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- Niklasson, Bo, et al.
(author)
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Prenatal viral exposure followed by adult stress produces glucose intolerance in a mouse model
- 2006
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In: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 49:9, s. 2192-2199
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Journal article (peer-reviewed)abstract
- Aims/hypothesis: It has been suggested that the uterine environment may influence metabolic disease occurring later in adult life, and that adult stress may promote disease outcome. Using a mouse model, we tested whether in utero exposure to Ljungan virus (LV) followed by adult exposure to stress produces diabetes. The influence of the timing of viral exposure over the course of pregnancy was also tested. Materials and methods: Pregnant CD-1 mice were exposed i.p. to LV on pregnancy days 4, 8, 12 or 17. Adult male mice from these pregnancies were stressed by being kept in shared cages. Stress only, LV exposure in utero only, and no-stress/no virus exposure groups were also followed. Outcome variables included bodyweight, epididymal fat weight, baseline glucose, glucose tolerance tests (60 and 120 min) and serum insulin. Results: We demonstrated that male mice developed a type 2-like diabetes, including obesity, as adults if infected during pregnancy with LV. Diabetes at the age of 11 weeks was more severe in mice whose mothers were infected earlier than in those whose mothers were infected later in pregnancy. Only animals infected in utero and kept under stress developed diabetes; infection or stress alone did not cause disease. Conclusions/interpretation: This work demonstrates that a type 2 diabetes-like disease can be virus-induced in a mouse model. Early in utero viral insults can set the stage for disease occurring during adult life, but the final manifestation of diabetes is dependent on the combination of early viral exposure and stress in adult life.
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- Sanjeevi, C. B., et al.
(author)
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Association between autoantibody markers and subtypes of DR4 and DR4-DQ in Swedish children with insulin-dependent diabetes reveals closer association of tyrosine pyrophosphatase autoimmunity with DR4 than DQ8
- 1998
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In: Tissue Antigens. - : Wiley. - 0001-2815 .- 1399-0039. ; 51:3, s. 281-286
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Journal article (peer-reviewed)abstract
- HLA DQA1(*)0301-DQB1(*)0302 (DQ8) and DQA1(*)0501-DQB1(*)0201 (DQ2) are positively and DQA1(*)0102-DQB1(*)0602 (DQ6) negatively associated with IDDM. In DQA1(*)0301-DQB1(*)0302 (DQ8)-positive patients, susceptibility is also mediated by DRB1(*)0401. The aim of the study was to determine the association between HLA-DR4 and DQ and the presence of GAD65, ICA512, and insulin autoantibodies as well as ICA in 425 Swedish children with IDDM and 367 controls in the age group of 0-15 years. We found that ICA512 autoantibodies were associated primarily with DRB1(*)0401 and not with DQA1(*)0301-DQB1(*)0302 (DQ8). No such hierarchy could be demonstrated for insulin autoantibodies, which were associated with both DQA1(*)0301-DQB1(*)0302 (DQ8) and DRB1(*)0401. GAD65 autoantibodies, known to be closely associated with DQA1(*)0501-DQB1(*)0201 (DQ2)-DRB1(*)0301 haplotype, also showed no preferential association with DQA1(*)0301-DQB1(*)0302 (DQ8) versus DRB1(*)04. These results suggest that the immune response to different β-cell autoantigens may be mediated via HLA class II molecules from different loci. Design of the antigen-specific immuno-intervention trials should take into account these HLA-DR and DQ subtype associations.
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- Törn, C., et al.
(author)
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Prognostic factors for the course of beta cell function in autoimmune diabetes
- 2000
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In: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 85:12, s. 4619-4623
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Journal article (peer-reviewed)abstract
- This study presents a 2-yr follow-up of 281 patients, aged 15-34 yr, diagnosed with diabetes between 1992 and 1993. At diagnosis, 224 (80%) patients were positive for at least one of the following autoantibodies: islet cell antibodies (ICAs), glutamic acid decarboxylase antibodies (GADAs), or tyrosine phosphatase antibodies (IA-2As), the remaining 57 (20%) patients were negative for all three autoantibodies. At diagnosis, C-peptide levels were lower (0.27, 0.16-0.40 nmol/L) in autoantibody-positive patients compared with autoantibody-negative patients (0.51, 0.28-0.78 nmol/L, P < 0.001). After 2 yr, C-peptide levels had decreased significantly in patients with autoimmune diabetes (0.20, 0.10-0.37 nmol/L, P = 0.0018), but not in autoantibody-negative patients. In patients with autoimmune diabetes, a low initial level of C-peptide (odds ratio, 2.6, 95% confidence interval, 1.7-4.0) and a high level of GADAs (odds ratio, 2.5, 95% confidence interval, 1.1-5.7) were risk factors for a C-peptide level below the reference level of 0.25 nmol/L 2 yr after diagnosis. Body mass index had a significant effect in the multivariate analysis only when initial C-peptide was not considered. Factors such as age, gender, levels of ICA or IA-2A or insulin autoantibodies (analyzed in a subset of 180 patients) had no effect on the decrease in ▀-cell function. It is concluded that the absence of pancreatic islet autoantibodies at diagnosis were highly predictive for a maintained ▀-cell function during the 2 yr after diagnosis, whereas high levels of GADA indicated a course of decreased ▀-cell function with low levels of C-peptide. In autoimmune diabetes, an initial low level of C-peptide was a strong risk factor for a decrease in ▀-cell function and conversely high C-peptide levels were protective. Other factors such as age, gender, body mass index, levels of ICA, IA-2A or IAA had no prognostic importance.
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