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Growing evidence supports that pharmacological application of growth differentiation factor 15 (GDF15) suppresses appetite but also promotes sickness-like behaviors in rodents via GDNF family receptor α-like (GFRAL)-dependent mechanisms. Conversely, the endogenous regulation of GDF15 and its physiological effects on energy homeostasis and behavior remain elusive. Here we show, in four independent human studies that prolonged endurance exercise increases circulating GDF15 to levels otherwise only observed in pathophysiological conditions. This exercise-induced increase can be recapitulated in mice and is accompanied by increased Gdf15 expression in the liver, skeletal muscle, and heart muscle. However, whereas pharmacological GDF15 inhibits appetite and suppresses voluntary running activity via GFRAL, the physiological induction of GDF15 by exercise does not. In summary, exercise-induced circulating GDF15 correlates with the duration of endurance exercise. Yet, higher GDF15 levels after exercise are not sufficient to evoke canonical pharmacological GDF15 effects on appetite or responsible for diminishing exercise motivation., The physiological role of GDF15 remains poorly defined. Here, the authors show that circulating GDF15 increases in response to prolonged exercise, but that this exercise-induced GDF15, unlike pharmacological GDF15, does not affect post-exercise food intake or exercise motivation.

The aim of this parallel-group, double-blinded (study personnel and participants), randomised clinical trial was to assess the interaction between metformin and exercise training on postprandial glucose in glucose-intolerant individuals. Glucose-intolerant (2 h OGTT glucose of 7.8–11.0 mmol/l and/or HbA1c of 39–47 mmol/mol [5.7–6.5%] or glucose-lowering-medication naive type 2 diabetes), overweight/obese (BMI 25–42 kg/m2) individuals were randomly allocated to a placebo study group (PLA, n = 15) or a metformin study group (MET, n = 14), and underwent 3 experimental days: BASELINE (before randomisation), MEDICATION (after 3 weeks of metformin [2 g/day] or placebo treatment) and TRAINING (after 12 weeks of exercise training in combination with metformin/placebo treatment). Training consisted of supervised bicycle interval sessions with a mean intensity of 64% of Wattmax for 45 min, 4 times/week. The primary outcome was postprandial glucose (mean glucose concentration) during a mixed meal tolerance test (MMTT), which was assessed on each experimental day. For within-group differences, a group × time interaction was assessed using two-way repeated measures ANOVA. Between-group changes of the outcomes at different timepoints were compared using unpaired two-tailed Student’s t tests. Postprandial glucose improved from BASELINE to TRAINING in both the PLA group and the MET group (∆PLA: −0.7 [95% CI −1.4, 0.0] mmol/l, p = 0.05 and ∆MET: −0.7 [−1.5, −0.0] mmol/l, p = 0.03), with no between-group difference (p = 0.92). In PLA, the entire reduction was seen from MEDICATION to TRAINING (−0.8 [−1.3, −0.1] mmol/l, p = 0.01). Conversely, in MET, the entire reduction was observed from BASELINE to MEDICATION (−0.9 [−1.6, −0.2] mmol/l, p = 0.01). The reductions in mean glucose concentration during the MMTT from BASELINE to TRAINING were dependent on differential time effects: in the PLA group, a decrease was observed at timepoint (t) = 120 min (p = 0.009), whereas in the MET group, a reduction occurred at t = 30 min (p

