Effect of Anakinra on Insulin Sensitivity in Type 1 Diabetes Mellitus
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.
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