Explore the vast range of titles available.

Type 2 diabetes mellitus (T2DM) is associated with metabolic dysregulation and chronic inflammation, and regular exercise may provide a strong stimulus for improving both. In this review, we first discuss the link between inflammation and metabolism. Next, we give an update on the clinical metabolic effects of exercise in T2DM patients with special focus on which parameters to consider for optimizing metabolic improvements. We then discuss the mechanisms whereby exercise exerts its anti‐inflammatory and related metabolic effects. Evidence exists that interleukin (IL)‐1β is involved in pancreatic β‐cell damage, whereas tumor necrosis factor (TNF)‐α appears to be a key molecule in peripheral insulin resistance. Mechanistic studies in humans suggest that moderate acute elevations in IL‐6, as provoked by exercise, exert direct anti‐inflammatory effects by an inhibition of TNF‐α and by stimulating IL‐1ra (IL‐1 receptor antagonist), thereby limiting IL‐1β signaling. In addition, IL‐6 has direct impact on glucose and lipid metabolism. Moreover, indirect anti‐inflammatory effects of exercise may be mediated via improvements in, for example, body composition. While waiting for the outcome of long‐term randomized clinical training studies with hard end points, it should be emphasized that physical activity represents a natural strong anti‐inflammatory and metabolism‐improving strategy with minor side effects. The February 2016 issue contains a Special Feature on the Effects of exercise on the immune system and metabolism coming into the Olympic year. The role of the immune system in exercise is complex and challenging. Too little exercise can depress the immune system. In contrast, too much exercise can also lead to a compromised immune system. This is a challenge that athletes face as they prepare for competition. Immunology & Cell Biology thanks the coordinators of this Special Feature ‐ Mark Febbraio and Graeme Lancaster ‐ for their planning and input.

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.

As of April, 2023, 23 accelerated approvals for cancer indications granted by the US Food and Drug Administration (FDA) since 1992 have been withdrawn from the US market, with 17 (74%) of 23 withdrawn in the past 3 years. The marketing authorisation status of these indications in the EU has not been reported. A review of relevant documents from the FDA and the European Medicines Agency (EMA) was done to investigate whether the accelerated approvals for cancer indications withdrawn by the FDA have a marketing authorisation in the EU to date, and to compare the approval history of these indications by the EMA and FDA. We found that, as of April 20, 2023, nine (39%) of 23 withdrawn accelerated approvals for cancer indications in the USA have a marketing authorisation in the EU for a similar indication. By comparison, only two conditional marketing authorisations for cancer indications have been withdrawn from the EU; both are no longer approved in the USA. These findings indicate a discrepancy in the approval policies between the FDA and EMA and imply either that some patient groups in the USA do not get access to relevant medical treatment, or that some patient groups in the EU are treated with medicine without a positive benefit–risk balance. These discrepancies could potentially be reduced by increased collaboration and information sharing between the two agencies.

Aims/hypothesisIL-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.MethodsIn 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.ResultsNineteen 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 < 0.001), while GLP-1 AUC values showed a small non-significant decrease of 13% at 4 weeks after the last tocilizumab infusion (0.87 [0.67, 1.12]; p = 0.261).Conclusions/interpretationIL-6 is implicated in the regulation of GLP-1 in humans. IL-6 receptor blockade lowered active GLP-1 levels in response to a meal and an acute exercise bout in a reversible manner, without lasting effects beyond IL-6 receptor blockade.Trial registrationClinicaltrials.gov NCT01073826.FundingDanish National Research Foundation. Danish Council for Independent Research. Novo Nordisk Foundation. Danish Centre for Strategic Research in Type 2 Diabetes. European Foundation for the Study of Diabetes. Swiss National Research Foundation.

