Interleukin-1 Receptor Antagonist and Insulin Sensitivity

Overview

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.

Full Title of Study: “Effect of Interleukin-1 Receptor Antagonist on Insulin Sensitivity in Obese, Insulin Resistant Individuals”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: March 2010

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.

Interventions

  • Drug: Anakinra (Kineret)
    • anakinra 150 mg s/c. daily for four weeks
  • Drug: Placebo
    • placebo s/c daily for four weeks

Arms, Groups and Cohorts

  • Experimental: Anakinra group
    • Anakinra 150 mg/day during four weeks
  • Placebo Comparator: Placebo
    • Placebo during four weeks

Clinical Trial Outcome Measures

Primary Measures

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

Secondary Measures

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

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Radboud University Medical Center
  • Provider of Information About this Clinical Study
    • Prof. Dr. C.J. Tack, Radboud University Nijmegen Medical Centre
  • Overall Official(s)
    • C J Tack, Prof Dr, Study Chair, Radboud University Medical Center

References

Larsen CM, Faulenbach M, Vaag A, Volund A, Ehses JA, Seifert B, Mandrup-Poulsen T, Donath MY. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med. 2007 Apr 12;356(15):1517-26. doi: 10.1056/NEJMoa065213.

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