariate regression analyses were performed to identify determinants of cardiorespiratory fitness. Cardiorespiratory fitness reference classes for V˙O2,peak and Wpeak were established by stratifying the sample upon identified determinants. Absolute V˙O2,peak (1.87 ± 0.47 vs. 2.40 ± 0.59 l/min) and Wpeak (131 ± 26 vs. 168 ± 44 W) were lower in women than men (both p<0.001). Same pattern was found for relative V˙O2,peak and Wpeak, respectively (both p < 0.05). In women, measured V˙O2,peak was lower than predicted by Wasserman (p < 0.001) but not by Riddle (p = 0.961). In men, V˙O2,peak was lower than calculated by both Wasserman and Riddle formulas (both p ≤ 0.003). Multivariate analyses revealed height and age to be the main determinants of cardiorespiratory fitness in both sexes. Subsequent statistical analyses of calculated reference fitness classes revealed that V˙O2,peak and Wpeak differed between the age- and height-defined groups in both sexes (all p < 0.001). CONCLUSION: Data indicate that the evaluation of cardiorespiratory fitness in subjects with severe obesity is largely biased by selected references values for comparison. Our newly established reference fitness classes upon height and age might be helpful in the clinical context when dealing with obese patients.

Timing Modulates the Effect of Sleep Loss on Glucose Homeostasis.

CONTEXT: Chronobiological factors may modulate the impact of sleep loss on glucose homeostasis. However, these interactions have not been systematically assessed in humans. OBJECTIVE: To assess the effect of sleep loss during the late vs early night on glucose homeostasis. DESIGN: Fifteen normal-weight men participated in three conditions of a randomized, balanced crossover study comprising two conditions with shortened sleep (i.e., 4 hours of sleep during the first or the second half of the night) and a control condition with 8 hours of sleep. Glucose, insulin, cortisol, and glucagon were measured. Insulin sensitivity and secretion were assessed with a Botnia clamp. RESULTS: Compared with regular sleep duration, sleep loss reduced insulin sensitivity (M-value; P = 0.031) irrespective of early- or late-night timing (P = 0.691). The disposition index (i.e., the ß-cell response adjusted for insulin sensitivity) also tended to be impaired by short sleep (P = 0.056) but not by sleep timing (P = 0.543). In contrast, sleep loss in the second half but not the first half of the night induced reductions in morning glucagon and cortisol levels (P < 0.031) followed by a transient increase in cortisol (P < 0.044). CONCLUSIONS: Although sleep deprivation acutely reduced insulin sensitivity irrespective of its nocturnal timing, sleep loss in the early morning compromised α-cell and hypothalamic-pituitary-adrenal axis activity to a greater extent than sleep loss in the first half of the night. This pattern suggests that the timing of sleep restriction can partly potentiate its deleterious metabolic effects.

Sleep Loss Disrupts Morning-to-Evening Differences in Human White Adipose Tissue Transcriptome.

CONTEXT: Chronodisruption, as caused by such conditions as perturbations of 24-hour rhythms of physiology and behavior, may promote the development of metabolic diseases. OBJECTIVE: To assess the acute effects of sleep curtailment on circadian regulation (i.e., morning-to-evening differences) of white adipose tissue (WAT) transcriptome in normal-weight men. DESIGN: Fifteen healthy men aged 18 to 30 years (mean ± SEM, 24.0 ± 0.9years) were studied. In randomized, balanced order they underwent three separate nights with regular sleep duration (8 hours of sleep between 11:00 pm and 7:00 am), sleep restriction (4 hours of sleep between 3:00 am and 7:00 am), and sleep deprivation (no sleep at all). Sleep was polysomnographically evaluated. WAT biopsy samples were taken twice at 9:00 pm and 7:00 am to assess morning-to-evening differences. WAT transcriptome profile was assessed by RNA sequencing, and expression of relevant circadian core clock genes were analyzed. Glucose homeostasis, lipid profile, and adipokines were assessed. RESULTS: Sleep restriction dramatically blunted morning-to-evening transcriptome variations with further dampening after sleep deprivation. Although most core clock genes remained stably rhythmic, morning-to-evening regulated pathways of carbohydrate and lipid metabolism were highly sensitive to sleep loss. In particular, genes associated with carbohydrate breakdown lost rhythmicity after sleep deprivation, with an overall trend toward an upregulation in the morning. In line with specific transcriptional changes in WAT, retinol-binding-protein 4 was increased and ß-cell secretory capacity was diminished. CONCLUSIONS: Acute sleep loss induces a profound restructuring of morning-to-evening WAT transcriptome with uncoupling from the local clock machinery, resulting in increased WAT carbohydrate turnover and impaired glucose homeostasis. Our data support an optimization of sleep duration and timing to prevent metabolic disorders such as obesity and type 2 diabetes.