Age- and islet autoimmunity-associated differences in amino acid and lipid metabolites in children at risk for type 1 diabetes

Abstract

Objective: Islet autoimmunity precedes type 1 diabetes and often initiates in childhood. Phenotypic variation in islet autoimmunity relative to the age of its development suggests heterogeneous mechanisms of autoimmune activation. To support this notion, we examined whether serum metabolite profiles differ between children with respect to islet autoantibody status and the age of islet autoantibody development.

Research design and methods: The study analyzed 29 metabolites of amino acid metabolism and 511 lipids assigned to 12 lipid clusters in children, with a type 1 diabetic parent, who first developed autoantibodies at age 2 years or younger (n = 13), at age 8 years or older (n = 22), or remained autoantibody-negative, and were matched for age, date of birth, and HLA genotypes (n = 35). Ultraperformance liquid chromatography and mass spectroscopy were used to measure metabolites and lipids quantitatively in the first autoantibody-positive and matched autoantibody-negative serum samples and in a second sample after 1 year of follow-up.

Results: Differences in the metabolite profiles were observed relative to age and islet autoantibody status. Independent of age-related differences, autoantibody-positive children had higher levels of odd-chain triglycerides and polyunsaturated fatty acid-containing phospholipids than autoantibody-negative children and independent of age at first autoantibody appearance (P < 0.0001). Consistent with our hypothesis, children who developed autoantibodies by age 2 years had twofold lower concentration of methionine compared with those who developed autoantibodies in late childhood or remained autoantibody-negative (P < 0.0001).

Conclusions: Distinct metabolic profiles are associated with age and islet autoimmunity. Pathways that use methionine are potentially relevant for developing islet autoantibodies in early infancy.

FIG. 1.

Flowchart of study population for the metabolomic analysis. Heavy boxed categories (N = 70) were included in the analysis (material at −80°C was available). All 70 children were tested for metabolomics at seroconversion to islet autoantibodies (ABs) or at the respective age in AB− children as well as 1 year thereafter. T1D, type 1 diabetes.

FIG. 2.

Islet autoimmunity–associated differences. Concentrations of metabolites of the amino acid metabolism (left panels) and lipid metabolism (right panels) are plotted for islet autoantibody-positive (AB+) children (n = 35) and autoantibody-negative (AB−) children (n = 35). Only metabolites where significant differences were observed (P < 0.05) are shown. Medians are indicated.

FIG. 3.

Islet autoimmunity–associated differences stratified by age. Upper panels: Concentrations of methionine and LC8 are plotted for islet autoantibody-positive (AB+) children developing AB at age ≤2 or ≥8 years, and age-matched autoantibody-negative (AB−) children, respectively. Medians are indicated. Lower panels: Methionine concentrations are plotted against LC8 concentrations for children age ≤2 years (lower left panel) and children age ≥8 years (lower right panel). Concentrations are negatively correlated in the younger age-group (r = −0.6, P = 0.001) but do not correlate in the older age-group (P = 0.9). Islet AB+ children (●) and AB− children (○) are indicated. Circled are children with a low methionine/high LC8 profile. (A high-quality color representation of this figure is available in the online issue.)

FIG. 4.

Metabolite concentrations are relatively consistent over time. The concentrations of methionine (left panels) and LC8 (right panels) in the first sample at seroconversion and respectively matched samples from autoantibody-negative (AB−) children are plotted against the concentrations in a second sample obtained 1 year later. Correlations are shown for children age ≤2 years (upper panels) and ≥8 years (lower panels). Islet autoantibody-positive (AB+) children (●) and AB− children (○) are indicated.

FIG. 5.

Methionine concentrations preseroconversion. A: Comparison of methionine concentration in the preseroconversion samples from early autoantibody-positive (AB+) children and their matched control subjects. B: Methionine concentrations in sequential samples from preseroconversion to postseroconversion in the early AB+ children (n = 13, left panel) and their matched control subjects (n = 13, right panel). AB−, autoantibody-negative.