effect of anakinra on insulin sensitivity in type 1 diabetes mellitus

Conditions: Diabetes Mellitus

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.

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.

Eligibility criteria:
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

Keywords: insulin sensitivity interleukin-1 receptor antagonist inflammation hyperglycemia-induced insulin resistance