Effect of Anakinra on Insulin Sensitivity in Type 1 Diabetes Mellitus

Diabetes Mellitus Clinical Trial

Official title:

Effect of Interleukin-1 Receptor Antagonist on Insulin Sensitivity in Type 1 Diabetes Mellitus.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01285245
• Other study ID #: NL34377.091.10
• Secondary ID: 2010-023479-24
• Status: Recruiting
• Phase: Phase 2
• First received: November 26, 2010
• Last updated: April 13, 2011
• Start date: April 2011
• Est. completion date: December 2011

Study information

• Verified date: November 2010
• Source: Radboud University
• Contact: Edwin JP van Asseldonk, MD
• Phone: +31243619857
• Email: e.vanasseldonk[@]aig.umcn.nl
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to test whether anakinra is able to reduce insulin resistance.

This will be tested in overweighted type I diabetes mellitus patients, which have no residual beta-cell function. By using this patient group, all positive effects on glycemic control should be the consequence of improved insulin sensitivity.

Description:

Although typically associated with type 2 diabetes, insulin resistance has been documented in Type 1 diabetes. Insulin resistance may also play an important role in the pathophysiology of type 1 diabetes mellitus. Once diabetes has emerged chronically elevated glucose levels further induce insulin resistance (glucose toxicity).

Inflammation is an important link between obesity and insulin resistance. The mechanism of hyperglycemia-induced insulin resistance is not clear, but evidently must be related to high glucose levels. There are indications that chronic hyperglycemia can induce inflammation, for example hyperglycemia induces IL-1β release, and recent studies have shown an interaction with thioredoxin interacting protein (TXNIP), at the level of the beta-cell but also, as found by our own group, at the level of the adipose tissue

All together, these findings suggest that blocking IL-1β-receptor activation by the interleukin-1 receptor antagonist anakinra, may reverse insulin resistance associated both with obesity and/or chronic hyperglycemia. When applied in (hyperglycemic) subjects with type 2 diabetes, blocking IL-1β should diminish the effects of glucose toxicity both at the level of beta-cell function as at the level of insulin sensitivity. When applied in (hyperglycemic) subjects with type 1 diabetes, the effects of glucose toxicity at the level of insulin sensitivity should decrease.

In order to be able to study an isolated effect of IL-1β blockade on insulin sensitivity, this study will test this hypothesis in subjects with type 1 diabetes and hence provide a proof of principle in vivo in humans for a proposed link between hyperglycemia, inflammation and insulin resistance.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 16
• Est. completion date: December 2011
• Est. primary completion date: September 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Type 1 diabetes for more than 5 years

• Body mass index of > 25 kg/m2

• Insulin requirement > 0.5 U/kg bodyweight

• HbA1c>7.5%, stable glycemic control

Exclusion Criteria:

• Inability to give informed consent

• Presence of any medical condition that might interfere with the current study protocol.

• Immunodeficiency or immunosuppressive treatment (including TNFa blocking agents and corticosteroids)

• Anti-inflammatory drugs (including nonsteroidal anti-inflammatory drugs, 100 mg or less of aspirin per day is allowed)

• Signs of current infection (fever, C-reactive protein (CRP) > 30 mmol/l, treatment with antibiotics, previous or current diagnosis of tuberculosis.

• A history of recurrent infections

• Pregnancy or breast-feeding (contraception of at least 3 months before inclusion is required for fertile women)

• Liver disease (aspartate aminotransferase or alanine aminotransferase level of more than three times the upper limit of normal range)

• Renal disease (creatinine > 130 µmol/l

• Neutropenia < 2 x 109/l

Study Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• Insulin Resistance

Intervention

Drug:
• kineret
once daily 100 mg of kineret subcutaneously for 8 days

Locations

Country	Name	City	State
Netherlands	Radboud University Nijmegen Medical Centre	Nijmegen

Sponsors (1)

Lead Sponsor	Collaborator
Radboud University

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	insulin sensitivity as determined by euglycemic hyperinsulinemic clamp	insulin sensitivity measured by euglycemic hyperinsulinemic clamp	change in insulin sensitivity after 1 week of treatment with anakinra as compared to baseline	No
Secondary	glycemic control	HbA1c, fasting glucose	baseline, after 1 week of treatment and 4 weeks after treatment termination	No
Secondary	adipocyte insulin sensitivity		baseline, after 1 week of treatment, 4 weeks after treatment termination	No
Secondary	circulating hormonal and inflammatory factors and lipid profile		baseline, after 1 week of treatment, 4 weeks after treatment termination	No
Secondary	insulin sensitivity as determined by euglycemic hyperinsulinemic clamp	insulin sensitivity measured by euglycemic hyperinsulinemic clamp	change in insulin sensitivity 4 weeks after stopping anakinra treatment as compared to baseline	No