Role of Interleukin-1 in the Regulation of Muscle Derived Interleukin-6 During Exercise (MUSIL)

Aim: Evaluate the regulation of muscle derived Interleukin-6 (IL-6)during exercise and in particular whether it is regulated by the Interleukin-1 (IL-1) system.

Rationale: It has been shown that IL-1 antagonism improves glycemia and insulin secretion in patients with type 2 Diabetes. However, IL-1 antagonism also decreases IL-6 levels. The effect if IL-6 on the glucose metabolism has been unclear in the past and subject to intense debate, with recent evidence indicating a beneficial role in regulating glucose metabolism. However little is known about regulation of muscle-induced IL-6 produced during exercise. It is therefore our aim to investigate whether exercise induced increases in IL-6 are dependent on the IL-1 system. If IL-1 antagonism does decrease IL-6 and along with it, the beneficial potential of IL-6, this may require additional medication like IL-6 substitution or dipeptidyl peptidase-IV (DPP-IV)antagonists.

In addition, the investigators will assess the effect of IL-1 antagonism on insulin and Glucagon like peptide-1 (GLP-1) secretion as well as muscle soreness,fatigue and vascular function in response to an acute exercise bout.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: IL-1Ra; Drug: Placebo

Detailed Description

This is a randomized placebo-controlled, double blind, cross-over, proof-of-concept study.

The study will consist of one screening visit followed by 3 study visits. During the first two study visits, the subjects (20 apparently healthy, lean men) will perform a submaximal exercise bout on a treadmill for 60 minutes. Subjects will be randomly assigned into two groups consisting each of 10 subjects receiving study medication in a double-blinded, crossed over manner.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Switzerland
  • Basel, Switzerland
    • University Hospital of Basel, Division of Endocrinology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• male
• non-smoking
• apparently healthy
• BMI > 18 and < 26kg/m2
• Age 20-50 years
• Regular exercise including a minimum of two runs weekly of a total duration of > 2h
• Willingness to use contraceptive measures adequate to prevent the subject's partner from becoming pregnant during the study. Adequate contraceptive measures include hormonal methods used for two or more cycles prior to Screening (e.g., oral contraceptive pills, contraceptive patch, or contraceptive vaginal ring), double barrier methods (e.g., contraceptive sponge, diaphragm used in conjunction with contraceptive foam or jelly, and condom used in conjunction with contraceptive foam or jelly), intrauterine methods (IUD), sterilization (e.g., tubal ligation or a monogamous relationship with a vasectomized partner), and abstinence.

Exclusion Criteria:

• Clinical signs of infection in the week before inclusion or history of infection during the last 3 months (CRP > 5mg/L)
• Impaired fasting glucose (fasting plasma glucose > 5.5mmol/L)
• Hematologic disease (leukocyte count < 1.5x109/L, hemoglobin < 11 g/dL, platelets < 100 x 103/uL)
• Kidney disease (creatinine > 1.5 mg/dL for men and 1.4mg/dL for woman)
• Liver disease (transaminases > 2x upper normal range)
• Heart disease
• Pulmonary disease
• Inflammatory disease
• History of carcinoma
• History of tuberculosis
• Alcohol consumption > 40g/d
• Known allergy to Kineret
• Current treatment with any drug in the week before inclusion, including vitamin supplementation (especially vitamin C and E)
• Use of any investigational drug within 30 days prior to enrollment or within 5 half-lives of the investigational drug, whichever is longer
• Subject refusing or unable to give written informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; 100mg, s.c., once only
Active Comparator: IL-1Ra	Drug: IL-1Ra; 100mg, s.c, once only

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
IL6	Change of IL6 during exercise stimulation at baseline compared to change of IL6 during exercise stimulation at day 7

Secondary Outcome Measures

Outcome Measure	Time Frame
change of inflammatory markers (CRP, Tumor Necrosis Factor alpha, IL-1Ra)	Change of inflammatory markers during exercise stimulation at baseline compared to change of inflammatory markers during exercise stimulation at day 7
Muscle soreness	Change in muscle soreness before and after exercise stimulation at baseline compared to change in muscle soreness before and after exercise stimulation at day 7
Activity induced Fatigue (ACTIF) Scale	Change in ACTIF before and after exercise stimulation at baseline compared to change in ACTIF before and after exercise stimulation at day 7
Depression	Change in depression during exercise stimulation at baseline compared to change in depression at day 7
Change of vascular function (CAVI, pulse wave velocity, AVR)	Change in vascular function during exercise stimulation at baseline compared to change of vascular function at day 7
glucose metabolism	Change glucose metabolism during exercise stimulation at basleine compared to change in glucose metabolism during exercise stimulation at day 7
Cognition	Change in cognition during exercise stimulation at baseline compared to change in cognition at day 7
Motor strength	Change in motor strength during exercise stimulation at baseline compared to change in motor stength at day 7
Insulin	Change in insulin during exercise stimulation at baseline compared to change in insulin at day 7
Glucagon	Change in glucagon during exercise stimulation at baseline compared to change in glucagon at day 7
GLP-1	Change in GLP-1 during exercise stimulation at baseline compared to change in GLP-1 at day 7
Cortisol	Change in cortisol during exercise stimulation at baseline compared to change in cortisol at day 7
Creatinkinase	Change in creatinkinase during exercise stimulation at baseline compared to change in creatinkinase at day 7
Growth hormone	Change of growth hormone during exercise stimulation at baseline compared to change of growth hormone during exercise stimulation at day 7
Copeptin	Change of copeptin during exercise stimulation at baseline compared to change of copeptin during exercise stimulation at day 7

Collaborators and Investigators

• Sponsor: Marc Y.Donath
• Investigators: Principal Investigator: Marc Y Donath, MD, University of Basel

Publications and helpful links

General Publications

• Nordmann TM, Seelig E, Timper K, Cordes M, Coslovsky M, Hanssen H, Schmidt-Trucksass A, Donath MY. Muscle-Derived IL-6 Is Not Regulated by IL-1 during Exercise. A Double Blind, Placebo-Controlled, Randomized Crossover Study. PLoS One. 2015 Oct 8;10(10):e0139662. doi: 10.1371/journal.pone.0139662. eCollection 2015.

Study record dates

Study Major Dates

• Study Start: December 1, 2011
• Primary Completion (Actual): October 1, 2013
• Study Completion (Actual): October 1, 2013

Study Registration Dates

• First Submitted: February 29, 2012
• First Submitted That Met QC Criteria: January 15, 2013
• First Posted (Estimate): January 18, 2013

Study Record Updates

• Last Update Posted (Estimate): January 8, 2014
• Last Update Submitted That Met QC Criteria: January 7, 2014
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Keywords: Inflammation; IL-6; IL-1
• Additional Relevant MeSH Terms: Antirheumatic Agents; Interleukin 1 Receptor Antagonist Protein
• Other Study ID Numbers: MUSIL 294/10