IL-6 Regulation of Substrate Metabolism and Influence of Obesity

Rigshospitalet

Status: Completed

Conditions: Healthy; Obesity

Treatments: Drug: Saline 0.9%; Drug: Tocilizumab infusion

Study type: Interventional

Funder types: Other

Identifiers

NCT03967691

TOSS

Details and patient eligibility

About

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.

Full 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.

Enrollment: 22 patients

Sex: Male

Ages: 18 to 60 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Basic Science

Allocation: Non-Randomized

Interventional model: Crossover Assignment

Masking: Single Blind

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22 participants in 3 patient groups, including a placebo group

Saline infusion

Placebo Comparator group

Description:

Subjects will be infused with saline (placebo) on study day 1

Treatment:

Drug: Saline 0.9%

Tocilizumab infusion

Active Comparator group

Description:

Subjects will be infused with tocilizumab on study day 2

Treatment:

Drug: Tocilizumab infusion

Saline infusion under tocilizumab influence

Other group

Description:

Subjects will be infused withsaline (but still under the influence of tocilizumab) on study day 3

Treatment:

Drug: Saline 0.9%