Ectopic Adipose Tissue, Exercise Training and IL-6

Adiposity Clinical Trial

Official title:

The Role of Exercise Training Combined With Tocilizumab on Visceral and Epicardial Adipose Tissue and Gastric Emptying in a High Risk Population: an Exploratory Double-blind, Placebo-controlled Randomised Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02901496
• Other study ID #: H-16018062
• Status: Completed
• Phase: N/A
• Start date: August 2016
• Est. completion date: April 2018

Study information

• Verified date: June 2022
• Source: Rigshospitalet, Denmark
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Aim: Exercise training improves the risk of cardiometabolic diseases; yet the underlying mechanisms are unclear. Exercise induces release of IL-6 from skeletal muscle. Acute elevations in IL-6 improve lipid and glucose metabolism, the latter partly through a delayed gastric emptying. Physical inactivity causes accumulation of visceral fat (VAT). Visceral and epicardial adipose tissue (EAT) is more inflamed than subcutaneous adipose tissue. Thus, the investigators hypothesize that exercise-induced IL-6 mediates the exercise-induced reduction in EAT and VAT. Secondly, the investigators hypothesize that exercise-induced adaptations in glucose metabolism and gastric motility are dependent on IL-6. Finally the investigators hypothesise that both endurance and resistance exercise training reduce VAT and EAT.

Primary aim: To investigate the effects of exercise training on VAT and to determine to what extend IL-6 mediates this effect.

Secondary aims: 1) To determine whether 12 weeks of endurance and strength training can reduce the amount of EAT. 2) To study whether the effects of exercise on glucose metabolism and gastric emptying are dependent on IL-6.

Methods: Inclusion: 70 inactive men and women, >18 years, waist to height ratio > 0.5 and/or waist circumference ≥ 88 cm (women); waist circumference ≥ 102 cm (men) Design: A 12-week, double-blinded randomised, placebo-controlled exercise intervention study.

Intervention: Subjects will be randomised to one of five groups: i) Tocilizumab (IL-6 receptor antibody) and endurance training, ii) Placebo to Tocilizumab and endurance training, iii) Tocilizumab, no exercise iv) Placebo to Tocilizumab and no training, and v) Placebo to Tocilizumab, and resistance training. Tocilizumab/placebo dose will be administered (according to standard recommendations) before the first training session, and maintained during the 12-week training program. Training will be supervised to ensure intensity and compliance. Subjects will be instructed not to change eating habits and informed that this study does not aim for a weight loss.

Statistical considerations: Study investigators are blinded to treatment allocation. Dropouts will be replaced. A sample size of 70 subjects is needed to detect a 10% change in visceral adipose, with a power of 80% and a significance level of 0.05.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 83
• Est. completion date: April 2018
• Est. primary completion date: April 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 100 Years

Eligibility

Inclusion Criteria:

• Men and women

• Sedentary

• Waist to height ratio = ½ and/or waist circumference = 88 cm (women); waist circumference = 102 cm (men)

• Age = 18 y

Exclusion Criteria:

• Pregnancy

• Diagnosed with diabetes (HbA1c = 48 mmol/mol or fasting glucose = 7.0 mmol/l)

• Diagnosed with ischemic heart disease

• Atrial fibrillation

• Treatment with biologic rheumatic drugs, systemic prednisolone or other immunosuppressive treatments

• Health conditions that prevents individuals from participating in the exercise training intervention e.g. severe obesity

• Patients who cannot undergo MRI scans (e.g. kidney disease, metallic implants or claustrophobia)

Related Conditions & MeSH terms

• Adiposity
• Obesity

Intervention

Behavioral:
• Endurance Exercise Training
Three months of supervised training. Interval training, 3 sessions weekly of 45 min. During intervals the intensity will be minimum 70 % of VO2 max
• Resistance Exercise Training
Three months of supervised resistance training. Subjects will perform 3 weekly sessions of 45 min. The intensity will be kept at minimum 60% of 1RM.
• No Exercise
Control to exercise

Drug:
• Tocilizumab
Tocilizumab infusion will be administered monthly (8 mg/kg body weight i.v., maximun 800 mg). Each subject will receive 3 infusions during the study period.
• Placebo
Saline infusion will be administered monthly (same volume as Tocilizumab). Each subject will receive 3 infusions during the study period.