Acute and adaptive changes in systemic markers of oxidatively generated nucleic acid modifications (i.e., 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo)) as well as inflammatory cytokines (i.e., C-reactive protein, interleukin-6, interleukin-10, and tumour necrosis factor alpha), a liver hormone (i.e., fibroblast growth factor 21 (FGF21)), and bone metabolism markers (sclerostin, osteocalcin, C-terminal telopeptide, and N-terminal propeptide of type 1 procollagen) were investigated following a marathon in 20 study participants. Immediate changes were observed in inflammatory cytokines, FGF21, and bone metabolism markers following the marathon. In contrast, no immediate changes in urinary excretion of 8-oxodG and 8-oxoGuo were evident. Four days after the marathon, decreased urinary excretion of 8-oxodG (-2.9 (95% CI -4.8;-1.1) nmol/24 h,8-oxodG: 8-oxo-7,8-dihydro-2'-deoxyguanosine; 8-oxoGuo: 8-oxo-7,8-dihydroguanosine; CI: confidence interval; CTX: C-terminal telopeptide of type 1 collagen; DXA: dual-energy X-ray absorptiometry; ELISA: enzyme-linked immunosorbent assay; FGF21: Fibroblast growth factor 21; h: hour; hsCRP: high sensitivity C-reactive protein; IL: interleukin; IQR: interquartile range; MS: mass spectrometry: P1NP: N-terminal propeptide of type 1 procollagen; TNFα: tumour necrosis factor alpha; UPLC: ultra-performance liquid chromatography.

Metformin and exercise both improve glycemic control, but in vitro studies have indicated that an interaction between metformin and exercise occurs in skeletal muscle, suggesting a blunting effect of metformin on exercise training adaptations. Two studies (a double-blind, parallel-group, randomized clinical trial conducted in 29 glucose-intolerant individuals and a double-blind, cross-over trial conducted in 15 healthy lean males) were included in this paper. In both studies, the effect of acute exercise ± metformin treatment on different skeletal muscle variables, previously suggested to be involved in a pharmaco-physiological interaction between metformin and exercise, was assessed. Furthermore, in the parallel-group trial, the effect of 12 weeks of exercise training was assessed. Skeletal muscle biopsies were obtained before and after acute exercise and 12 weeks of exercise training, and mitochondrial respiration, oxidative stress and AMPK activation was determined. Metformin did not significantly affect the effects of acute exercise or exercise training on mitochondrial respiration, oxidative stress or AMPK activation, indicating that the response to acute exercise and exercise training adaptations in skeletal muscle is not affected by metformin treatment. Further studies are needed to investigate whether an interaction between metformin and exercise is present in other tissues, e.g., the gut. Trial registration: ClinicalTrials.gov (NCT03316690 and NCT02951260). Novelty: Metformin does not affect exercise-induced alterations in mitochondrial respiratory capacity in human skeletal muscle. Metformin does not affect exercise-induced alterations in systemic levels of oxidative stress nor emission of reactive oxygen species from human skeletal muscle. Metformin does not affect exercise-induced AMPK activation in human skeletal muscle.

Human obesity is associated with decreased circulating adiponectin and elevated leptin levels. In vitro experiments and studies in high fat diet (HFD)-fed mice suggest that interleukin-6 (IL-6) may regulate adiponectin and leptin release from white adipose tissue (WAT). Herein, we aimed to investigate whether IL-6 receptor blockade affects the levels of circulating adiponectin and leptin in obese human individuals. To this end, serum samples collected during a multicenter, double-blind clinical trial were analyzed. In the latter study, obese human subjects with or without type 2 diabetes were randomly assigned to recurrent placebo or intravenous tocilizumab (an IL-6 receptor antibody) administration during a 12-week exercise training intervention. Twelve weeks of tocilizumab administration (in combination with exercise training) trend wise enhanced the decrease in circulating leptin levels (−2.7 ± 8.2% in the placebo vs. −20.6 ± 5.6% in tocilizumab, p = 0.08) and significantly enhanced the increase in circulating adiponectin (3.4 ± 3.7% in the placebo vs. 27.0 ± 6.6% in tocilizumab, p = 0.01). In addition, circulating adiponectin levels were negatively correlated with the homeostatic model assessment of insulin resistance (HOMA-IR), indicating that increased adiponectin levels positively affect insulin sensitivity in people with obesity. In conclusion, IL-6 receptor blockade increases circulating adiponectin levels in people with obesity.

