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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.

Helga Ellingsgaard et al . show that secretion of interleukin-6 by muscle in response to exercise, or injection of recombinant protein, increases the expression of the incretin GLP-1 by both intestinal cells and by pancreatic alpha cells, thus potentiating insulin release and improving glycemic control. These results identify a new endocrine loop linking energy demands to homeostatic control while also suggesting further targets for type 2 diabetes therapy. Exercise, obesity and type 2 diabetes are associated with elevated plasma concentrations of interleukin-6 (IL-6). Glucagon-like peptide-1 (GLP-1) is a hormone that induces insulin secretion. Here we show that administration of IL-6 or elevated IL-6 concentrations in response to exercise stimulate GLP-1 secretion from intestinal L cells and pancreatic alpha cells, improving insulin secretion and glycemia. IL-6 increased GLP-1 production from alpha cells through increased proglucagon (which is encoded by GCG ) and prohormone convertase 1/3 expression. In models of type 2 diabetes, the beneficial effects of IL-6 were maintained, and IL-6 neutralization resulted in further elevation of glycemia and reduced pancreatic GLP-1. Hence, IL-6 mediates crosstalk between insulin-sensitive tissues, intestinal L cells and pancreatic islets to adapt to changes in insulin demand. This previously unidentified endocrine loop implicates IL-6 in the regulation of insulin secretion and suggests that drugs modulating this loop may be useful in type 2 diabetes.

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).

Increased Number of Islet-Associated Macrophages in Type 2 Diabetes Jan A. Ehses 1 , Aurel Perren 2 , Elisabeth Eppler 3 , Pascale Ribaux 4 , John A. Pospisilik 5 , Ranit Maor-Cahn 1 , Xavier Gueripel 2 , Helga Ellingsgaard 1 , Marten K.J. Schneider 6 , Gregoire Biollaz 7 , Adriano Fontana 7 , Manfred Reinecke 3 , Francoise Homo-Delarche 8 and Marc Y. Donath 1 1 Division of Endocrinology and Diabetes and Center for Integrated Human Physiology, University Hospital of Zürich, Zürich, Switzerland 2 Department of Pathology, University Hospital of Zürich, Zürich, Switzerland 3 Division of Neuroendocrinology, Institute of Anatomy, University of Zürich, Zürich, Switzerland 4 Department of Genetic Medicine and Development, University Medical Center, Geneva, Switzerland 5 Institute of Molecular Biotechnology, Austrian Academy of Science, Vienna, Austria 6 Laboratory for Transplantation Immunology, University Hospital of Zürich, Zürich, Switzerland 7 Division of Clinical Immunology, University Hospital of Zürich, Zürich, Switzerland 8 Unité mixte de recherches 7059, National Center for Scientific Research, Paris 7 University/D. Diderot, Paris, France Address correspondence and reprint requests to Dr. Jan A. Ehses, Division of Endocrinology and Diabetes, University Hospital of Zürich, Rämistrasse 100, Zürich 8091, Switzerland. E-mail: jan.ehses{at}usz.ch . Or to Dr. Marc Y. Donath, Division of Endocrinology and Diabetes, University Hospital of Zürich, Rämistrasse 100, Zürich 8091, Switzerland. E-mail: marc.donath{at}usz.ch Abstract Activation of the innate immune system in obesity is a risk factor for the development of type 2 diabetes. The aim of the current study was to investigate the notion that increased numbers of macrophages exist in the islets of type 2 diabetes patients and that this may be explained by a dysregulation of islet-derived inflammatory factors. Increased islet-associated immune cells were observed in human type 2 diabetic patients, high-fat–fed C57BL/6J mice, the GK rat, and the db/db mouse. When cultured islets were exposed to a type 2 diabetic milieu or when islets were isolated from high-fat–fed mice, increased islet-derived inflammatory factors were produced and released, including interleukin (IL)-6, IL-8, chemokine KC, granulocyte colony-stimulating factor, and macrophage inflammatory protein 1α. The specificity of this response was investigated by direct comparison to nonislet pancreatic tissue and β-cell lines and was not mimicked by the induction of islet cell death. Further, this inflammatory response was found to be biologically functional, as conditioned medium from human islets exposed to a type 2 diabetic milieu could induce increased migration of monocytes and neutrophils. This migration was blocked by IL-8 neutralization, and IL-8 was localized to the human pancreatic α-cell. Therefore, islet-derived inflammatory factors are regulated by a type 2 diabetic milieu and may contribute to the macrophage infiltration of pancreatic islets that we observe in type 2 diabetes. AEC, 3-amino-9-ethylcarbazole ECM, extracellular matrix FITC, fluorescein isothiocyanate G-CSF, granulocyte colony-stimulating factor IL, interleukin IP-10, interferon-inducible protein 10 MHC, major histocompatibility complex MIP, macrophage inflammatory protein Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 19 June 2007. DOI: 10.2337/db06-1650. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted May 21, 2007. Received November 26, 2006. DIABETES

