Effect of Anakinra on Insulin Sensitivity in Type 1 Diabetes Mellitus

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Diabetes Mellitus

Intervention / Treatment
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* Drug: kineret


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: kineret<br> | Drug: kineret<br>* once daily 100 mg of kineret subcutaneously for 8 days<br>* Other names: interleukin-1 receptor antagonist;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| glycemic control | HbA1c, fasting glucose | baseline, after 1 week of treatment and 4 weeks after treatment termination | 
| 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 | insulin sensitivity measured by euglycemic hyperinsulinemic clamp | change in insulin sensitivity 4 weeks after stopping anakinra treatment as compared to baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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insulin sensitivity, interleukin-1 receptor antagonist, inflammation, hyperglycemia-induced insulin resistance