Healthy, Obesity
Conditions
Keywords
Interleukin-6, Tocilizumab, Exercise, Substrate Metabolism, Lipolysis
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.
Interventions
DRUGTocilizumab infusion
Tocilizumab (8mg/kg body weight diluted to 100 ml NaCl 0.9%) will be infused over 1 hour
DRUGSaline 0.9%
100 ml NaCl 0.9% will be infused over 1 hour
Sponsors
Rigshospitalet, Denmark
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Masking description
Only subjects will be masked regarding order of saline and tocilizumab infusion.
Intervention model description
The study is designed in a placebo-controlled crossover manner, consisting of a screening visit and three study visits/study days. the Subjects will be infused with saline (placebo) on two of the study days and tocilizumab on one of the study days.
Eligibility
Sex/Gender
MALE
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
* BMI \< 18 and \> 25 kg/m2 or ≥ 30 and ≤ 40 kg/m2 * Healthy (based on screening)
Exclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Cortisol | 0-28 days | Change in cortisol 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 |
| 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 |
| Respiratory exchange ratio (RER) | 0-28 days | RER 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 |
| Glucose | 0-28 days | Change in glucose 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 |
| C-peptide | 0-28 days | Change in c-peptide 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 |
| Noradrenaline | 0-28 days | Changes in noradrenaline 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 |
| Free fatty acids | 0-28 days | Change in free fatty acids 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 |
| Insulin | 0-28 days | Changes in insulin during rest and exercise in the presence of tocilizumab as compared to placebo |
Countries
Denmark
Outcome results
None listed