IL-6 Regulation of Substrate Metabolism and Influence of Obesity
- Conditions
- HealthyObesity
- Interventions
- Drug: Saline 0.9%
- Registration Number
- NCT03967691
- Lead Sponsor
- Rigshospitalet, Denmark
- Brief Summary
The aim of the study is to investigate the effects of blocking IL-6 signaling with tocilizumab on lipid, glucose and protein metabolism during rest and exercise in healthy and obese humans.
Interleukin-6 is a molecule produced by a variety of cells and impacts on energy metabolism during fasting and fed conditions. Systemic IL-6 levels are low but increase acutely in response to fasting, exercise and infection, and also chronically in response to obesity and other conditions of lowgrade inflammation.Our recent human intervention study showed that IL-6 receptor blockade prevents exercise training from reducing visceral fat mass.
Whether IL-6 receptor blockade directly regulates lipolysis and/or lipid oxidation in humans is however unclear. Therefore, this study will be performed to investigate the physiological role of IL-6 on lipid, glucose and protein metabolism in humans.
- Detailed Description
The aim of the study is to assess changes in substrate kinetics, that is, lipolytic rate, rate of appearance and disappearance of free fatty acids, fatty acid oxidation, glucose rate of appearance and disappearance and protein synthesis and degradation during rest and exercise with and without IL-6 receptor blockade. We will assess the acute effects of blocking IL-6 as well as the long-term consequences of IL-6 receptor blockade on all the above parameters.
Overall, we hypothesize that blocking IL-6 changes substrate kinetics. More specifically we hypothesize that blocking IL-6 reduces the appearance of free fatty acids, reduces the lipolytic rate and lipid oxidation. We hypothesize that the consequences of blocking IL-6 will be observed during resting and exercising conditions and both immediately and longterm after IL-6 receptor blockade. We hypothesize that IL-6 receptor blockade results in an increased respiratory exchange ratio (RER) and thus increased reliance on glucose as substrate.
In this study 10 healthy males and 10 obese males will be included. Subjects will be infused with saline on 2 of the study days and tocilizumab on 1 of the study days.
Isotope dilution techniques with \[6,6-2H2\]Glucose, \[1,1,2,3,3-D5\]glycerol, K-\[U-13C16\]palmitate, L-\[ring-D5\]phenylalanine, L-\[D2\]tyrosine will be applied to assess lipid, glucose and protein kinetics. Respiratory exchange ratio will be measured by indirect calorimetry. The BORG scale will be used to assess the perceived exertion during exercise.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Male
- Target Recruitment
- 22
- BMI < 18 and > 25 kg/m2 or ≥ 30 and ≤ 40 kg/m2
- Healthy (based on screening)
- Smoking
- Severe thyroid or heart disease
- inflammatory diseases
- current infection
- liver disease
- kidney disease
- immunosuppressive disease
- corticosteroid use
- regular NSAID usage
- aspirin use >100 mg/d
- history of carcinoma
- history of tuberculosis
- anemia
- neutropenia
- low platelets
- bleeding disorders
- obstructive pulmonary disease
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Saline infusion Saline 0.9% Subjects will be infused with saline (placebo) on study day 1 Saline infusion under tocilizumab influence Saline 0.9% Subjects will be infused withsaline (but still under the influence of tocilizumab) on study day 3 Tocilizumab infusion Tocilizumab infusion Subjects will be infused with tocilizumab on study day 2
- Primary Outcome Measures
Name Time Method Lipolytic rate 0-28 days Rate of appearance and disappearance of glycerol and palmitate, fatty acid oxidation during rest and exercise in the presence of tocilizumab as compared to placebo
- Secondary Outcome Measures
Name Time Method Noradrenaline 0-28 days Changes in noradrenaline during rest and exercise in the presence of tocilizumab as compared to placebo
Protein metabolism 0-28 days Rate of appearance and disappearance of phenylalanine and tyrosine during rest and exercise in the presence of tocilizumab as compared to placebo
Perceived exhaustion during exercise 0-28 days Borg scale (rate of perceived exertion during exercise; score range from minimum 6 to maximum 20; 6 = "no feeling of exertion", 20 = "very, very hard") in the presence of tocilizumab as compared to placebo
C-peptide 0-28 days Change in c-peptide during rest and exercise in the presence of tocilizumab as compared to placebo
Glucagon 0-28 days Change in glucagon during rest and exercise in the presence of tocilizumab as compared to placebo
Adrenaline 0-28 days Change in adrenaline during rest and exercise in the presence of tocilizumab as compared to placebo
Glucose kinetics 0-28 days Rate of appearance and disappearance of glucose during rest and exercise in the presence of tocilizumab as compared to placebo
Triglycerides 0-28 days Changes in triglycerides during rest and exercise in the presence of tocilizumab as compared to placebo
Respiratory exchange ratio (RER) 0-28 days RER during rest and exercise in the presence of tocilizumab as compared to placebo
Glucose 0-28 days Change in glucose during rest and exercise in the presence of tocilizumab as compared to placebo
Insulin 0-28 days Changes in insulin during rest and exercise in the presence of tocilizumab as compared to placebo
Free fatty acids 0-28 days Change in free fatty acids during rest and exercise in the presence of tocilizumab as compared to placebo
Cortisol 0-28 days Change in cortisol during rest and exercise in the presence of tocilizumab as compared to placebo
Interleukin 6 0-28 days Change in IL-6 during rest and exercise in the presence of tocilizumab as compared to placebo
Trial Locations
- Locations (1)
Rigshospitalet, Centre of Inflammation and Metabolism (CIM) Centre for Physical Activity Research (CFAS)
🇩🇰Copenhagen, Denmark