| 1. |
- Oresic, Matej, 1967-, et al.
(author)
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Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes
- 2008
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In: Journal of Experimental Medicine. - New York, USA : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 205:13, s. 2975-2984
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Journal article (peer-reviewed)abstract
- The risk determinants of type 1 diabetes, initiators of autoimmune response, mechanisms regulating progress toward beta cell failure, and factors determining time of presentation of clinical diabetes are poorly understood. We investigated changes in the serum metabolome prospectively in children who later progressed to type 1 diabetes. Serum metabolite profiles were compared between sample series drawn from 56 children who progressed to type 1 diabetes and 73 controls who remained nondiabetic and permanently autoantibody negative. Individuals who developed diabetes had reduced serum levels of succinic acid and phosphatidylcholine (PC) at birth, reduced levels of triglycerides and antioxidant ether phospholipids throughout the follow up, and increased levels of proinflammatory lysoPCs several months before seroconversion to autoantibody positivity. The lipid changes were not attributable to HLA-associated genetic risk. The appearance of insulin and glutamic acid decarboxylase autoantibodies was preceded by diminished ketoleucine and elevated glutamic acid. The metabolic profile was partially normalized after the seroconversion. Autoimmunity may thus be a relatively late response to the early metabolic disturbances. Recognition of these preautoimmune alterations may aid in studies of disease pathogenesis and may open a time window for novel type 1 diabetes prevention strategies.
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| 2. |
- Hagopian, William A., et al.
(author)
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TEDDY- The environmental determinants of diabetes in the young - An observational clinical trial
- 2006
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In: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923. ; 1079, s. 320-326
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Journal article (peer-reviewed)abstract
- The aim of the TEDDY study is to identify infectious agents, dietary factors, or other environmental agents, including psychosocial factors, which may either trigger islet autoimmunity, type 1 diabetes mellitus (T1DM), or both. The study has two end points: (a) appearance of islet autoantibodies and (b) clinical diagnosis of T1DM. Six clinical centers screen newborns for high-risk HLA genotypes. As of December 2005 a total of 54,470 newborns have been screened. High-risk HLA genotypes among 53,560 general population (GP) infants were 2576 (4.8%) and among 910 newborns with a first-degree relative (FDR) were 194 (21%). A total of 1061 children have been enrolled. The initial enrollment results demonstrate the feasibility of this complex and demanding a prospective study.
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| 3. |
- Laine, Antti-Pekka, et al.
(author)
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Two insulin gene single nucleotide polymorphisms associated with type 1 diabetes risk in the Finnish and Swedish populations
- 2007
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In: Disease Markers. - : Hindawi Limited. - 0278-0240 .- 1875-8630. ; 23:3, s. 139-45
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Journal article (peer-reviewed)abstract
- We have developed high-throughput tests for the detection of the insulin gene region SNPs -23HphI and -2221MspI. The potential of these markers to enhance the efficiency of type 1 diabetes risk screening was then evaluated by analyzing them in Finnish and Swedish populations. Blood spots on filter paper were analyzed using PCR followed by sequence-specific hybridization and time-resolved fluorometry reading. Distribution of the genotypes at both positions differed significantly among the affected children compared to the controls. The risk genotypes (CC, AA) were significantly more common in Finland than in Sweden, both among patients and controls. The VNTR genotype homozygous for the protective class III alleles showed a significantly stronger protective effect than the heterozygote (p=0.02). Analyzing both SNPs enabled the detection of VNTR class III subclasses IIIA and IIIB. The observed significance between effects of the protective genotypes was due to the strong protective effect of the IIIA/IIIA genotype. IIIA/IIIA was the only genotype with significant discrepancy between protective effects compared to the other class III genotypes. These observations suggest that heterogeneity between the protective IDDM2 lineages could exist, and analyzing both -23HphI and -2221MspI would thus potentially enhance the sensitivity and specificity of type 1 diabetes risk estimation.
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| 4. |
- Mäkelä, Miia, et al.
