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.
Islet autoantibodies precede the development of type 1 diabetes and can appear throughout childhood (1). In prospective studies of offspring of parents with type 1 diabetes, we have observed a peak incidence of islet autoantibody appearance at the age of ∼1 year, followed by a decline through age 2 to 5 years and a subsequent rise in incidence toward puberty together with the rise in incidence of developing other autoantibodies such as thyroid peroxidase antibodies (2–4). The characteristics of the islet autoantibodies that develop in the first 2 years are not the same as those that develop later (4). Early antibodies frequently start with insulin autoantibodies (IAA), are high affinity, and spread to multiple targets, whereas children who develop islet autoantibodies late start with IAA or GAD autoantibodies (GADA) that are less likely to spread to other targets (4,5). These observations suggest age-dependent differences in the events that lead to islet autoimmunity or in the immune response to the event.
Metabolic phenotypes have been used to identify heterogeneity between subjects. The metabolomic profile has been shown to differ in a manner that is associated with genetics, environment, feeding, and disease (6–9). In type 1 diabetes, specific differences are present in islet autoantibody-positive children before islet autoantibody development (10). These could reflect early environmental exposures that influence the autoimmunization process. With respect to the heterogeneity in islet autoimmunity, we reasoned that if the age-related differences in islet autoantibody appearance reflected different immunizing events, we would observe differences in metabolomic profiles in early versus late developers of islet autoantibodies. Here we tested this by analyzing metabolomic profiles in children who developed islet autoantibodies in the first (age 1 to 2 years) and second (age ≥8 years) age peaks and in matched islet autoantibody-negative control subjects. We found differences that are dependent on age, islet autoantibody positivity, and the age of islet autoantibody development that support our hypothesis.
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.
Islet autoantibodies precede the development of type 1 diabetes and can appear throughout childhood (1). In prospective studies of offspring of parents with type 1 diabetes, we have observed a peak incidence of islet autoantibody appearance at the age of ∼1 year, followed by a decline through age 2 to 5 years and a subsequent rise in incidence toward puberty together with the rise in incidence of developing other autoantibodies such as thyroid peroxidase antibodies (2–4). The characteristics of the islet autoantibodies that develop in the first 2 years are not the same as those that develop later (4). Early antibodies frequently start with insulin autoantibodies (IAA), are high affinity, and spread to multiple targets, whereas children who develop islet autoantibodies late start with IAA or GAD autoantibodies (GADA) that are less likely to spread to other targets (4,5). These observations suggest age-dependent differences in the events that lead to islet autoimmunity or in the immune response to the event.
Metabolic phenotypes have been used to identify heterogeneity between subjects. The metabolomic profile has been shown to differ in a manner that is associated with genetics, environment, feeding, and disease (6–9). In type 1 diabetes, specific differences are present in islet autoantibody-positive children before islet autoantibody development (10). These could reflect early environmental exposures that influence the autoimmunization process. With respect to the heterogeneity in islet autoimmunity, we reasoned that if the age-related differences in islet autoantibody appearance reflected different immunizing events, we would observe differences in metabolomic profiles in early versus late developers of islet autoantibodies. Here we tested this by analyzing metabolomic profiles in children who developed islet autoantibodies in the first (age 1 to 2 years) and second (age ≥8 years) age peaks and in matched islet autoantibody-negative control subjects. We found differences that are dependent on age, islet autoantibody positivity, and the age of islet autoantibody development that support our hypothesis.
| Original language | English |
|---|---|
| Pages (from-to) | 2740-2747 |
| Number of pages | 8 |
| Journal | Diabetes |
| Volume | 60 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - 2011 |
| MoE publication type | A1 Journal article-refereed |