A decrease in the number of functional insulin-producing β-cells contributes to the pathophysiology of type 2 diabetes. Opinions diverge regarding the relative contribution of a decrease in β-cell mass versus an intrinsic defect in the secretory machinery. Here we review the evidence that glucose, dyslipidemia, cytokines, leptin, autoimmunity, and some sulfonylureas may contribute to the maladaptation of β-cells. With respect to these causal factors, we focus on Fas, the ATP-sensitive K+ channel, insulin receptor substrate 2, oxidative stress, nuclear factor-κB, endoplasmic reticulum stress, and mitochondrial dysfunction as their respective mechanisms of action. Interestingly, most of these factors are involved in inflammatory processes in addition to playing a role in both the regulation of β-cell secretory function and cell turnover. Thus, the mechanisms regulating β-cell proliferation, apoptosis, and function are inseparable processes.

Whilst the exercise‐induced myokine interleukin‐6 (IL‐6) plays a beneficial role in cardiac structural adaptations, its influence on exercise‐induced functional cardiac outcomes remains unknown. We hypothesised that IL‐6 activity is required for exercise‐induced improvements in left ventricular global longitudinal strain (LV GLS). In an exploratory study 52 individuals with abdominal obesity were randomised to 12 weeks’ high‐intensity exercise or no exercise in combination with IL‐6 receptor inhibition (IL‐6i) or placebo. LV strain and volume measurements were assessed by cardiac magnetic resonance. Exercise improved LV GLS by −5.4% [95% CI: −9.1% to −1.6%] (P = 0.007). Comparing the change from baseline in LV GLS in the exercise + placebo group (−4.8% [95% CI: −7.4% to −2.2%]; P < 0.0004) to the exercise + IL‐6i group (−1.1% [95% CI: −3.8% to 1.6%]; P = 0.42), the exercise + placebo group changed −3.7% [95% CI: −7.4% to −0.02%] (P = 0.049) more than the exercise + IL6i group. However, the interaction effect between exercise and IL‐6i was insignificant (4.5% [95% CI: −0.8% to 9.9%]; P = 0.09). Similarly, the exercise + placebo group improved LV global circumferential strain by −3.1% [95% CI: −6.0% to −0.1%] (P = 0.04) more compared to the exercise + IL‐6i group, yet we found an insignificant interaction between exercise and IL‐6i (4.2% [95% CI: −1.8% to 10.3%]; P = 0.16). There was no effect of IL‐6i on exercise‐induced changes to volume rates. This study underscores the importance of IL‐6 in improving LV GLS in individuals with abdominal obesity suggesting a role for IL‐6 in cardiac functional exercise adaptations. What is the central question of this study? Interleukin‐6 (IL‐6) is a myokine that is released from skeletal muscle following exercise and is involved in structural cardiac adaptations to exercise: is IL‐6 activity also involved in functional cardiac exercise adaptations? What is the main finding? In this randomised placebo‐controlled clinical trial in individuals with abdominal obesity, inhibition of IL‐6, relative to placebo, attenuated exercise‐induced left ventricular global longitudinal strain improvements measured by magnetic resonance. The findings indicate that IL‐6 may be involved in exercise‐induced improvements in cardiac function.

Interleukin-6 (IL-6) is systemically elevated in obesity and is a predictive factor to develop type 2 diabetes. Pancreatic islet pathology in type 2 diabetes is characterized by reduced β-cell function and mass, an increased proportion of α-cells relative to β-cells, and α-cell dysfunction. Here we show that the α cell is a primary target of IL-6 actions. Beginning with investigating the tissue-specific expression pattern of the IL-6 receptor (IL-6R) in both mice and rats, we find the highest expression of the IL-6R in the endocrine pancreas, with highest expression on the α-cell. The islet IL-6R is functional, and IL-6 acutely regulates both pro-glucagon mRNA and glucagon secretion in mouse and human islets, with no acute effect on insulin secretion. Furthermore, IL-6 stimulates α-cell proliferation, prevents apoptosis due to metabolic stress, and regulates α-cell mass in vivo. Using IL-6 KO mice fed a high-fat diet, we find that IL-6 is necessary for high-fat diet-induced increased α-cell mass, an effect that occurs early in response to diet change. Further, after high-fat diet feeding, IL-6 KO mice without expansion of α-cell mass display decreased fasting glucagon levels. However, despite these α-cell effects, high-fat feeding of IL-6 KO mice results in increased fed glycemia due to impaired insulin secretion, with unchanged insulin sensitivity and similar body weights. Thus, we conclude that IL-6 is necessary for the expansion of pancreatic α-cell mass in response to high-fat diet feeding, and we suggest that this expansion may be needed for functional β-cell compensation to increased metabolic demand.

