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Objective: The wolframin gene, WFS1, encodes a glucoprotein involved in the calcium homeostasis of the endoplasmatic reticulum; WFS1 is critical for the function and survival of the pancreatic beta-cells. Genetic variation within the WFS1 gene is known to be associated with T2D and for rare variants the Wolfram syndrome. The aim of this study was to investigate the impact of a common genetic variant (rs10010131) of the WFS1 gene on disease progression in a group of children newly diagnosed with T1D. Methods: The study is a multicenter longitudinal investigation with 18 participating paediatric centres from 15 countries. Clinical information and blood samples were collected from 275 children less than 16 years at diagnosis and at 1, 6, and 12 months after onset. Genotyping of the rs10010131 variant was done by KBioscience using an in-house KASPar assay system. Statistics: C-peptide, HbA1c, IDAA1c and proinsulin were analysed by multiple regression using age at onset, gender, DKA at onset, HLA class II risk groups, and genotypes as explanatory factors in a compound symmetric repeated measurement model. Results: The genotype frequencies were: 17% (AA), 48% (AG), 35% (GG), where the G allele is the wildtype allele. In a dominant model the G allele carriers of the rs10010131 variant was significantly positively associated with stimulated C-peptide (est.: 1.73, P < 0.0001), negatively with HbA1c (est.: )0.49, P = 0.005), negatively with IDAA1c (est.: )0.67, P = 0.02) and positively with proinsulin (est.: 1.55, P = 0.005) the first 12 month after disease onset compared to the AA genotype carriers. Conclusions: A common variant of the WFS1 gene is highly associated with better residual beta-cell function and corresponding better metabolic control during disease progression in new onset T1D compared to AA genotype

Objectives: Direct measurement of C-peptide has been recommended to provide the most appropriate primary outcome in trials evaluating the efficacy of therapies to preserve beta-cell function. The aim of the present study was to quantitatively characterize the natural history of disease progression as assessed by stimulated C-peptide the first 12 months after diagnosis in children with new onset T1D in two independent cohorts collected over a time interval of 6 years. Furthermore the purpose was to assess whether the natural history of disease has changed over time. Materials and methods: The International Hvidoere cohort, year 1999–2000: 275 children from 22 paediatric centers; the Danish cohort, year 2005–2006: 130 children from 4 paediatric centers. All patients went through a 90-minutes Boost-test 1, 3 (only the Danish cohort), 6, 12 months to characterize the residual betacell function. All samples were centrally analyzed. The linearity of the slope of decline in stimulated C-peptide was analyzed from 3–12 months on a logarithmic scale. Linear mixed-effect models were used to determine cohort differences. Results: Maximum values of stimulated C-peptide were reached at a duration of three months. Thereafter there was a linear decline in stimulated C-peptide for all age groups above 5 years in both cohorts. The mean value for the disappearance rate in stimulated C-peptide was 7.2 ± 0.9%/month for the Hvidoere and 9.4 ± 0.8%/month for the Danish cohort (NS, P = 0.12). The combined slope for both cohorts was calculated to 8.0 ± 0.7%/ month.This is in the same range as the value reported of 0.019 nmol/l/month (1982-1985) by Wallensteen corresponding to a relative change of 9.5%/month. Conclusion: Thus, the natural history of disease progression during the first 12 months after diagnosis has not changed considerably

Context: Conflicting evidence exists as to whether the Pro12Ala single nucleotide polymorphism of the type 2 diabetes susceptibility gene peroxisome proliferator-activated receptor gamma (PPARG) also confers risk for type 1 diabetes (T1D). Objective: The objective of this study was to investigate the PPARG gene in relation to residual beta-cell function and glycemic control in newly diagnosed T1D. Design: Prospective, non-interventional, 12-month follow-up study, conducted in 18 centers in 15 countries. Patients: Two hundred and fifty-seven children and adolescents (aged < 16 yr) with newly diagnosed T1D. Main outcome measures: Beta-cell function was determined as 90-min meal-stimulated C-peptide (Boost test) 1, 6, and 12 months after diagnosis. Hemoglobin A1c (HbA1c) and daily insulin dose (IU/kg/d) were recorded at 1, 3, 6, 9, and 12 months after diagnosis. Haplotypes within PPARG were estimated by SNPHAP program. Statistical analyses were performed in a repeated measurements model. Results: Five haplotypes within PPARG were generated (h1, 68.4%; h2, 16.3%; h3, 8.3%; h4, 3.5%; and hx, 3.5%). Compared with the most frequent h1 haplotype, the haplotypes h3 and h4 of the PPARG associated with residual beta-cell function during the first year of clinical disease: h3 with a 27% lower C-peptide (p = 0.02) and h4 with a 39% lower C-peptide (p = 0.01). Haplotype h4 also associated with a 0.86% (absolute) higher HbA1c, after adjustment for the insulin dose (p = 0.02). Conclusion: Variation in the PPARG locus may influence disease progression during the first year after the presentation of T1D Udgivelsesdato: 2008/8

Udgivelsesdato: 2008

The ATP-dependent K+-channel (K(ATP)) is critical for glucose sensing and normal glucagon and insulin secretion from pancreatic endocrine alpha- and beta-cells. Gastrointestinal endocrine L- and K-cells are also glucose-sensing cells secreting glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotrophic polypeptide (GIP) respectively. The aims of this study were to 1) investigate the expression and co-localisation of the K(ATP) channel subunits, Kir6.2 and SUR1, in human L- and K-cells and 2) investigate if a common hyperactive variant of the Kir6.2 subunit, Glu23Lys, exerts a functional impact on glucose-sensing tissues in vivo that may affect the overall glycaemic control in children with new-onset type 1 diabetes.

Udgivelsesdato: 2007/8