Meal-regulated Substrate Metabolism, Influence of Obesity and IL-6

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

NA

Total Enrollment

25 participants

Study Classification

INTERVENTIONAL

Study Start Date

2021-04-09

Study Completion Date

2021-08-01

Brief Summary

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The overall purpose of this explorative yet quantitative study project is to understand how blocking IL-6 signaling leads to the expansion of adipose tissue mass in humans in vivo. The aim is to gain in depth knowledge about how IL-6 receptor blockade affects human lipid, glucose and protein metabolism, specifically the uptake and storage of substrates from a meal vs. their utilization, hence the balance determining whether one gains or loses fat mass.

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Detailed Description

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Lacking IL-6 signaling leads to an expansion of adipose tissue mass in rodents and humans. However, the underlying mechanisms have not been identified.This project aims to investigate the overall hypothesis that IL-6 receptor blockade changes substrate metabolism during postabsorptive and postprandial states to favor storage over mobilization of fat and to favor glucose over fat as a source for energy production. This hypothesis finds some support in the literature: Infusion of recombinant IL-6 into humans, leading to high concentrations of IL-6 in the circulation, stimulates lipolysis and free fatty acid oxidation.

Therefore, the investigators hypothesize that IL-6 receptor blockade impairs the mobilization of FFA from adipose tissue and impairs fat oxidation in skeletal muscle in the postabsorptive state. In the postprandial, state the investigators hypothesize that IL-6 receptor blockade reduces the insulin-induced uptake and deposition of fat by adipose tissue and skeletal muscle, therefore contributing to ectopic fat deposition in the liver.

In this study 12 lean and 12 obese male participants will be included. The participants will attend one screening visit and two study visits. The IL-6 receptor antibody tocilizumab will be infused on study visit 1.

Isotope dilution techniques, blood flow measurements, arterio-venous differences across adipose tissue and skeletal muscle, fat and skeletal muscle biopsies will be used to assess lipid, glucose and protein kinetics on a whole-body as well as fat and skeletal muscle level in the fasting state and after the ingestion of a liquid mixed-meal. Respiratory exchange ratio will be measured by indirect calorimetry.

Conditions

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Obesity Healthy

Study Design

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Allocation Method

NON_RANDOMIZED

Intervention Model

CROSSOVER

The study is designed in a placebo-controlled crossover manner, consisting of a screening visit and two study visits. Due to the 4-week wash out period of the IL-6 receptor antibody tocilizumab, the order of study visits will be identical in all subjects; hence, study visits will not be randomized. Subjects will be infused with tocilizumab at the end of study visit 1. This will allow us to study the effect of tocilizumab on study visit 2.

Primary Study Purpose

BASIC_SCIENCE

Blinding Strategy

SINGLE

Participants

Only subjects will be masked regarding order of saline and tocilizumab infusion

Study Groups

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Study day 1 (study visit 1)

Baseline measurements (pre-intervention) are obtained on study visit 1.

Group Type PLACEBO_COMPARATOR

Tocilizumab

Intervention Type DRUG

Baseline: Tocilizumab (infusion of 8 mg/kg bodyweight or a maximum of 800 mg) will be infused over 60 minutes at the end for the study day, therefore study visit 1 (study day 1) measurements are baseline.

Study day 21 (study visit 2)

Post-intervention measurements: Participants will be under the influence of tocilizumab, which was injected at the end of study visit 1.

Group Type ACTIVE_COMPARATOR

Saline 0.9%

Intervention Type DRUG

Participants are under influence of tocilizumab since the effect of the drug will last for 4 weeks. Participants will be infused with saline at study visit 2 (study day 21). Placebo to tocilizumab will be saline (NaCl 0.9%) as tocilizumab is a colorless solution and has to be diluted with NaCl 0.9% prior to administration

Interventions

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Tocilizumab

Baseline: Tocilizumab (infusion of 8 mg/kg bodyweight or a maximum of 800 mg) will be infused over 60 minutes at the end for the study day, therefore study visit 1 (study day 1) measurements are baseline.

Intervention Type DRUG

Saline 0.9%

Participants are under influence of tocilizumab since the effect of the drug will last for 4 weeks. Participants will be infused with saline at study visit 2 (study day 21). Placebo to tocilizumab will be saline (NaCl 0.9%) as tocilizumab is a colorless solution and has to be diluted with NaCl 0.9% prior to administration

Intervention Type DRUG

Other Intervention Names

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RoActemra

Eligibility Criteria

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Inclusion Criteria

Healthy males:

* Age ≥ 18 years and ≤ 40 years
* BMI \< 18 and \> 25 kg/m2
* Healthy (based on screening)
* Stable body weight for 6 months

Obese males:

* Age ≥ 18 years and ≤ 40 years
* BMI ≥ 30 and ≤ 40 kg/m2
* Healthy (based on screening)
* Stable body weight for 6 months

Exclusion Criteria

* Smoking
* Evidence of severe thyroid or heart disease, inflammatory diseases, current infection, liver disease (transaminases \>2x upper normal range), kidney disease (creatinine \>1.5 mg/dl), known immunosuppressive disease, corticosteroid use, regular NSAID or paracetamol usage, aspirin use \>100 mg/d, history of carcinoma, history of tuberculosis, anemia (hematocrit \<33%), WBC \<2 x 10\^3/ul, platelets \<100 x 10\^3/ul, bleeding disorders, obstructive pulmonary disease
* Femoral hernia, vascular prosthesis, vascular thrombosis
* Previous nerve damage, many previous femoral catheter installations

Minimum Eligible Age

18 Years

Maximum Eligible Age

40 Years

Eligible Sex

MALE

Accepts Healthy Volunteers

Yes