Journal Article

Sustained Effects of Interleukin-1 Receptor Antagonist Treatment in Type 2 Diabetes

Faulenbach, Mirjam, Mandrup-Poulsen, Thomas, Donath, Marc Y, Ehses, Jan A, Vaag, Allan, Larsen, Claus M

2009

Overview

OBJECTIVE: Interleukin (IL)-1 impairs insulin secretion and induces β-cell apoptosis. Pancreatic β-cell IL-1 expression is increased and interleukin-1 receptor antagonist (IL-1Ra) expression reduced in patients with type 2 diabetes. Treatment with recombinant IL-1Ra improves glycemia and β-cell function and reduces inflammatory markers in patients with type 2 diabetes. Here we investigated the durability of these responses. RESEARCH DESIGN AND METHODS: Among 70 ambulatory patients who had type 2 diabetes, A1C >7.5%, and BMI >27 kg/m² and were randomly assigned to receive 13 weeks of anakinra, a recombinant human IL-1Ra, or placebo, 67 completed treatment and were included in this double-blind 39-week follow-up study. Primary outcome was change in β-cell function after anakinra withdrawal. Analysis was done by intention to treat. RESULTS: Thirty-nine weeks after anakinra withdrawal, the proinsulin-to-insulin (PI/I) ratio but not stimulated C-peptide remained improved (by -0.07 [95% CI -0.14 to -0.02], P = 0.011) compared with values in placebo-treated patients. Interestingly, a subgroup characterized by genetically determined low baseline IL-1Ra serum levels maintained the improved stimulated C-peptide obtained by 13 weeks of IL-1Ra treatment. Reductions in C-reactive protein (-3.2 mg/l [-6.2 to -1.1], P = 0.014) and in IL-6 (-1.4 ng/l [-2.6 to -0.3], P = 0.036) were maintained until the end of study. CONCLUSIONS: IL-1 blockade with anakinra induces improvement of the PI/I ratio and markers of systemic inflammation lasting 39 weeks after treatment withdrawal.

• Publisher: American Diabetes Association
• Subject: administration & dosage / antagonists / Antirheumatic Agents / Antirheumatic Agents - administration & dosage / Antirheumatic Agents - blood / Antirheumatic Agents - therapeutic use / Apoptosis / Biological and medical sciences / blood / blood glucose / blood serum / body mass index / c-peptide / C-reactive protein / Cells / Clinical Medicine / Control / Diabetes / Diabetes Mellitus, Type 2 / Diabetes Mellitus, Type 2 - drug therapy / Diabetes. Impaired glucose tolerance / drug effects / Drug therapy / Drugs / durability / Endocrine pancreas. Apud cells (diseases) / Endocrinology and Diabetes / Endocrinopathies / Endokrinologi och diabetes / Etiopathogenesis. Screening. Investigations. Target tissue resistance / Female / Health aspects / Hospitals / Humans / Hyperglycemia / inflammation / insulin secretion / Insulin-Secreting Cells / Insulin-Secreting Cells - drug effects / Insulin-Secreting Cells - metabolism / Interleukin 1 Receptor Antagonist Protein / Interleukin 1 Receptor Antagonist Protein - administration & dosage / Interleukin 1 Receptor Antagonist Protein - blood / Interleukin 1 Receptor Antagonist Protein - therapeutic use / Interleukin-1 / interleukin-6 / Klinisk medicin / Male / Measurement / Medical and Health Sciences / Medical sciences / Medicin och hälsovetenskap / Metabolic diseases / metabolism / Miscellaneous / noninsulin-dependent diabetes mellitus / Original Research / patients / Physical examinations / Public health. Hygiene / Public health. Hygiene-occupational medicine / Regression analysis / therapeutic use / Type 2 diabetes / Young Adult