Children developing type 1 diabetes before 6 years of age have increased linear growth independent of HLA genotypes.

AIMS/HYPOTHESIS: High birthweight and increased childhood growth are risk factors for type 1 diabetes. Relative birthweight is associated with HLA genotypes that confer a high risk of diabetes. Our aims were to test whether young children prior to clinical onset of type 1 diabetes have increased: (1) birthweight or birth length standard deviation scores (SDS); (2) height development SDS; or (3) BMI SDS during first 18 months of life and whether these parameters are related to HLA genotypes or mid-parental height (MPH). METHODS: Birthweight, birth length, weight and height were obtained from 58 type 1 diabetes children and 155 controls matched for HLA or not in the Diabetes Prediction in Skåne study. RESULTS: Birth length SDS corrected for MPH was increased in children developing diabetes compared with all (p < 0.048) and with non-HLA- (p < 0.050) but not with HLA-matched controls. Children developing diabetes had increased height gain at 0 to 18 months of age (p < 0.005). Diabetic children were significantly taller from 6 to 18 months of age when correcting for MPH compared with non-HLA-matched as well as HLA-matched controls, but BMI was not increased. CONCLUSIONS/INTERPRETATION: Birth length SDS was associated with diabetes risk HLA. When corrected for MPH, children developing diabetes were taller at birth than non-HLA- but not taller than HLA-matched controls. Diabetic children had increased MPH-corrected height up to 18 months of age compared with both HLA- and non-HLA-matched controls. High-risk HLA affects prenatal growth, but other factors may explain the increased postnatal linear growth in children developing diabetes

Reduced display of conformational epitopes in the N-terminal truncated GAD65 isoform : relevance for people with stiff person syndrome or DQ8/8-positive Type 1 diabetes mellitus

Aims: To investigate whether the N-terminal truncated glutamic acid decarboxylase 65 (GAD65) isoform is as well recognized by people with stiff person syndrome as it is by people with Type 1 diabetes, and whether conformational GAD65 antibody epitopes are displayed properly by the isoform. Methods: GAD65 antibody-positive healthy individuals (n=13), people with stiff-person syndrome (n=15) and children with new-onset Type 1 diabetes (n=654) were analysed to determine binding to full-length GAD65 and the N-terminal truncated GAD65 isoform in each of these settings. GAD65 autoantibody epitope specificity was correlated with binding ratios of full-length GAD65/N-terminal truncated GAD65. Results: The N-terminal truncated GAD65 isoform was significantly less recognized in GAD65Ab-positive people with stiff-person syndrome (P=0.002) and in healthy individuals (P=0.0001) than in people with Type 1 diabetes. Moreover, at least two specific conformational GAD65Ab epitopes were not, or were only partially, presented by the N-terminal truncated GAD65 isoform compared to full-length GAD65. Finally, an N-terminal conformational GAD65Ab epitope was significantly less recognized in DQ8/8 positive individuals with Type 1 diabetes (P=0.02). Conclusions: In people with stiff person syndrome preferred binding to the full-length GAD65 isoform over the N-terminal truncated molecule was observed. This binding characteristic is probably attributable to reduced presentation of two conformational epitopes by the N-terminal truncated molecule. These findings support the notion of disease-specific GAD65Ab epitope specificities and emphasize the need to evaluate the applicability of novel assays for different medical conditions

The three ZNT8 autoantibody variants together improve the diagnostic sensitivity of childhood and adolescent type 1 diabetes.

Aims: We tested whether autoantibodies to all three ZnT8RWQ variants, GAD65, insulinoma-associated protein 2 (IA-2), insulin and autoantibodies to islet cell cytoplasm (ICA) in combination with human leukocyte antigen (HLA) would improve the diagnostic sensitivity of childhood type 1 diabetes by detecting the children who otherwise would have been autoantibody-negative. Methods: A total of 686 patients diagnosed in 1996-2005 in Skåne were analyzed for all the seven autoantibodies [arginin 325 zinc transporter 8 autoantibody (ZnT8RA), tryptophan 325 zinc transporter 8 autoantibody (ZnT8WA), glutamine 325 Zinc transporter 8 autoantibody (ZnT8QA), autoantibodies to glutamic acid decarboxylase (GADA), Autoantibodies to islet-antigen-2 (IA-2A), insulin autoantibodies (IAA) and ICA] in addition to HLA-DQ genotypes. Results: Zinc transporter 8 autoantibody to either one or all three amino acid variants at position 325 (ZnT8RWQA) was found in 65% (449/686) of the patients. The frequency was independent of age at diagnosis. The ZnT8RWQA reduced the frequency of autoantibody-negative patients from 7.5 to 5.4%-a reduction by 28%. Only 2 of 108 (2%) patients who are below 5 years of age had no autoantibody at diagnosis. Diagnosis without any islet autoantibody increased with increasing age at onset. DQA1-B1(*)X-0604 was associated with both ZnT8RA (p = 0.002) and ZnT8WA (p = 0.01) but not with ZnT8QA (p = 0.07). Kappa agreement analysis showed moderate (>0.40) to fair (>0.20) agreement between pairs of autoantibodies for all combinations of GADA, IA-2A, ZnT8RWQA and ICA but only slight ( < 0.19) agreement for any combination with IAA. Conclusions: This study revealed that (1) the ZnT8RWQA was common, independent of age; (2) multiple autoantibodies were common among the young; (3) DQA1-B1(*)X-0604 increased the risk for ZnT8RA and ZnT8WA; (4) agreement between autoantibody pairs was common for all combinations except IAA. These results suggest that ZnT8RWQA is a necessary complement to the classification and prediction of childhood type 1 diabetes as well as to randomize the subjects in the prevention and intervention of clinical trials