The Perfect Storm? Gluten and type 1 diabetes

Abstract: Aim: The general objective of the present research was to study the association between type 1 diabetes and celiac disease, and the effects of dietary gluten on the risk of developing type 1 diabetes. More specific aims were as follows: to estimate the prevalence of celiac-disease-associated autoantibodies in children with type 1 diabetes; to study the connection between non-HLA genetic risk markers and autoantibodies associated with type 1 diabetes and celiac disease during the first year after diagnosis of type 1 diabetes; to investigate the effect of gluten on the risk of developing type 1 diabetes; to evaluate the impact of perinatal factors on the risk of developing both type 1 diabetes and celiac disease. Methods: Serum samples from children with (Studies I and II) or without (Study I) type 1 diabetes were analyzed using a combined deamidated gliadin peptide and tissue transglutaminase antibody assay, and also a tissue transglutaminase autoantibody radioligand binding assay. BALB/c mice and NOD mice were used in Study III, and FACS, qPCR, and immunohistology were performed to assess the effects of a gluten-free diet versus a standard diet on expression of the NK cell receptor NKG2D and its ligands. In Study IV, the Medical Birth Register was used to identify all singletons born in Sweden between 1987 and 1993, and the Swedish National Inpatient Register was used to identify cases of type 1 diabetes and celiac disease. Thereafter, multinomial logistic regression models were employed to estimate odds ratios with 95% confidence intervals for having type 1 diabetes, celiac disease, or both these disorders in relation to factors known to be associated with celiac disease. Results and conclusions: There was a discrepancy in levels of the celiac-related antibodies between children with type 1 diabetes in Denmark and those in Sweden, independent of HLA genotype, which suggests a difference in exposure to environmental factors between these two neighboring countries. Approximately 5% of children with type 1 diabetes developed celiac disease autoimmunity (CDA) during the first year of type 1 diabetes. Furthermore, a subpopulation was homozygous for IL18RAP, which may modulate the risk of developing CDA in type 1 diabetes. In animal experiments, dietary gluten seemed to affect the immune system of both immune-competent BALB/c mice and diabetes-prone NOD mice, and a gluten-free diet lowered expression of NKG2D and its ligands. Comorbidity of type 1 diabetes and celiac disease was associated with several perinatal risk factors, including Caesarean section, birth during summer, female gender, and being born to mother born in Sweden.