Effect of Anakinra on Insulin Sensitivity in Type 1 Diabetes Mellitus

Sponsor

Radboud University Medical Center (Other)

Overall Status

Unknown status

CT.gov ID

NCT01285245

Collaborator

(none)

Enrollment

Location

Arm

Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus	Drug: kineret	Phase 2

Detailed 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

16 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Apr 1, 2011

Anticipated Primary Completion Date :

Sep 1, 2011

Anticipated Study Completion Date :

Dec 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: kineret	Drug: kineret once daily 100 mg of kineret subcutaneously for 8 days Other Names: anakinra interleukin-1 receptor antagonist

Arm

Intervention/Treatment

Experimental: kineret

Drug: kineret

once daily 100 mg of kineret subcutaneously for 8 days

Other Names:

anakinra

interleukin-1 receptor antagonist

Outcome Measures

Primary Outcome Measures

insulin sensitivity as determined by euglycemic hyperinsulinemic clamp [change in insulin sensitivity after 1 week of treatment with anakinra as compared to baseline]
insulin sensitivity measured by euglycemic hyperinsulinemic clamp

Secondary Outcome Measures

glycemic control [baseline, after 1 week of treatment and 4 weeks after treatment termination]
HbA1c, fasting glucose
adipocyte insulin sensitivity [baseline, after 1 week of treatment, 4 weeks after treatment termination]
circulating hormonal and inflammatory factors and lipid profile [baseline, after 1 week of treatment, 4 weeks after treatment termination]
insulin sensitivity as determined by euglycemic hyperinsulinemic clamp [change in insulin sensitivity 4 weeks after stopping anakinra treatment as compared to baseline]
insulin sensitivity measured by euglycemic hyperinsulinemic clamp

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 TNFα 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