Clinical trial NCT03967691: IL-6 Regulation of Substrate Metabolism and Influence of Obesity
Official title: IL-6 Regulation of Substrate Metabolism and Influence of Obesity
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Obesity
Healthy
Keywords: Interleukin-6
Tocilizumab
Exercise
Substrate Metabolism
Lipolysis
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
First posted: 2019-05-30
Enrollment: 22
Sex: MALE
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER
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.
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: 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

Primary outcomes:
measure: Lipolytic rate
timeFrame: 0-28 days
Secondary outcomes:
measure: Glucose kinetics
timeFrame: 0-28 days
measure: Protein metabolism
timeFrame: 0-28 days
measure: Respiratory exchange ratio (RER)
timeFrame: 0-28 days
measure: Perceived exhaustion during exercise
timeFrame: 0-28 days
measure: Glucose
timeFrame: 0-28 days
measure: Insulin
timeFrame: 0-28 days
measure: C-peptide
timeFrame: 0-28 days
measure: Glucagon
timeFrame: 0-28 days
measure: Cortisol
timeFrame: 0-28 days
measure: Adrenaline
timeFrame: 0-28 days
measure: Noradrenaline
timeFrame: 0-28 days
measure: Interleukin 6
timeFrame: 0-28 days
measure: Free fatty acids
timeFrame: 0-28 days
measure: Triglycerides
timeFrame: 0-28 days
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Rigshospitalet, Centre of Inflammation and Metabolism (CIM) Centre for Physical Activity Research (CFAS)
Study officials:
affiliation: CFAS, Rigshospitalet
name: Helga Ellingsgaard, Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Trinh B, Peletier M, Simonsen C, Plomgaard P, Karstoft K, Pedersen BK, van Hall G, Ellingsgaard H. Amino Acid Metabolism and Protein Turnover in Lean and Obese Humans During Exercise-Effect of IL-6 Receptor Blockade. J Clin Endocrinol Metab. 2022 Jun 16;107(7):1854-1864. doi: 10.1210/clinem/dgac239.
citation: Trinh B, Peletier M, Simonsen C, Plomgaard P, Karstoft K, Klarlund Pedersen B, van Hall G, Ellingsgaard H. Blocking endogenous IL-6 impairs mobilization of free fatty acids during rest and exercise in lean and obese men. Cell Rep Med. 2021 Sep 9;2(9):100396. doi: 10.1016/j.xcrm.2021.100396. eCollection 2021 Sep 21.