Diabetes Mellitus
Conditions
Keywords
insulin sensitivity, interleukin-1 receptor antagonist, inflammation, hyperglycemia-induced insulin resistance
Brief 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.
Detailed 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.
Interventions
DRUGkineret
once daily 100 mg of kineret subcutaneously for 8 days
Sponsors
Radboud University Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| insulin sensitivity as determined by euglycemic hyperinsulinemic clamp | change in insulin sensitivity after 1 week of treatment with anakinra as compared to baseline | insulin sensitivity measured by euglycemic hyperinsulinemic clamp |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| glycemic control | baseline, after 1 week of treatment and 4 weeks after treatment termination | HbA1c, fasting glucose |
| 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 | change in insulin sensitivity 4 weeks after stopping anakinra treatment as compared to baseline | insulin sensitivity measured by euglycemic hyperinsulinemic clamp |
Countries
Netherlands
Contacts
Primary ContactEdwin JP van Asseldonk, MD
Outcome results
None listed