The systemic immune network in recent onset type 1 diabetes: central role of interleukin-1 receptor antagonist (DIATOR Trial)

Abstract

Background: The hypothesis was tested that the systemic immune milieu in recent-onset type 1 diabetes is associated with residual beta cell function and other metabolic patient characteristics.

Methods and findings: All patients (n = 89, 40% female) of the Diabetes and Atorvastatin (DIATOR) Trial were analyzed at recruitment, i.e. prior to receiving the study medication. Inclusion criteria were insulin dependent diabetes for 2 weeks to 3 months, age range 18-39 years, and islet cell autoantibodies. Blood samples were analyzed for 14 immune mediators by standard methods. Concentrations of all mediators correlated with at least one other mediator (p<0.05, Spearman correlation) giving rise to a network. Interleukin 1 receptor antagonist (IL1-RA) held a central position and was associated with both pro- and anti-inflammatory mediators. Further central elements were the pro-inflammatory mediators CRP and IL-6, the soluble adhesion molecules sICAM-1 and E-selectin, and MCP-4 which held a central position in the chemokine network. The two Th1-associated mediators IFNγ and IP-10 remained outside the network but correlated with each other. All correlations were positive (r = 0.25-0.72), i.e., high levels of pro-inflammatory mediators were accompanied by increased levels of anti-inflammatory mediators. IL-1RA was the only mediator associated with fasting and liquid mixed meal stimulated C-peptide concentrations (r = 0.31 and 0.24, p = 0.003 and 0.025, after adjustment for age, sex, BMI). There were associations between the immune mediator network and BMI (IL-1RA, CRP, IL-6, MCP-4, MIP-1ß) but few or no associations with HbA1c, insulin dose, lipid parameters, age or sex.

Conclusions: In patients with recent onset type 1 diabetes, systemic acute phase proteins, cytokines, chemokines and soluble adhesion molecules form a network. Among the few central elements IL-1RA has a dominant role. IL-1RA is associated with all other groups of mediators and is the only mediator which correlates (positively) with residual beta cell function.

Trial registration: ClinicalTrials.gov registration number: NCT00974740.

Conflict of interest statement

Competing Interests: T. Heise is and L. Heinemann was employed by Profil Institute of Metabolic Research which was contracted to conduct the trial. N.C. Schloot is employed by Lilly Deutschland GmbH. Co-author C. Herder is an Academic Editor with PlOS ONE. The trial was supported by an unrestricted grant from Pfizer Pharma GmbH, Berlin, Germany. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1. Systemic immune mediator network in patients with recent onset type 1 diabetes.

Shown are all significant correlations (p

Figure 2. Association of the immune mediator network with metabolic and general characteristics.

Associations were found primarily with core elements of the network, with a major role of IL-1RA. Peripheral elements of the network show only few correlations of systemic concentrations with metabolic parameters, and none with general characteristics. Blood lipid parameters show no association with immune mediators, with one exception. All correlations (Spearman rank) with p