Clinical trial NCT00928876: Interleukin-1 Receptor Antagonist and Insulin Sensitivity
Official title: Effect of Interleukin-1 Receptor Antagonist on Insulin Sensitivity in Obese, Insulin Resistant Individuals
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Diabetes Mellitus, Type 2
Insulin Resistance
Keywords: anakinra
Diabetes mellitus, type 2
Insulin resistance
Interleukin-1beta
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
First posted: 2009-06-26
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: to determine the effect of Interleukin-1 receptor antagonist on insulin sensitivity, as derived from glucose infusion rate measured by euglycemic hyperinsulinemic clamp
timeFrame: after four weeks of treatment
Secondary outcomes:
measure: pancreatic beta cell function als tested by oral glucose tolerance test, pro-insulin/insulin ratio
timeFrame: after four weeks of treatment
measure: lipid profile
timeFrame: after four weeks of treatment
measure: systemic inflammation
timeFrame: after four weeks of treatment
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Rabdoud University Nijmegen Medical Centre
Study officials:
affiliation: Radboud University Medical Center
name: C J Tack, Prof Dr
role: STUDY_CHAIR
References:
citation: 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.
citation: van Asseldonk EJ, Stienstra R, Koenen TB, Joosten LA, Netea MG, Tack CJ. Treatment with Anakinra improves disposition index but not insulin sensitivity in nondiabetic subjects with the metabolic syndrome: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2011 Jul;96(7):2119-26. doi: 10.1210/jc.2010-2992. Epub 2011 Apr 20.