Evaluating ImmuNe Changes in the Evolution of Pre Type 1 Diabetes With Adult ONset

Overview

Little is known about how type 1 diabetes or coeliac disease develop in adults. Studies following children at risk of type 1 diabetes from birth have shown that the marker of type 1 diabetes autoimmunity (antibodies against the insulin producing cells in the pancreas (Glutamic Acid Decarboxylase Autoantibodies (GADA), Insulin Autoantibodies (IAA), Zinc Transporter 8 Autoantibodies (ZnT8), Anti-tyrosine phosphatase-like insulinoma antigen 2 (IA-2))) can develop many years before glucose levels are raised and diabetes is diagnosed. In adults, it is unclear when antibodies develop in relation to high blood glucose levels and the diagnosis of type 1 diabetes. Similarly in coeliac disease it is unclear to what degree Tissue transglutaminase autoantibodies (TTG) in adults proceed the development of clinically diagnosed disease. The investigators will use samples collected and stored in The Exeter 10,000 volunteer research bank (https://exetercrfnihr.org/about/exeter-10000/) and so no new sample collection is required. This includes \~8000 participants with no history of coeliac disease or diabetes at recruitment. The investigators wish to determine prevalence of autoantibodies in the background adult population split by the highest genetic risk for type 1 diabetes and separately coeliac disease compared to a control population with lower genetic risk for these conditions. The investigators will also evaluate the proportion of these identified cases progressing to clinically diagnosed disease. The aim of this study is to investigate evidence of autoimmunity prior to disease development and generate pilot data for the validity of screening based on genetic predisposition for type 1 diabetes and coeliac disease.

Detecting the early stages of type 1 diabetes in children is possible and has positive implications for clinical care. Studies following children at risk of type 1 diabetes from birth have shown that islet autoantibodies against (Glutamic Acid Decarboxylase (GADA), Insulin (IAA), Zinc Transporter 8 (ZnT8), Anti-tyrosine phosphatase-like insulinoma antigen 2 (IA-2))) can develop many years before diabetes is diagnosed. This makes islet-autoantibodies an excellent biomarker of early disease with the development of multiple (≥2) positive islet-autoantibodies marking the first stage of type 1 diabetes. Many studies in children have looked at strategies for increasing islet autoantibody detection given the high numbers needed to test if screening at the whole population level. This includes targeting for autoantibody testing those with a type 1 diabetes: family history and/or raised genetic risk. Identifying type 1 diabetes early matters as it can reduce the proportion of cases presenting with severe symptoms including with diabetic ketoacidosis. This is coupled to recent FDA approval of Teplizumab therapy aiming to slow down the progression of early type 1 diabetes. Little is known about the early development or early case detection of type 1 diabetes in adults despite representing the majority of all cases. Despite the potential benefits of pre-clinical type 1 diabetes detection in children very little is known about the stages of development of type 1 diabetes in adults. Therefore as noted in a recent Type 1 Diabetes research Steering Committee meeting "The optimal strategies for identification of at-risk adults needs to be studied". This is despite over half of all type 1 diabetes cases developing in adults. Our recent work examining adult-onset type 1 diabetes at presentation suggests that when adult-onset type 1 diabetes cases are defined robustly, characteristics include high type 1 diabetes genetic risk, rapid progression of C-peptide loss and high (\>90%) rates of islet autoantibody positivity. Of these adult autoantibody positive cases \~60% were multi-autoantibody positive. Previous literature suggesting type 1 diabetes is a more benign disease in older adults likely reflects the increasingly recognised misclassification of clinically defined type 1 diabetes cases in this age group. The high rates of islet autoantibodies at diagnosis and associated high genetic risk in adult-onset type 1 diabetes cases suggests targeted screening for early disease in this age group, using these biomarkers as undertaken in children, is a possibility. Studies recruiting first degree relatives of individuals have included adults (typically up to 45 years of age) showing detection of individuals at risk of type 1 diabetes is possible, even if progression from stage 1 to clinical disease appears reduced with increasing age at autoantibody detection. However, as in children, the majority of type 1 diabetes cases in adults develop in those without a family history of the disease and therefore genetic risk guided screening offers an attractive alternative strategy but research into the validity of this approach is lacking. Little is known about early Coeliac disease development in adults. Coeliac disease is similarly increasingly recognised in adults but the early development of the disease is unclear. Development of coeliac disease is associated with raised genetic risk which can be captured by a coeliac genetic risk score. Recognition of coeliac disease is difficult particularly in adults and early detection has been suggested to be associated with improved outcomes. Datasets with genetics and stored samples allow pragmatic insights into the feasibility of targeted screening for early adult-onset type 1 diabetes and coeliac disease. The investigators will use samples collected and stored in The Exeter 10,000 adult volunteer research bank (https://exetercrfnihr.org/about/exeter-10000/) which includes ∼8000 participants with no history of diabetes at recruitment (a median 10 years ago (minimum 3 years since recruitment)). This will allow islet autoantibody measurement without the need for additional sample collection. All participants have genotype data available and have given permission for the Exeter 10,000 team to prospectively access their health records. This dataset allows a pragmatic and cost-effective assessment of using genetic predisposition to type 1 diabetes and coeliac disease to guide islet-autoantibody/ tissue-transglutaminase testing in adults. This will provide vital pilot data which can help guide future screening strategies for detecting pre-clinical type 1 diabetes and coeliac disease in adults.