(author)
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Enteral virus infections in early childhood and an enhanced type 1 diabetes-associated antibody response to dietary insulin
- 2006
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In: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411 .- 1095-9157. ; 27:1, s. 54-61
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Journal article (peer-reviewed)abstract
- Enteral virus infections may trigger the development of β-cell-specific autoimmunity by interacting with the gut-associated lymphoid system. We analyzed the effect of three different virus infections on immunization to dietary insulin in children carrying increased genetic risk for type 1 diabetes. Forty-six of 238 children developed multiple diabetes-associated autoantibodies and 31 clinical diabetes (median follow-up time 75 months). Insulin-binding antibodies were measured with EIA method (median follow-up time 24 months). Antibodies to enteroviruses, rotavirus and adenovirus were measured with EIA in samples drawn at birth and the ages of 3 and 6 months. Nineteen enterovirus, 14 rotavirus and 8 adenovirus infections were diagnosed. At the ages of 6, 12, and 18 months, the concentrations of insulin-binding antibodies were higher in children with postnatal entero-, rota- and/or adenovirus infections than in children without these infections. Children who subsequently developed ICA or IA-2 antibodies or clinical type 1 diabetes had higher concentrations of insulin-binding antibodies than children who remained autoantibody negative. Our data suggest that enteral virus infections can enhance immune response to insulin, induced primarily by bovine insulin in cow's milk. An enhanced antibody response to dietary insulin preceded the development of β-cell specific autoimmunity and type 1 diabetes. © 2006 Elsevier Ltd. All rights reserved.
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| 5. |
- Nikkilä, Janne, et al.
(author)
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Gender-dependent progression of systemic metabolic states in early childhood
- 2008
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In: Molecular Systems Biology. - : Nature Publishing Group. - 1744-4292 .- 1744-4292. ; 4
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Journal article (peer-reviewed)abstract
- Little is known about the human intra-individual metabolic profile changes over an extended period of time. Here, we introduce a novel concept suggesting that children even at a very young age can be categorized in terms of metabolic state as they advance in development. The hidden Markov models were used as a method for discovering the underlying progression in the metabolic state. We applied the methodology to study metabolic trajectories in children between birth and 4 years of age, based on a series of samples selected from a large birth cohort study. We found multiple previously unknown age- and gender-related metabolome changes of potential medical significance. Specifically, we found that the major developmental state differences between girls and boys are attributed to sphingolipids. In addition, we demonstrated the feasibility of state-based alignment of personal metabolic trajectories. We show that children have different development rates at the level of metabolome and thus the state-based approach may be advantageous when applying metabolome profiling in search of markers for subtle (patho)physiological changes.
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| 6. |
- Wahlberg, Jeanette, 1969-
(author)
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Environmental determinants associated with Type 1 diabetes-related autoantibodies in children
- 2005
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Doctoral thesis (other academic/artistic)abstract
- Background Type 1 diabetes is a severe disease, which affects children with potentially severe consequences. The global incidence of Type 1 diabetes is increasing rapidly especially in young children. Second to Finland, Sweden has the highest incidence of Type 1 diabetes in the world.The rapidly increasing incidence cannot be explained by a possible variability of the presence of risk genes in the population, but rather environmental factors.Therefore, environmental factors contributing to ß-cell auto immunity should be of importance for the process leading up to clinical Type I diabetes in genetically predisposed individuals. Those factors should preferably be revealed early in life. The aim of this thesis was to investigate a large population of Swedish children in order to identify environmental factors, which could contribute to the autoimmune reaction towards insulin-producing ß-cells.Material and methodsFamilies from the prospective population-based ABIS-project (All Babies in southeast Sweden) were studied. Blood samples from children were analysed at birth, one year and 2½ years of age for diabetes-related autoantibodies towards Tyrosine phosphatase (IA-2A) and Glutamic Acid Decarboxylase (GAD). The parents completed questionnaires at birth, one year and 2½ years of age.Results Short breast-feeding period, early exposure to cow's milk formula and late introduction of gluten-containing foods as well as large consumption of cow's milk at the age of one year were all risk determinants for development of autoantibodies at 2½ years of age. Combined early introduction of cow's milk formula and late introduction of gluten-containing food increased the risk six times for acquiring persistent autoantibodies at 2½ years of age. Parenting stress and experiences of serious life events were associated with the induction of diabetes-related autoimmunity. Infections during pregnancy are related to diabetes-related autoantibodies in cord blood and at the age of one year.Allergic symptoms such as rash, wheezing, allergy against fur-bearing animals and food allergies implied a risk for development of diabetes-related autoantibodies. Autoantibodies in cord blood had disappeared at the age of one year, and can therefore not be used as a screening method to predict diabetes in the general population.ConclusionsNone of the examined risk factors alone can explain Type 1 diabetes-related autoimmunity; but early nutrition, parental stress and infections can contribute to the development of diabetes-related autoantibodies.Autoantibodies in cord blood cannot be used to predict later diabetes-related autoimmunity. Different aberrances in the immune system seem to co-exist in certain individuals.
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