Locations

Country	Name	City	State
Denmark	Rigshospitalet, Centre of Inflammation and Metabolism (CIM) Centre for Physical Activity Research (CFAS)	Copenhagen

Sponsors (1)

Lead Sponsor	Collaborator
Rigshospitalet, Denmark

Country where clinical trial is conducted

Denmark, 

References & Publications (1)

Wedell-Neergaard AS, Lang Lehrskov L, Christensen RH, Legaard GE, Dorph E, Larsen MK, Launbo N, Fagerlind SR, Seide SK, Nymand S, Ball M, Vinum N, Dahl CN, Henneberg M, Ried-Larsen M, Nybing JD, Christensen R, Rosenmeier JB, Karstoft K, Pedersen BK, Ellin — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Peri- and paracardial adipose tissue volume (measured by MRI)		0, 12 weeks
Other	Body composition analysis (measured by Dual-energy X-ray absorptiometry)		0, 4, 8 and 12 weeks
Other	Waist circumference (measured in cm)		0, 4, 8 and 12 weeks
Other	BMI (kg/m^2, weight in kilograms, height in meters)		0, 4, 8 and 12 weeks
Other	Resting blood pressure as a measure of cardiovascular function		0, 12 weeks
Other	Maximal aerobic capacity (cardiovascular fitness) (VO2 peak)		0, 12 weeks
Other	Muscle strength measured by one repetition maximum (1RM)		0, 12 weeks
Other	Oral glucose tolerance test		0, 12 weeks
Other	Glycemic control during mixed meal tolerance test		0, 12 weeks
Other	Free-living glycemic control using continuous glucose monitoring		0, 12 weeks
Other	Pro- and anti-inflammatory cytokines(Interleukin-6, Interleukin-1ra, Interleukin-1, Interleukin-18, Interleukin-15, Interleukin-10)		0,4, 8 and 12 weeks
Other	soluble Interleukin-6 receptor (sIL-6R)		0,4, 8 and 12 weeks
Other	soluble gp130		0,4, 8 and 12 weeks
Other	Adipose characteristic by blood markers	Blood sampling	0,4, 8 and 12 weeks
Other	Cortisol	Blood sampling	0,4, 8 and 12 weeks
Other	Catecholamines (Epinephrine and norepinephrine)		0,4, 8 and 12 weeks
Other	leukocytes	Blood sampling	0,4, 8 and 12 weeks, (Timepoints: 0, 22, 45, 01:45, 02:45, at week 0 and 12)
Other	Glucagon	blood sampling	0,4, 8 and 12 weeks
Other	Blood lipid	Blood sampling	0,4, 8 and 12 weeks
Other	Cardiovascular function assessed by blood markers		0,4, 8 and 12 weeks
Other	Inflammation status assessed by blood markers		0,4, 8 and 12 weeks
Other	Adipose biopsy to assess the adipokine expression signature		0, 12 weeks
Other	Photo of subjects	To asses if the visual appearance of the stomach is reflecting the amount of visceral fat mass and to see if there is a difference in the visual appearance before and after the intervention	0, 12 weeks
Other	Faecal and urine samples to asses changes in the microbiome		0, 12 weeks
Other	Change in sleepiness	Self-report using the Epworth questionnaire	0, 12 weeks
Other	Exercise factors during an acute exercise bout	cortisol, il-6, epinephrine and norepinephrine	Timepoints: 0, 22, 45, 01:45, 02:45, before and after the intervention (0,12 weeks)
Other	Glucose metabolism during an acute exercise bout	At each timepoint exercise factors: cortisol, il-6, epinephrine and norepinephrine will be measured. Furthermore pro anti-inflammatory cytokines, glucose, insulin, C-peptide, C-reactive protein will be reported.	Timepoints: 0, 22, 45, 01:45, 02:45, before and after the intervention (0,12 weeks)
Other	Whole blood stimulation with Lipopolysaccharide and phytohaemagglutinin	in vitro stimulation of whole blood.	During the acute exercise bout at Timepoints: 0, 22, 45, 01:45, 02:45, before and after the intervention (0,12 weeks)
Other	Fibroblast growth factor 21		During the acute exercise bout at Timepoints: 0, 22, 45, 01:45, 02:45, before and after the intervention (0,12 weeks)
