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IL-6 Regulation of Substrate Metabolism and Influence of Obesity
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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Obesity Healthy | Drug: Tocilizumab infusion Drug: Saline 0.9% | Not Applicable |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 22 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Crossover Assignment |
| 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. |
| Masking: | Single (Participant) |
| Masking Description: | Only subjects will be masked regarding order of saline and tocilizumab infusion. |
| Primary Purpose: | Basic Science |
| Official Title: | IL-6 Regulation of Substrate Metabolism and Influence of Obesity |
| Actual Study Start Date : | June 12, 2019 |
| Actual Primary Completion Date : | April 3, 2020 |
| Actual Study Completion Date : | April 3, 2020 |
| Arm | Intervention/treatment |
|---|---|
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Placebo Comparator: Saline infusion
Subjects will be infused with saline (placebo) on study day 1
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Drug: Saline 0.9%
100 ml NaCl 0.9% will be infused over 1 hour
Other Name: Saline
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Active Comparator: Tocilizumab infusion
Subjects will be infused with tocilizumab on study day 2
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Drug: Tocilizumab infusion
Tocilizumab (8mg/kg body weight diluted to 100 ml NaCl 0.9%) will be infused over 1 hour
Other Name: RoActemra
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Saline infusion under tocilizumab influence
Subjects will be infused withsaline (but still under the influence of tocilizumab) on study day 3
|
Drug: Saline 0.9%
100 ml NaCl 0.9% will be infused over 1 hour
Other Name: Saline
|
- Lipolytic rate [ Time Frame: 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
- Glucose kinetics [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 0-28 days ]RER during rest and exercise in the presence of tocilizumab as compared to placebo
- Perceived exhaustion during exercise [ Time Frame: 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 [ Time Frame: 0-28 days ]Change in glucose during rest and exercise in the presence of tocilizumab as compared to placebo
- Insulin [ Time Frame: 0-28 days ]Changes in insulin during rest and exercise in the presence of tocilizumab as compared to placebo
- C-peptide [ Time Frame: 0-28 days ]Change in c-peptide during rest and exercise in the presence of tocilizumab as compared to placebo
- Glucagon [ Time Frame: 0-28 days ]Change in glucagon during rest and exercise in the presence of tocilizumab as compared to placebo
- Cortisol [ Time Frame: 0-28 days ]Change in cortisol during rest and exercise in the presence of tocilizumab as compared to placebo
- Adrenaline [ Time Frame: 0-28 days ]Change in adrenaline during rest and exercise in the presence of tocilizumab as compared to placebo
- Noradrenaline [ Time Frame: 0-28 days ]Changes in noradrenaline during rest and exercise in the presence of tocilizumab as compared to placebo
- Interleukin 6 [ Time Frame: 0-28 days ]Change in IL-6 during rest and exercise in the presence of tocilizumab as compared to placebo
- Free fatty acids [ Time Frame: 0-28 days ]Change in free fatty acids during rest and exercise in the presence of tocilizumab as compared to placebo
- Triglycerides [ Time Frame: 0-28 days ]Changes in triglycerides during rest and exercise in the presence of tocilizumab as compared to placebo
| Ages Eligible for Study: | 18 Years to 60 Years (Adult) |
| Sexes Eligible for Study: | Male |
| Accepts 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
| Denmark | |
| Rigshospitalet, Centre of Inflammation and Metabolism (CIM) Centre for Physical Activity Research (CFAS) | |
| Copenhagen, Denmark, 2100 | |
| Principal Investigator: | Helga Ellingsgaard, Ph.D. | CFAS, Rigshospitalet |
| Tracking Information | |||||
|---|---|---|---|---|---|
| First Submitted Date ICMJE | May 22, 2019 | ||||
| First Posted Date ICMJE | May 30, 2019 | ||||
| Last Update Posted Date | October 8, 2020 | ||||
| Actual Study Start Date ICMJE | June 12, 2019 | ||||
| Actual Primary Completion Date | April 3, 2020 (Final data collection date for primary outcome measure) | ||||
| Current Primary Outcome Measures ICMJE |
Lipolytic rate [ Time Frame: 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
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| Original Primary Outcome Measures ICMJE | Same as current | ||||
| Change History | |||||
| Current Secondary Outcome Measures ICMJE |
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| Original Secondary Outcome Measures ICMJE | Same as current | ||||
| Current Other Pre-specified Outcome Measures | Not Provided | ||||
| Original Other Pre-specified Outcome Measures | Not Provided | ||||
| Descriptive Information | |||||
| Brief Title ICMJE | IL-6 Regulation of Substrate Metabolism and Influence of Obesity | ||||
| Official Title ICMJE | IL-6 Regulation of Substrate Metabolism and Influence of Obesity | ||||
| 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. |
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| 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. |
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| Study Type ICMJE | Interventional | ||||
| Study Phase ICMJE | Not Applicable | ||||
| Study Design ICMJE | Allocation: Non-Randomized Intervention Model: Crossover Assignment 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. Masking: Single (Participant)Masking Description: Only subjects will be masked regarding order of saline and tocilizumab infusion. Primary Purpose: Basic Science
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| Condition ICMJE |
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| Intervention ICMJE |
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| Study Arms ICMJE |
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| Publications * | Not Provided | ||||
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* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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| Recruitment Information | |||||
| Recruitment Status ICMJE | Completed | ||||
| Actual Enrollment ICMJE |
22 | ||||
| Original Estimated Enrollment ICMJE |
20 | ||||
| Actual Study Completion Date ICMJE | April 3, 2020 | ||||
| Actual Primary Completion Date | April 3, 2020 (Final data collection date for primary outcome measure) | ||||
| Eligibility Criteria ICMJE |
Inclusion Criteria:
Exclusion Criteria:
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| Sex/Gender ICMJE |
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| Ages ICMJE | 18 Years to 60 Years (Adult) | ||||
| Accepts Healthy Volunteers ICMJE | Yes | ||||
| Contacts ICMJE | Contact information is only displayed when the study is recruiting subjects | ||||
| Listed Location Countries ICMJE | Denmark | ||||
| Removed Location Countries | |||||
| Administrative Information | |||||
| NCT Number ICMJE | NCT03967691 | ||||
| Other Study ID Numbers ICMJE | TOSS | ||||
| Has Data Monitoring Committee | No | ||||
| U.S. FDA-regulated Product |
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| IPD Sharing Statement ICMJE |
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| Responsible Party | Helga Ellingsgaard, Rigshospitalet, Denmark | ||||
| Study Sponsor ICMJE | Rigshospitalet, Denmark | ||||
| Collaborators ICMJE | Not Provided | ||||
| Investigators ICMJE |
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| PRS Account | Rigshospitalet, Denmark | ||||
| Verification Date | October 2020 | ||||
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ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |
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