Clinical trial NCT01285245: Effect of Anakinra on Insulin Sensitivity in Type 1 Diabetes Mellitus
Official title: Effect of Interleukin-1 Receptor Antagonist on Insulin Sensitivity in Type 1 Diabetes Mellitus.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Diabetes Mellitus
Keywords: insulin sensitivity
interleukin-1 receptor antagonist
inflammation
hyperglycemia-induced insulin resistance
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
First posted: 2011-01-27
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: insulin sensitivity as determined by euglycemic hyperinsulinemic clamp
timeFrame: change in insulin sensitivity after 1 week of treatment with anakinra as compared to baseline
Secondary outcomes:
measure: glycemic control
timeFrame: baseline, after 1 week of treatment and 4 weeks after treatment termination
measure: adipocyte insulin sensitivity
timeFrame: baseline, after 1 week of treatment, 4 weeks after treatment termination
measure: circulating hormonal and inflammatory factors and lipid profile
timeFrame: baseline, after 1 week of treatment, 4 weeks after treatment termination
measure: insulin sensitivity as determined by euglycemic hyperinsulinemic clamp
timeFrame: change in insulin sensitivity 4 weeks after stopping anakinra treatment as compared to baseline
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboud University Nijmegen Medical Centre
Study officials:
affiliation: Radboud University Medical Center
name: Cees J Tack, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: