Effect of Anakinra on Insulin Sensitivity in Type 1 Diabetes Mellitus

Radboud University Medical Center

Status and phase

Unknown

Phase 2

Conditions

Diabetes Mellitus

Treatments

Drug: kineret

Study type

Interventional

Funder types

Other

Identifiers

NCT01285245

NL34377.091.10

2010-023479-24 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment

16 estimated patients

Sex

All

Ages

18 to 65 years old

Volunteers

No 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