Aims/hypothesisWe aimed to investigate the short-term efficacy and safety of three glucose-lowering interventions in overweight or obese individuals with prediabetes defined by HbA1c.MethodsThe PRE-D Trial was a randomised, controlled, parallel, multi-arm, open-label, non-blinded trial performed at Steno Diabetes Center Copenhagen, Gentofte, Denmark. One hundred and twenty participants with BMI ≥25 kg/m2, 30–70 years of age, and prediabetes (HbA1c 39–47 mmol/mol [5.7–6.4%]) were randomised 1:1:1:1 to dapagliflozin (10 mg once daily), metformin (1700 mg daily), interval-based exercise (5 days/week, 30 min/session) or control (habitual lifestyle). Participants were examined at baseline and at 6, 13 and 26 weeks after randomisation. The primary outcome was the 13 week change in glycaemic variability (calculated as mean amplitude of glycaemic excursions [MAGE]) determined using a continuous glucose monitoring system (pre-specified minimal clinically important difference in MAGE ∼30%).ResultsOne hundred and twelve participants attended the examination at 13 weeks and 111 attended the follow-up visit at 26 weeks. Compared with the control group, there was a small decrease in MAGE in the dapagliflozin group (17.1% [95% CI 0.7, 30.8], p = 0.042) and a small, non-significant, reduction in the exercise group (15.3% [95% CI −1.2, 29.1], p = 0.067), whereas MAGE was unchanged in the metformin group (0.1% [95% CI −16.1, 19.4], p = 0.991)). Compared with the metformin group, MAGE was 17.2% (95% CI 0.8, 30.9; p = 0.041) lower in the dapagliflozin group and 15.4% (95% CI −1.1, 29.1; p = 0.065) lower in the exercise group after 13 weeks, with no difference between exercise and dapagliflozin (2.2% [95% CI −14.8, 22.5], p = 0.815). One serious adverse event occurred in the control group (lung cancer).Conclusions/interpretationTreatment with dapagliflozin and interval-based exercise lead to similar but small improvements in glycaemic variability compared with control and metformin therapy. The clinical importance of these findings in prediabetes is uncertain.Trial registrationClinicalTrials.gov NCT02695810FundingThe study was funded by the Novo Nordisk Foundation, AstraZeneca AB, the Danish Innovation Foundation, the University of Copenhagen and Ascensia Diabetes Care Denmark ApS

Introduction Behavioural and psychological symptoms of dementia (BPSD) should only rarely and briefly be treated with antipsychotics. Despite recommendations to the contrary, the use of antipsychotics in nursing home residents with dementia is widespread and followed by serious adverse effects. Intervention studies on methods to reduce the use of antipsychotics in persons with dementia are few and needed. The aim of this protocol is to describe the rationale and content of the intervention DEprescribing and Care to reduce Antipsychotics in DEmentia (DECADE)-a hybrid effectiveness-implementation pilot study. Materials and methods This is a protocol of a prospective hybrid effectiveness-implementation pilot study. The primary aim of DECADE is to reduce the use of antipsychotic drugs by 50% in 50% of nursing home residents with dementia while maintaining or improving BPSD. The intervention is implemented in six nursing homes including approximately 190 residents with dementia and consists of Academic Detailing, medication review, education of nursing home staff, and care plans. The evaluation of feasibility and potential effectiveness is an overall assessment of all clinical and process outcomes. Logistic regression analyses will be used to investigate factors characterizing situations with prescription of antipsychotics. BPSD is analysed with a before- and after design using self-controlled case series methods and the use of antipsychotics is analysed as interrupted time series. Discussion This protocol describes a study that will provide an indication of DECADE effectiveness and a model for upscaling and further evaluation in a controlled design.

Aims/hypothesisThe aim was to investigate whether an intensive lifestyle intervention, with high volumes of exercise, improves beta cell function and to explore the role of low-grade inflammation and body weight.MethodsThis was a randomised, assessor-blinded, controlled trial. Ninety-eight individuals with type 2 diabetes (duration <10 years), BMI of 25–40 kg/m2, no use of insulin and taking fewer than three glucose-lowering medications were randomised (2:1) to either the standard care plus intensive lifestyle group or the standard care alone group. Standard care consisted of individual guidance on disease management, lifestyle advice and blinded regulation of medication following a pre-specified algorithm. The intensive lifestyle intervention consisted of aerobic exercise sessions that took place 5–6 times per week, combined with resistance exercise sessions 2–3 times per week, with a concomitant dietary intervention aiming for a BMI of 25 kg/m2. In this secondary analysis beta cell function was assessed from the 2 h OGTT-derived disposition index, which is defined as the product of the Matsuda and the insulinogenic indices.ResultsAt baseline, individuals were 54.8 years (SD 8.9), 47% women, type 2 diabetes duration 5 years (IQR 3–8) and HbA1c was 49.3 mmol/mol (SD 9.2); 6.7% (SD 0.8). The intensive lifestyle group showed 40% greater improvement in the disposition index compared with the standard care group (ratio of geometric mean change [RGM] 1.40 [95% CI 1.01, 1.94]) from baseline to 12 months’ follow-up. Plasma concentration of IL-1 receptor antagonist (IL-1ra) decreased 30% more in the intensive lifestyle group compared with the standard care group (RGM 0.70 [95% CI 0.58, 0.85]). Statistical single mediation analysis estimated that the intervention effect on the change in IL-1ra and the change in body weight explained to a similar extent (59%) the variance in the intervention effect on the disposition index.Conclusions/interpretationOur findings show that incorporating an intensive lifestyle intervention, with high volumes of exercise, in individuals with type 2 diabetes has the potential to improve beta cell function, associated with a decrease in low-grade inflammation and/or body weight.Trial registrationClinicalTrials.gov NCT02417012

