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Metabolomics makes a mark: early changes associated with autoimmune diabetes.

Leslie RD, Beyan H - Diabetes (2011)

View Article: PubMed Central - PubMed

Affiliation: Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK. r.d.g.leslie@qmul.ac.uk

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History, to the Roman Cicero, is “the witness of time, the life of memory, the mistress of life. ” But history can be a cruel mistress, illustrating all we have not achieved... Autoantibody-positive children, with an IFIH1 disease-protective genotype, progress less rapidly to diabetes than those with different genotypes... It is also less complex than genomic or proteomic analyses, given the numbers of human endogenous metabolites (several thousand) compared with gene variants (multiple polymorphisms of ∼3 × 10 human genes) and proteins (∼5 × 10 –10, including splicing variants and posttranslational modifications)... A remarkable study of 56 children who progressed to type 1 diabetes found that phosphatidylcholine was reduced at birth, independent of HLA risk, with increased levels of proinflammatory lysophosphatidylcholine several months before seroconversion to autoantibody positivity, but not thereafter... Methionine, like choline, is an epigenetic regulator, the former because it is a methyl-donor, important in transmethylation and one-carbon moiety pathways... Methionine is, therefore, involved in DNA methylation, an epigenetic effect putatively involved in autoimmunity... However, the low plasma methionine in the young high disease-risk subset is not likely to cause diabetes, since it is only found in very young autoantibody-positive children, more likely reflecting a marker for rapid disease progression... These observations bring us back to the heterogeneity of autoimmune diabetes according to age at diagnosis, which is severe and insulin dependent in childhood but often mild and noninsulin requiring in adulthood... That heterogeneity highlights the differential character of the disease process beyond clinical differences... Thus, children at diagnosis compared with adults have higher HLA genetic risk, more antigen-specific autoantibodies, and greater insulin deficiency... Autoantibodies appearing after age 8 years are often directed against single antigens, at low titer, with reduced predictive value... If, as seems likely, autoantibodies reflect disease-associated environmental events, then the timing of that critical exposure impacts clinical outcome... Autoimmune diabetes has a broad clinical spectrum according to age at diagnosis... That spectrum is now shown to result from differential immunogenetic and nongenetic effects, including metabolic effects, in the prediabetic period, and these effects influence the likelihood and rate of disease progression (Fig. 1).

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Minimal model of autoimmune diabetes. Tissue inflammation (around insulin secreting cells in purple with CD3 cells in green and CD3/CD45 cells in yellow) is reflected in the production of serum autoantibodies. Factors are detailed that may predispose in genetically susceptible subjects to 1) autoantibodies and 2) progression to clinical disease. Autoantibodies to glutamic acid decarboxylase (GADA); insulinoma-associated antigen 2 (IA-2A); zinc transporter 8 (ZnT8A); insulin (IAA). (A high-quality digital representation of this figure is available in the online issue.)
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Figure 1: Minimal model of autoimmune diabetes. Tissue inflammation (around insulin secreting cells in purple with CD3 cells in green and CD3/CD45 cells in yellow) is reflected in the production of serum autoantibodies. Factors are detailed that may predispose in genetically susceptible subjects to 1) autoantibodies and 2) progression to clinical disease. Autoantibodies to glutamic acid decarboxylase (GADA); insulinoma-associated antigen 2 (IA-2A); zinc transporter 8 (ZnT8A); insulin (IAA). (A high-quality digital representation of this figure is available in the online issue.)

Mentions: These observations bring us back to the heterogeneity of autoimmune diabetes according to age at diagnosis, which is severe and insulin dependent in childhood but often mild and noninsulin requiring in adulthood (15). That heterogeneity highlights the differential character of the disease process beyond clinical differences. Thus, children at diagnosis compared with adults have higher HLA genetic risk, more antigen-specific autoantibodies, and greater insulin deficiency (15). Genetic risk aside, such heterogeneity could result from similar environmental events operating at disparate times, different factors operating at the same time, or both. Evidence supports the latter (Fig. 1). Age at diagnosis is strongly correlated with age of appearance of the first autoantibody; when autoantibodies appear before age 5 years, they tend to be multiple, antigen-specific, isotype restricted, high titer, and highly predictive of disease (4). Autoantibodies appearing after age 8 years are often directed against single antigens, at low titer, with reduced predictive value (4). If, as seems likely, autoantibodies reflect disease-associated environmental events, then the timing of that critical exposure impacts clinical outcome. Such distinctions are now shown to encompass metabolic changes, including low plasma methionine, with the caveat that metabolomics, like autoantibodies, may be an epiphenomenon. As when immunogenetic changes were initially identified, future developments will be methodological and descriptive—the former through improved assays and sample collection, the latter by exploiting cohort studies, other diseases, and animal models to define the robustness, specificity, and causation of the results (16).


