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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Role of Interleukin-1 in the Regulation of Muscle Derived Interleukin-6 During Exercise

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: IL-1Ra
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: IL-1Ra<br> | Drug: IL-1Ra<br>* 100mg, s.c, once only<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* 100mg, s.c., once only<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IL-1, IL-6, Inflammation