IL-6 Regulation of Substrate Metabolism and Influence of Obesity

Healthy Clinical Trial

Official title:

IL-6 Regulation of Substrate Metabolism and Influence of Obesity

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03967691
• Other study ID #: TOSS
• Status: Completed
• Phase: N/A
• Start date: June 12, 2019
• Est. completion date: April 3, 2020

Study information

• Verified date: October 2020
• Source: Rigshospitalet, Denmark
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 22
• Est. completion date: April 3, 2020
• Est. primary completion date: April 3, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Healthy
• Obesity

Intervention

Drug:
• Tocilizumab infusion
Tocilizumab (8mg/kg body weight diluted to 100 ml NaCl 0.9%) will be infused over 1 hour
• Saline 0.9%
100 ml NaCl 0.9% will be infused over 1 hour

Locations

Country	Name	City	State
Denmark	Rigshospitalet, Centre of Inflammation and Metabolism (CIM) Centre for Physical Activity Research (CFAS)	Copenhagen

Sponsors (1)

Lead Sponsor	Collaborator
Rigshospitalet, Denmark

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Lipolytic rate	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	0-28 days
Secondary	Glucose kinetics	Rate of appearance and disappearance of glucose during rest and exercise in the presence of tocilizumab as compared to placebo	0-28 days
Secondary	Protein metabolism	Rate of appearance and disappearance of phenylalanine and tyrosine during rest and exercise in the presence of tocilizumab as compared to placebo	0-28 days
Secondary	Respiratory exchange ratio (RER)	RER during rest and exercise in the presence of tocilizumab as compared to placebo	0-28 days
Secondary	Perceived exhaustion during exercise	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	0-28 days
Secondary	Glucose	Change in glucose during rest and exercise in the presence of tocilizumab as compared to placebo	0-28 days
Secondary	Insulin	Changes in insulin during rest and exercise in the presence of tocilizumab as compared to placebo	0-28 days
Secondary	C-peptide	Change in c-peptide during rest and exercise in the presence of tocilizumab as compared to placebo	0-28 days
Secondary	Glucagon	Change in glucagon during rest and exercise in the presence of tocilizumab as compared to placebo	0-28 days
Secondary	Cortisol	Change in cortisol during rest and exercise in the presence of tocilizumab as compared to placebo	0-28 days
Secondary	Adrenaline	Change in adrenaline during rest and exercise in the presence of tocilizumab as compared to placebo	0-28 days
Secondary	Noradrenaline	Changes in noradrenaline during rest and exercise in the presence of tocilizumab as compared to placebo	0-28 days
Secondary	Interleukin 6	Change in IL-6 during rest and exercise in the presence of tocilizumab as compared to placebo	0-28 days
Secondary	Free fatty acids	Change in free fatty acids during rest and exercise in the presence of tocilizumab as compared to placebo	0-28 days
Secondary	Triglycerides	Changes in triglycerides during rest and exercise in the presence of tocilizumab as compared to placebo	0-28 days