Metabolomics makes a mark: early changes associated with autoimmune diabetes.

Leslie RD, Beyan H - Diabetes (2011)

Minimal model of autoimmune diabetes. Tissue inflammation (around insulin secreting cells in purple with CD3 cells in green and CD3/CD45 cells in yellow) is reflected in the production of serum autoantibodies. Factors are detailed that may predispose in genetically susceptible subjects to 1) autoantibodies and 2) progression to clinical disease. Autoantibodies to glutamic acid decarboxylase (GADA); insulinoma-associated antigen 2 (IA-2A); zinc transporter 8 (ZnT8A); insulin (IAA). (A high-quality digital 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=PMC3198102&req=5

Figure 1: Minimal model of autoimmune diabetes. Tissue inflammation (around insulin secreting cells in purple with CD3 cells in green and CD3/CD45 cells in yellow) is reflected in the production of serum autoantibodies. Factors are detailed that may predispose in genetically susceptible subjects to 1) autoantibodies and 2) progression to clinical disease. Autoantibodies to glutamic acid decarboxylase (GADA); insulinoma-associated antigen 2 (IA-2A); zinc transporter 8 (ZnT8A); insulin (IAA). (A high-quality digital representation of this figure is available in the online issue.)
Mentions: These observations bring us back to the heterogeneity of autoimmune diabetes according to age at diagnosis, which is severe and insulin dependent in childhood but often mild and noninsulin requiring in adulthood (15). That heterogeneity highlights the differential character of the disease process beyond clinical differences. Thus, children at diagnosis compared with adults have higher HLA genetic risk, more antigen-specific autoantibodies, and greater insulin deficiency (15). Genetic risk aside, such heterogeneity could result from similar environmental events operating at disparate times, different factors operating at the same time, or both. Evidence supports the latter (Fig. 1). Age at diagnosis is strongly correlated with age of appearance of the first autoantibody; when autoantibodies appear before age 5 years, they tend to be multiple, antigen-specific, isotype restricted, high titer, and highly predictive of disease (4). Autoantibodies appearing after age 8 years are often directed against single antigens, at low titer, with reduced predictive value (4). If, as seems likely, autoantibodies reflect disease-associated environmental events, then the timing of that critical exposure impacts clinical outcome. Such distinctions are now shown to encompass metabolic changes, including low plasma methionine, with the caveat that metabolomics, like autoantibodies, may be an epiphenomenon. As when immunogenetic changes were initially identified, future developments will be methodological and descriptive—the former through improved assays and sample collection, the latter by exploiting cohort studies, other diseases, and animal models to define the robustness, specificity, and causation of the results (16).

View Article: PubMed Central - PubMed

Affiliation: Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK. r.d.g.leslie@qmul.ac.uk

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

History, to the Roman Cicero, is “the witness of time, the life of memory, the mistress of life. ” But history can be a cruel mistress, illustrating all we have not achieved... Autoantibody-positive children, with an IFIH1 disease-protective genotype, progress less rapidly to diabetes than those with different genotypes... It is also less complex than genomic or proteomic analyses, given the numbers of human endogenous metabolites (several thousand) compared with gene variants (multiple polymorphisms of ∼3 × 10 human genes) and proteins (∼5 × 10 –10, including splicing variants and posttranslational modifications)... A remarkable study of 56 children who progressed to type 1 diabetes found that phosphatidylcholine was reduced at birth, independent of HLA risk, with increased levels of proinflammatory lysophosphatidylcholine several months before seroconversion to autoantibody positivity, but not thereafter... Methionine, like choline, is an epigenetic regulator, the former because it is a methyl-donor, important in transmethylation and one-carbon moiety pathways... Methionine is, therefore, involved in DNA methylation, an epigenetic effect putatively involved in autoimmunity... However, the low plasma methionine in the young high disease-risk subset is not likely to cause diabetes, since it is only found in very young autoantibody-positive children, more likely reflecting a marker for rapid disease progression... These observations bring us back to the heterogeneity of autoimmune diabetes according to age at diagnosis, which is severe and insulin dependent in childhood but often mild and noninsulin requiring in adulthood... That heterogeneity highlights the differential character of the disease process beyond clinical differences... Thus, children at diagnosis compared with adults have higher HLA genetic risk, more antigen-specific autoantibodies, and greater insulin deficiency... Autoantibodies appearing after age 8 years are often directed against single antigens, at low titer, with reduced predictive value... If, as seems likely, autoantibodies reflect disease-associated environmental events, then the timing of that critical exposure impacts clinical outcome... Autoimmune diabetes has a broad clinical spectrum according to age at diagnosis... That spectrum is now shown to result from differential immunogenetic and nongenetic effects, including metabolic effects, in the prediabetic period, and these effects influence the likelihood and rate of disease progression (Fig. 1).

Show MeSH
Related in: MedlinePlus