Effect of Anakinra on Insulin Sensitivity in Type 1 Diabetes Mellitus

Effect of Interleukin-1 Receptor Antagonist 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.

Study Overview

• Status: Unknown
• Conditions: Diabetes Mellitus
• Intervention / Treatment: Drug: kineret

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.

• Study Type: Interventional
• Enrollment (Anticipated): 16
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Nijmegen, Netherlands, 6500HB
    • Recruiting
    • Radboud University Nijmegen Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: kineret	Drug: kineret; once daily 100 mg of kineret subcutaneously for 8 days; Other Names: anakinra; interleukin-1 receptor antagonist

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
insulin sensitivity as determined by euglycemic hyperinsulinemic clamp	insulin sensitivity measured by euglycemic hyperinsulinemic clamp	change in insulin sensitivity after 1 week of treatment with anakinra as compared to baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
glycemic control	HbA1c, fasting glucose	baseline, after 1 week of treatment and 4 weeks after treatment termination
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	insulin sensitivity measured by euglycemic hyperinsulinemic clamp	change in insulin sensitivity 4 weeks after stopping anakinra treatment as compared to baseline

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Principal Investigator: Cees J Tack, MD PhD, Radboud University Medical Center

Study record dates

Study Major Dates

• Study Start: April 1, 2011
• Primary Completion (Anticipated): September 1, 2011
• Study Completion (Anticipated): December 1, 2011

Study Registration Dates

• First Submitted: November 26, 2010
• First Submitted That Met QC Criteria: January 26, 2011
• First Posted (Estimate): January 27, 2011

Study Record Updates

• Last Update Posted (Estimate): April 14, 2011
• Last Update Submitted That Met QC Criteria: April 13, 2011
• Last Verified: November 1, 2010

More Information

Terms related to this study

• Keywords: insulin sensitivity; inflammation; interleukin-1 receptor antagonist; hyperglycemia-induced insulin resistance
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Hyperinsulinism; Hypersensitivity; Diabetes Mellitus; Diabetes Mellitus, Type 1; Insulin Resistance; Antirheumatic Agents; Interleukin 1 Receptor Antagonist Protein
• Other Study ID Numbers: NL34377.091.10; 2010-023479-24 (EudraCT Number)