Determine whether blockade of IL-1 had positive effects on insulin sensitivity in type 1 diabetic subjects without residual beta cel function
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
insulin sensitivity as determined by the euglycemic hyperinsulinemic clamp
technique
Secondary outcome
glycemic control
adipocyte insulin sensitivity
changes in circulating hormonal and inflammatory factors and lipid profile.
Background summary
Deminished insulin sensitivity is the primary defect in type 2 diabetes
mellitus and does also play an important role in the pathophysiology of type 1
diabetes mellitus. Obesity induced inflammation appears to be an important
factor in the origination of insulin resistance. Once diabetes
has emerged chronically elevated glucose levels are another factor in the
induction of insulin resistance.
TNFalpha and IL-6 are the best known pro-inflammatory cytokines which are
involved in the induction of insulin resistance. However there are multiple
studies which find a positive association between IL-1 and obesity too.
Furthermore IL-1 leads to insulin resistance in human adipocytes.
It has been shown before that blocking IL-1, using anakinra, in type 2 diabetic
patients results in better glycemic control. Another trial showed that an
anti-IL-1 antibody improved the glycemic control in mice.
Alltogether these results suggest that blocking of IL-1 should improve glucose
control. When this would be tested in type 2 diabetic subjects the blockade of
IL-1 would potentially have possitive effects on the beta-cell as well as on
the insulin sensitivity. A direct effect on one of these two mechanistic
possibilities could theoratically lead to an indirect improvement of the other
possibility by inhibition of glucose toxicity. In type 1 diabetics without
residual beta-cell function the effect of IL-1 blockade on glycemic control can
only be the direct effect of deminished insulin resistance.
Study objective
Determine whether blockade of IL-1 had positive effects on insulin sensitivity
in type 1 diabetic subjects without residual beta cel function
Study design
Open label research project. 15 Patients with type I diabetes mellitus are
treated during 1 week with interleukin-1 receptor antagonist (anakinra) 100 mg
subcutaneous once daily. Before, directly after and after 4 weeks insulin
sensitivity is determined using a clamp technique. At the same time points as
the clamp a fatbiopsy is taken.
Intervention
anakinra 100 mg subcutaneous once daily during 8 days.
Study burden and risks
There is a very low chance on serious side effects of the study medication,
evenmore because of the short treatment period. Furthermore the study
medication and the used dose is approved by EMA. Subjects are requested to
contact the researchers in case of fever or other complaints which might be
caused by the study.
In respect to the diagnostic procedures (euglycemic hyperinsulinemic clamp and
fatbiopsy) there is much experience in our research group and complications are
very uncommon.
The participating subjects are required to keep a diary and to visit the
hospital three times. This implies a reasonable time investment for the
subjects. At the other side the trial does not run for a long time interval.
Furthermore blood collection is planned on three time points, fatbiopsy is
taken on two occasions.
Postbus 9101
6500 HB Nijmegen
NL
Postbus 9101
6500 HB Nijmegen
NL
Listed location countries
Age
Inclusion criteria
Type 1 diabetes with absence of residual Beta-cell function
Age 18-65 yrs
Body mass index of > 25 kg/m2
Insulin requirement > 0.5 U/kg bodyweight
HbA1c > 8.5% for the last 6 months
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
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-023479-24-NL |
| CCMO | NL34377.091.10 |