Aim: Patients with Type 2 Diabetes Mellitus (T2DM) have increased risk of developing vascular complications due to chronic hyperglycemia. Glycemic variability (GV) has been suggested to play an even more important role in the risk of developing diabetic complications than sustained hyperglycemia. Physical activity (PA) has shown reducing effects on mean plasma glucose; however, the effect on GV in T2DM needs further description. The objective of this review is to evaluate the effect of PA on GV, assessed by continuous glucose monitoring (CGM) in people with T2DM. Methods: A systematic literature search was conducted on MEDLINE and Embase to find randomized controlled trials (RCTs) covering the aspects T2DM, PA, and CGM. Following eligibility screening, variables of population characteristics, PA interventions, and GV outcomes were extracted and processed through qualitative synthesis. Risk of bias (ROB) was assessed using Cochrane ROB tool v2.0. Results: Of 1,825 identified articles, 40 full texts were screened. In the ten included RCTs matching the eligibility criteria, sample sizes ranged from nine to 63, mean age from 51 (SD 11) to 65 (SD 2) years and mean T2DM duration from four (SD 3) to ten (SD 6) years. Eight RCTs examined GV following single bouts of exercise, while two RCTs examined GV following training interventions. One RCT applied parallel group design, while nine RCTs applied crossover design. Numeric reductions in GV following acute exercise were seen, with four RCTs reaching statistical significance. Numeric reductions in GV were seen following training interventions, with one RCT reaching statistical significance. Numeric reductions of GV after PA appeared independently of intensity and T2DM progression but higher in participants with high baseline HbA1c and GV than with low. 80% of the trials were evaluated as uncertain/high ROB. Conclusion: The systematic literature search revealed limited and biased evidence showing that acute PA numerically reduced GV in patients with T2DM. PA reduced GV independently of PA intensity and T2DM progression. Prolonged RCTs with low ROB are needed to confirm reducing effects of PA on GV and to assess the influence of patient- and intervention characteristics on the effect of PA on GV.

Context Interleukin 6 (IL-6) contributes to bone remodeling in preclinical studies. Clinical trials investigating the role of IL-6 in bone remodeling are limited. Objective To investigate if IL-6 regulates bone remodeling in humans. Design Plasma concentrations of the bone resorption marker carboxy-terminal type I collagen crosslinks (CTX) and of the bone formation marker procollagen type 1 N-terminal propeptide (P1NP) were measured during a mixed-meal tolerance test (MMTT) in 3 placebo-controlled human studies. Participants Five healthy individuals participated in study 1; 52 obese individuals, in study 2; and 10 healthy individuals, in study 3. Interventions Study 1 was a single-blinded crossover study consisting of a 1-h infusion of saline (placebo) or the IL-6 receptor antibody tocilizumab followed by an exercise bout. Study 2 was a randomized, double-blinded 12-week exercise training intervention study. Participants received infusions of saline or tocilizumab. Study 3 was a randomized, double-blinded, crossover study consisting of 30 min infusion of saline or IL-6. Main outcomes measures Effect of IL-6 on CTX levels. Results CTX was significantly (P < 0.01) decreased during MMTTs in all 3 studies. Treatment with tocilizumab did not affect exercise or meal induced changes in plasma CTX or P1NP concentrations acutely (study 1) or after a 12-week treatment period (study 2). Exogenous IL-6 had no effect on CTX or P1NP plasma concentrations (study 3). Conclusions IL-6 may not regulate bone remodeling in humans.