Other	oxidative burst in neutrophils		During the acute exercise bout at Timepoints: 0, 22, 45, 01:45, 02:45, before and after the intervention (0,12 weeks)
Other	gastrointestinal health	A questionnaire regarding gastrointestinal symptoms. A Visual Analog Score will be used.	0,12 weeks
Other	Physical activity	Self-report physical activity using The Minnesota Leisure Time Physical Activity Questionnaire	0 weeks
Other	Diet registration	Self-report diet registration for 3 days	0,4,12
Other	Satiety	self-report using a satiety questionnaire during mixed meal tolerance test	0,12
Other	Cardiac function measured by heart rate recovery		0, 12 weeks
Other	Muscle biopsy to assess expression of exercise induced cytokines		0, 12 weeks
Other	Coronary sinus flow reserve as a measure of global perfusion using MRI		0, 12 weeks
Other	Insulin during mixed meal tolerance test		Time Frame: 0, 12 weeks
Other	C-peptide during mixed meal tolerance test		Time Frame: 0, 12 weeks
Other	Glucagon during mixed meal tolerance test		Time Frame: 0, 12 weeks
Other	GLP-1 during mixed meal tolerance test		Time Frame: 0, 12 weeks
Other	Insulin sensitivity index (Matsuda) based on mixed meal tolerance test		Time Frame: 0, 12 weeks
Other	Insulin secretion index based on mixed meal tolerance test		Time Frame: 0, 12 weeks
Other	IL-6 released in respons to an exercise bout	IL-6 in plasma measured before and after an exercise bout	one of the first 3 and one of the last 3 exercise bouts
Primary	Changes in visceral fat mass	Visceral fat mass will be measured by MRI before and after the intervention. Difference in change in visceral fat mass from baseline to 12 weeks follow up will be compared between group: Endurancetraining + tocilizumab and group: Endurancetraining + placebo.	0, 12 weeks
Secondary	Changes in visceral fat mass	Difference in change in visceral fat mass from baseline to 12 weeks follow up will be compared between group: Endurancetraining + placebo and group: no training + placebo.	0, 12 weeks
Secondary	Changes in visceral fat mass	2. Difference in change in visceral fat mass from baseline to 12 weeks follow up will be compared between group: Endurancetraining + placebo and group: resistance training + placebo.	0, 12 weeks
Secondary	Changes in visceral fat mass	3. Difference in change in visceral fat mass from baseline to 12 weeks follow up will be compared between group: Endurancetraining + tocilizumab and group: no training + tocilizumab.	0, 12 weeks
Secondary	Changes in visceral fat mass	4. Difference in change in visceral fat mass from baseline to 12 weeks follow up will be compared between group: resistance training + placebo and group: no training + placebo.	0, 12 weeks
Secondary	Changes in visceral fat mass	5. Difference in change in visceral fat mass from baseline to 12 weeks follow up will be compared between group: no training + placebo and group: no training + tocilizumab.	0, 12 weeks
Secondary	Epicardial adipose tissue	Cardiac fat volume will be measured by a cardiac MRI scan before and after the interventions. All groups will be compared.	0, 12 weeks
Secondary	Gastric emptying	Gastric emptying will be measured by paracetamol blood levels (mmol/l) before and after the interventions.; The paracetamol levels will be compared between groups as follows. Group: Endurancetraining + tocilizumab and group: Endurancetraining + placebo. Group: Endurancetraining + placebo and group: no training + placebo. Group: Endurancetraining + tocilizumab and group: no training + tocilizumab. Group: No training + placebo and group: no training + tocilizumab.	0, 12 weeks