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

Pflueger M, Seppänen-Laakso T, Suortti T, Hyötyläinen T, Achenbach P, Bonifacio E, Orešič M, Ziegler AG - Diabetes (2011)

Bottom Line: 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.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).Distinct metabolic profiles are associated with age and islet autoimmunity.

View Article: PubMed Central - PubMed

Affiliation: Forschergruppe Diabetes eV at Helmholtz Center Munich, Neuherberg, Germany.

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.

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Related in: MedlinePlus

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.)
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Figure 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.)

Mentions: Methionine and LC8 lipids were analyzed in relation to the age of antibody development (Fig. 3). Methionine concentration differed markedly in the children who developed islet autoantibodies early compared with those who developed them late (P = 0.00009), but not between the two control groups. The median methionine levels were low in early antibody-positive children (17.4 μmol/L) compared with late autoantibody-positive children (30.7 μmol/L), early autoantibody-negative control children (36.3 μmol/L), and late autoantibody-negative control children (30.5 μmol/L; all P < 0.0001). In view of the observations in the stratified analysis, a multivariate analysis was performed to test for interaction between islet autoantibody positivity and age at autoantibody appearance in their contribution to methionine concentration. The model that included potential confounders was markedly improved by the inclusion of the interaction. Methionine concentration was significantly associated with islet autoantibody positivity (P = 5 × 10−11), the interaction of islet autoantibody positivity, and age of appearance (P = 7 × 10−9). This was also observed if only the cases of multiple islet autoantibodies were considered (P = 3 × 10−7 for islet autoantibodies; P = 3 × 10−5 for interaction).


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

Pflueger M, Seppänen-Laakso T, Suortti T, Hyötyläinen T, Achenbach P, Bonifacio E, Orešič M, Ziegler AG - Diabetes (2011)

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.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198092&req=5

Figure 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.)
Mentions: Methionine and LC8 lipids were analyzed in relation to the age of antibody development (Fig. 3). Methionine concentration differed markedly in the children who developed islet autoantibodies early compared with those who developed them late (P = 0.00009), but not between the two control groups. The median methionine levels were low in early antibody-positive children (17.4 μmol/L) compared with late autoantibody-positive children (30.7 μmol/L), early autoantibody-negative control children (36.3 μmol/L), and late autoantibody-negative control children (30.5 μmol/L; all P < 0.0001). In view of the observations in the stratified analysis, a multivariate analysis was performed to test for interaction between islet autoantibody positivity and age at autoantibody appearance in their contribution to methionine concentration. The model that included potential confounders was markedly improved by the inclusion of the interaction. Methionine concentration was significantly associated with islet autoantibody positivity (P = 5 × 10−11), the interaction of islet autoantibody positivity, and age of appearance (P = 7 × 10−9). This was also observed if only the cases of multiple islet autoantibodies were considered (P = 3 × 10−7 for islet autoantibodies; P = 3 × 10−5 for interaction).

Bottom Line: 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.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).Distinct metabolic profiles are associated with age and islet autoimmunity.

View Article: PubMed Central - PubMed

Affiliation: Forschergruppe Diabetes eV at Helmholtz Center Munich, Neuherberg, Germany.

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.

Show MeSH
Related in: MedlinePlus