IL-6 is a cytokine with various effects on metabolism. In mice, IL-6 improved beta cell function and glucose homeostasis via upregulation of glucagon-like peptide 1 (GLP-1), and IL-6 release from muscle during exercise potentiated this beneficial increase in GLP-1. This study aimed to identify whether exercise-induced IL-6 has a similar effect in humans. In a multicentre, double-blind clinical trial, we randomly assigned patients with type 2 diabetes or obesity to intravenous tocilizumab (an IL-6 receptor antagonist) 8 mg/kg every 4 weeks, oral sitagliptin (a dipeptidyl peptidase-4 inhibitor) 100 mg daily or double placebos (a placebo saline infusion every 4 weeks and a placebo pill once daily) during a 12 week training intervention. The primary endpoints were the difference in change of active GLP-1 response to an acute exercise bout and change in the AUC for the concentration–time curve of active GLP-1 during mixed meal tolerance tests at baseline and after the training intervention. Nineteen patients were allocated to tocilizumab, 17 to sitagliptin and 16 to placebos. During the acute exercise bout active GLP-1 levels were 26% lower with tocilizumab (multiplicative effect: 0.74 [95% CI 0.56, 0.98], p = 0.034) and 53% higher with sitagliptin (1.53 [1.15, 2.03], p = 0.004) compared with placebo. After the 12 week training intervention, the active GLP-1 AUC with sitagliptin was about twofold that with placebo (2.03 [1.56, 2.62]; p

Bed rest and physical inactivity are the consequences of hospital admission for many patients. Physical inactivity induces changes in glucose metabolism, but its effect on the incretin effect, which is reduced in, e.g., Type 2 diabetes, is unknown. To investigate how 8 days of strict bed rest affects the incretin effect, 10 healthy nonobese male volunteers underwent 8 days of strict bed rest. Before and after the intervention, all volunteers underwent an oral glucose tolerance test (OGTT) followed by an intravenous glucose infusion (IVGI) on the following day to mimic the blood glucose profile from the OGTT. Blood glucose, serum insulin, serum C-peptide, plasma incretin hormones [glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic peptide (GIP)], and serum glucagon were measured serially during both the OGTT and the IVGI. The incretin effect is calculated as the relative difference between the area under the curve for the insulin response during the OGTT and that of the corresponding IVGI, respectively. Concentrations of glucose, insulin, C-peptide, and GIP measured during the OGTT were higher after the bed rest intervention (all P < 0.05), whereas there was no difference in the levels of GLP-1 and Glucagon. Bed rest led to a mean loss of 2.4 kg of fat-free mass, and induced insulin resistance evaluated by the Matsuda index, but did not affect the incretin effect ( P = 0.6). In conclusion, 8 days of bed rest induces insulin resistance, but we did not see evidence of an associated change in the incretin effect.

Summary Gastric emptying is a critical regulator of postprandial glucose and delayed gastric emptying is an important mechanism of improved glycemic control achieved by short-acting glucagon-like peptide-1 (GLP-1) analogs in clinical practice. Here we report on a novel regulatory mechanism of gastric emptying in humans. We show that increasing interleukin (IL)-6 concentrations delays gastric emptying leading to reduced postprandial glycemia. IL-6 furthermore reduces insulin secretion in a GLP-1-dependent manner while effects on gastric emptying are GLP-1 independent. Inhibitory effects of IL-6 on gastric emptying were confirmed following exercise-induced increases in IL-6. Importantly, gastric- and insulin-reducing effects were maintained in individuals with type 2 diabetes. These data have clinical implications with respect to the use of IL-6 inhibition in autoimmune/inflammatory disease, and identify a novel target that could be exploited pharmacologically to delay gastric emptying and spare insulin, which may be beneficial for the beta cell in type 2 diabetes.