Aims/hypothesisThe 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.MethodsGlucose-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.ResultsPostprandial 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 < 0.001). V̇O2peak increased 15% (4.6 [3.3, 5.9] ml kg−1 min−1, p < 0.0001) from MEDICATION to TRAINING and body weight decreased (−4.0 [−5.2, −2.7] kg, p < 0.0001) from BASELINE to TRAINING, with no between-group differences (p = 0.7 and p = 0.5, respectively).Conclusions/interpretationMetformin plus exercise training was not superior to exercise training alone in improving postprandial glucose. The differential time effects during the MMTT suggest an interaction between the two modalities.FundingThe Beckett foundation, A.P Møller Foundation, DDA, the Research Foundation of Rigshospitalet and Trygfonden.Trial registrationClinicalTrials.gov (NCT03316690).

The objective was to investigate the feasibility and usability of electronic momentary assessment, goal-setting and personalized phone-calls on adherence to a 12-week self-conducted interval walking training (IWT) program, delivered by the InterWalk smartphone among patients with type 2 diabetes (T2D). In a two-arm pilot randomized controlled trial (Denmark, March 2014 to February 2015), patients with T2D (18-80 years with a Body Mass Index of 18 and 40 kg/m2) were randomly allocated to 12 weeks of IWT with (experimental) or without additional support (control). The primary outcome was the difference between groups in accumulated time of interval walking training across 12 weeks. All patients were encouraged to use the InterWalk application to perform IWT for ≥90 minute/week. Patients in the experimental group made individual goals regarding lifestyle change. Once a week inquiries about exercise adherence was made using an ecological momentary assessment (EMA). In case of consistent self-reported non-adherence, the patients would receive a phone-call inquiring about the reason for non-adherence. The control group did not receive additional support. Information about training adherence was assessed objectively. Usability of the EMA was assessed based on response rates and self-reported satisfaction after 12-weeks. Thirty-seven patients with T2D (66 years, 65% female, hemoglobin 1Ac 50.3 mmol/mol) where included (n = 18 and n = 19 in experimental and control group, respectively). The retention rate was 83%. The experimental group accumulated [95%CI] 345 [-7, 698] minutes of IWT more than the control group. The response rate for the text-messages was 83% (68% for males and 90% for females). Forty-one percent of the experimental and 25% of the control group were very satisfied with their participation. The combination inquiry about adherence using EMA, goal-setting with the possibility of follow-up phone calls are considered feasible interventions to attain training adherence when using the InterWalk app during a 12-week period in patients with T2D. Some uncertainty about the effect size of adherence remains. Clinicaltrials.gov NCT02089477.

Exercise increases blood and lymph flow in working muscles, potentially affecting the bioavailability and effect of subcutaneously administered drugs. The aim of this study was to assess the influence of a single exercise session on pharmacokinetics and pharmacodynamics of a single dose of subcutaneously administered unfractionated heparin. In a crossover design, 15 healthy males underwent four experimental days where 15,000 IU of unfractionated heparin was injected subcutaneously into the thigh of the non‐dominant leg. Following the injection, one of four interventions was performed in randomized order on four separate occasions, each lasting 1 h: (1) no exercise, (2) double‐legged exercise, (3) single‐legged exercise with the non‐dominant leg (where heparin was injected), and (4) single‐legged exercise with the dominant leg. Blood was sampled during and after the interventions and analyzed for activated partial thromboplastin time (aPTT) and plasma heparin via an anti‐factor Xa assay. The primary endpoint (maximum aPTT minus baseline aPTT) showed no statistically significant differences between interventions, nor did maximum minus baseline plasma heparin activities. However, after 1 h, change in aPTT was greater, following double‐legged exercise compared with no exercise (mean difference 3.5 s, 95% CI 0.8–6.2) and greater after single‐legged exercise with the non‐dominant leg compared with the dominant (9.7 s, 3.9–15.5). Similar results were observed for plasma heparin activities. In conclusion, exercise does not affect the overall pharmacokinetics and pharmacodynamics of unfractionated heparin but tends to accelerate absorption and hence effect. The study thus underscores that physical exercise affects temporal uptake of subcutaneously administered therapy.