Effect of Anakinra on Insulin Sensitivity in Type 1 Diabetes Mellitus

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.

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.

insulin sensitivity, interleukin-1 receptor antagonist, inflammation, hyperglycemia-induced insulin resistance

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