Physical activity and alternate-day fasting/caloric restriction may both ameliorate aspects of the metabolic syndrome, such as insulin resistance, visceral fat mass accumulation, and cognitive impairment by overlapping mechanisms. The purpose of this study was to test the hypothesis that alternate-day caloric restriction (ADCR) with overall energy balance would reduce insulin resistance and accumulation of visceral fat, in addition to improving cognitive functions, after 8 consecutive days in bed. Healthy, lean men ( n = 20) were randomized to 1) 8 days of bed rest with three daily isoenergetic meals (control group, n = 10); and 2) 8 days of bed rest with 25% of total energy requirements every other day and 175% of total energy requirements every other day (ADCR group). Oral glucose tolerance testing, dual-energy X-ray absorptiometry (DXA) scans, magnetic resonance imaging of the abdomen and brain, V̇o2max, and tests for cognitive function were performed before and after bed rest. In addition, daily fasting blood samples and 24-h glucose profiles by continuous glucose monitoring system were assessed during the 8 days of bed rest period. Bed rest induced insulin resistance, visceral fat accumulation, and worsening of mood. No positive effects emerged from ADCR on these negative health outcomes. Compared with the control group, ADCR was associated with improved and steadier glycemic control on fasting days and higher glycemic fluctuation and indexes of insulin resistance on overeating days. In contrast to our hypothesis, the metabolic impairment induced by 8 days of bed rest was not counteracted by ADCR with overall energy balance. NEW & NOTEWORTHY Alternate-day caloric restriction without overall energy reduction does not ameliorate the metabolic impairment induced in lean men by 8 days of bed rest.

Introduction The relationship between oxidative stress and physical activity is very complex. A single bout of exercise seems to induce oxidative stress, whereas regular exercise has been suggested to reduce oxidative stress. Here, we investigated the changes in oxidative RNA and DNA modifications in the week following a single bout of excessive exercise. Methods This observational study was conducted in relation to the Copenhagen Marathon 2018, Denmark. Male, non-professional runners (n=20) were examined before-, immediate after-, four days after-, and seven days after the marathon. Twenty-four-hour (24h) urine excretion of 8-oxo-7,8-dihydro-guanosine(8-oxoGuo) and 8-oxo-7,8-dihydro-2’-deoxyguanosine(8-oxodG) were determined using ultra performance liquid chromatography-tandem mass spectrometry as a measurement of oxidative RNA and DNA modifications, respectively. Results The runners were healthy, non-smokers with cardiorespiratory fitness level above average ((median (inter quartile range(IQR))): Age: 29.6(24.3;37.2) years, body mass index: 24.3(23.8;25.2) kg/m2, VO2max: 52.7(49.5;55.7) ml/min/kg). The baseline level of 8-oxoGuo and 8-oxodG were (median(IQR)): 33.9(29.2; 38.1) and 27.9(21.4; 30.8) nmol/24h, respectively. The level of 8-oxoGuo presented a marginal trend towards increase immediate after the marathon compared to baseline (Δmedian(IQR): 3.9 (-2.4;8.7) nmol/24h, P=0.12), no difference was found in 8-oxodG (-1.8(-4.3;2.6) nmol/24h, P=0.62). On day four, we observed a decrease in both 8-oxoGuo (-2.1(-8.4;0.1) nmol/24h, P=0.02) and 8-oxodG (-2.5(-4.0;0.1) nmol/24h, P Conclusion A single bout of strenuous exercise did not result in immediate increase in oxidative RNA and DNA modifications, however a marginal trend toward increased level of oxidative RNA modifications was observed. Both oxidative RNA and DNA modifications decreased four days after the marathon. The clinical implications of these results remain to be elucidated.

Admission to the hospital, and particularly to the intensive care unit, leads to a dramatic reduction in physical activity level, which alters the glucose metabolism towards a pre-diabetic state [1]. Critically ill patients often develop spontaneous hyperglycemia, which is related to an increase in morbidity and mortality [2, 3]. The incretin hormones glucagon-like peptide (GLP)-1 and gastric inhibitory polypeptide (GIP) are secreted from the gut in response to a glucose load and stimulate up to 70 % of the insulin secretion from the pancreatic beta cell in healthy persons, which is named the incretin effect [4]. The incretin effect is reduced in critically ill patients [5], but the underlying mechanism has not yet been determined.