Abstract Context Patients with colorectal cancer have increased risk of metabolic diseases including diabetes. Exercise training may counteract metabolic dysregulation, but the impact of exercise training on glycemic control, including postprandial glycemia, has never been explored in patients with colorectal cancer. Objective To examine the effects of home-based interval walking on aerobic and metabolic fitness and quality of life in patients with colorectal cancer. Design Randomized controlled trial. Setting Clinical research center. Participants Thirty-nine sedentary (<150 minutes moderate-intensity exercise per week) patients with stage I to III colorectal cancer who had completed primary treatment. Intervention Home-based interval walking 150 min/wk or usual care for 12 weeks. Main Outcome Measures Changes from baseline to week 12 in maximum oxygen uptake (VO2peak) by cardiopulmonary exercise test, glycemic control by oral glucose tolerance test (OGTT), body composition by dual-energy x-ray absorptiometry scan, blood biochemistry, and quality of life. Results Compared with control, interval walking had no effect on VO2peak [mean between-group difference: −0.32 mL O2 · kg−1 · min−1 (−2.09 to 1.45); P = 0.721] but significantly improved postprandial glycemic control with lower glucose OGTT area under the curve [−126 mM · min (−219 to −33); P = 0.009], 2-hour glucose concentration [−1.1 mM (−2.2 to 0.0); P = 0.056], and improved Matsuda index [1.94 (0.34; 3.54); P = 0.01]. Also, interval walking counteracted an increase in fat mass in the control group [−1.47 kg (−2.74 to −0.19); P = 0.025]. Conclusion A home-based interval-walking program led to substantial improvements in postprandial glycemic control and counteracted fat gain in posttreatment patients with colorectal cancer, possibly providing an effective strategy for prevention of secondary metabolic diseases. We show that home-based interval walking may be a feasible and effective strategy for prevention or treatment of secondary metabolic diseases in patients with colorectal cancer post–primary treatment.

IntroductionDyslipidaemia, affecting approximately 39% of adults worldwide, is a major risk factor for cardiovascular disease. Individuals with dyslipidaemia are often prescribed statins, which effectively lower plasma low-density lipoprotein cholesterol (LDL-C), thereby reducing the risk of cardiovascular events and mortality. Although statins lower LDL-C, emerging evidence suggests that they may counteract the beneficial adaptations to exercise in skeletal muscle mitochondria and whole-body aerobic capacity. The underlying mechanisms remain unclear, and there is a need for studies investigating how statins influence molecular adaptations to exercise. The primary objective of this study is to investigate the combined effects of statin therapy and focused exercise training on mitochondrial function and whole-body aerobic capacity in people with dyslipidaemia. The untargeted proteomic analysis will be incorporated to provide detailed insights into how statins may affect mitochondrial proteins and other muscle metabolic traits, offering molecular explanations for altered functional readouts at both the muscle and whole-body levels.Methods and analysisA total of 100 women and men (aged 40–65 years) diagnosed with dyslipidaemia without atherosclerotic cardiovascular disease will be enrolled in this 12-week, double-blinded, randomised, placebo-controlled trial. Participants will be randomised into one of four groups using a block randomisation approach to ensure an allocation ratio of 60:40 for exercise and non-exercise conditions, respectively. The four groups will be: (1) exercise+placebo, (2) exercise+atorvastatin (80 mg/day), (3) atorvastatin (80 mg/day) and (4) placebo. The primary outcome is mitochondrial function, measured by changes in skeletal muscle citrate synthase activity from baseline to post-intervention. Secondary outcomes include whole-body aerobic capacity (VO2peak) and proteomic analyses. Genetic analysis will be conducted to assess the role of genetic polymorphisms in individual responses to statins and exercise.Ethics and disseminationThe trial has received ethical approval from the Faroe Islands Ethical Committee (2024-10) and adheres to the Declaration of Helsinki and General Data Protection Regulation (GDPR). Results will be published in peer-reviewed international journals.Trial registration numberNCT06841536.