Diabetes and Celiac Disease

Introduction

The field of research is to uncover the genetic and environmental etiology of autoimmune (type 1) diabetes, celiac disease as well as narcolepsy. All three are devastating disorders often affecting children but may affect individuals at any age. The genetics of the disease is dissected also in the spontaneously diabetic BB rat.  Specific autoantibody markers are used to predict the clinical onset of diabetes or celiac disease. Longitudinal studies of children at increased risk allow studies of the pathogenesis until the clinical onset. Clinical studies are carried out in subjects with one or several autoantibodies as well as at the time of clinical diagnosis to prevent clinical onset or preserve residual beta cells.

Goal

The goals of our research are to identify the gene-environmental interactions that result in an HLA- associated appearance of autoantibodies against beta-cell autoantigens (insulin, GAD65, IA-2 and ZnT8 and minor autoantigens). The NIH-supported TEDDY study is focused to identify The Environmental Determinants of Diabetes in the Young including triggers of celiac disease (http://teddy.epi.usf.edu/ and http://www.med.lu.se/teddy). Individuals with two or more autoantibodies have an increased risk for autoimmune (type 1) diabetes and the mechanisms dictating progression to clinical onset are studies in both the TEDDY and the Diabetes Prediction in Skåne (DiPiS) (http://www.med.lu.se/dipis). Relatives to diabetes patients are screened for islet autoantibodies in TrialNet (https://www.diabetestrialnet.org/) to be randomized in prevention or intervention clinical trials (Figure 1). Other clinical studies in autoantibody positive subjects include alum-GAD65 vaccination, gluten free diet and probiotics in children at risk for celiac disease.

Impact

The TEDDY study has demonstrated that the incidence of insulin autoantibodies peaks at 1-3 years of age and declines thereafter. The trigger of this autoantibody is associated with HLA-DR4-DQ8. The incidence of GAD65 autoantibodies is triggered later but remains stable and is associated with HLA-DR3-DQ2. Second or third autoantibodies appear and mark progression to clinical onset. The disease is stage into stage 1 – beta cell autoimmunity but normal glucose tolerance and no symptoms; stage 2: beta cell autoimmunity, impaired glucose tolerance and no symptoms and stage 3: beta cell autoimmunity, diabetes and symptoms. Staging disease is important to clinical trials aiming at prevention or intervention. TrialNet preventions studies include oral insulin and abatacept (Figure 2).

Highlights

• http://www.lu.se/article/risk-glutenintolerans-hogst-i-sverige
   
• Krischer JP, Lynch KF, Schatz DA, Ilonen J, Lernmark Å, Hagopian WA, Rewers, MJ, She JX, Simell OG, Toppari J, Ziegler AG, Akolkar B, Bonifacio E; TEDDY Stud Group. The 6 year incidence of diabetes-associated autoantibodies in genetically at-risk children: the TEDDY study. Diabetologia. 58:980-987 (2015).
• Liu E, Lee HS, Aronsson CA, Hagopian WA, Koletzko S, Rewers MJ, Eisenbarth GS, Bingley PJ, Bonifacio E, Simell V, Agardh D; TEDDY Study Group. Risk of pediatric celiac disease according to HLA haplotype and country. N Engl J Med. 371:42-49 (2014).