Interleukin-1 Receptor Antagonist and Insulin Sensitivity

Study Overview
=================
Brief Summary
-----------------
Obesity is characterized by continuous low-grade inflammation. This is an important link between obesity and insulin resistance. Results from the investigators' own group of in vitro and in vivo research on mice show that Interleukin-1 is involved in the process of developing insulin resistance. Earlier it has been shown that interleukin-1 receptor antagonist in human subjects improves glycemic control. The investigators' hypothesis is that this is due to improved insulin sensitivity.

Detailed Description
-----------------
The prevalence of obesity is increasing fast. Obesity is one of the most common acquired risk factors for insulin resistance. As a consequence the prevalence of type 2 diabetes mellitus is rising fast as well. Interleukin 6 and Tumor Necrosis Factor alfa are well known pro-inflammatory cytokines that have been linked to insulin resistance. Results from our own group show that interleukin-1 is also involved in the process of developing insulin resistance. Earlier research projects studied the effect of Interleukin-1 receptor antagonist (Anakinra) on glycemic control in subjects with type 2 diabetes mellitus. It was shown that glycemic control was improved. The authors conclude that this is the result of improved function of pancreatic beta cells. These results are in contrast to our results of in vitro en in vivo research on mice, which show improved insulin sensitivity by Interleukin-1 receptor antagonist. A possible explanation for not finding an effect on insulin sensitivity by earlier research projects may be that it is difficult to reliable quantify insulin sensitivity in this group of patients with concurrent changes in glycemic control, extensive co-morbidity and medication use, who might be at the rather extreme end of insulin resistance. Furthermore a relatively low dose of Anakinra was used. Altogether we hypothesize that the effect of Interleukin-1 is not only mediated through better pancreatic beta-cell function, but that Interleukin-1 blocking by recombinant Interleukin-1 receptor antagonist will also diminish insulin resistance.

Official Title
-----------------
Effect of Interleukin-1 Receptor Antagonist on Insulin Sensitivity in Obese, Insulin Resistant Individuals

Conditions
-----------------
Diabetes Mellitus, Type 2, Insulin Resistance

Intervention / Treatment
-----------------
* Drug: Anakinra (Kineret)
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: adult subjects with a BMI > 30 kg/m2 3 or more characteristics of the metabolic syndrome Exclusion Criteria: inability to give informed consent age < 18 years known diabetes mellitus fasting plasma glucose > 7,0 mmol/l or HbA1c > 6,2% presence of any medical condition that might interfere with the current study protocol immunodeficiency of immunosuppressive treatment anti-inflammatory drugs (100 mg of aspirin/day is allowed) signs of current infection history of recurrent infections pregnancy or breast feeding liver disease renal disease neutropenia

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anakinra group<br>Anakinra 150 mg/day during four weeks | Drug: Anakinra (Kineret)<br>* anakinra 150 mg s/c. daily for four weeks<br>* Other names: kineret;|
| Placebo Comparator: Placebo<br>Placebo during four weeks | Drug: Placebo<br>* placebo s/c daily for four weeks<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| to determine the effect of Interleukin-1 receptor antagonist on insulin sensitivity, as derived from glucose infusion rate measured by euglycemic hyperinsulinemic clamp |  | after four weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pancreatic beta cell function als tested by oral glucose tolerance test, pro-insulin/insulin ratio |  | after four weeks of treatment | 
| lipid profile |  | after four weeks of treatment | 
| systemic inflammation |  | after four weeks of treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
anakinra, Diabetes mellitus, type 2, Insulin resistance, Interleukin-1beta