The Absence of Islet Autoantibodies in Clinically Diagnosed Older-Adult Onset Type 1 Diabetes Suggests an Alternative Pathology, Advocating for Routine Testing in This Age Group

Objective: Islet autoantibodies at diagnosis are not well studied in older-adult onset (>30years) type 1 diabetes due to difficulties of accurate diagnosis. We used a type 1 diabetes genetic risk score (T1DGRS) to identify type 1 diabetes aiming to evaluate the prevalence and pattern of autoantibodies in older-adult onset type 1 diabetes.Methods: We used a 30 variant T1DGRS in 1866 white-European individuals to genetically confirm a clinical diagnosis of new onset type 1 diabetes. We then assessed the prevalence and pattern of GADA, IA2A and ZnT8A within genetically consistent type 1 diabetes across three age groups (<18years (n=702), 18-30years (n=524) and >30years (n=588)).Findings: In autoantibody positive cases T1DGRS was consistent with 100% type 1 diabetes in each age group. Conversely in autoantibody negative cases, T1DGRS was consistent with 93%(56/60) of <18years, 55%(37/67) of 18-30years and just 23%(34/151) of >30years having type 1 diabetes. Restricting analysis to genetically consistent type 1 diabetes showed similar proportions of positive autoantibodies across age groups (92% <18years, 92% 18-30years, 93% >30years)[p=0.87]. GADA was the most common autoantibody in older-adult onset type 1 diabetes, identifying 95% of autoantibody positive cases versus 72% in those <18years.Interpretation: Older adult-onset type 1 diabetes has identical rates but different patterns of positive autoantibodies to childhood onset. In clinically suspected type 1 diabetes in older-adults, absence of autoantibodies strongly suggests non-autoimmune diabetes. Our findings suggest the need to change guidelines from measuring islet autoantibodies where there is diagnostic uncertainty to measuring at least GADA in all suspected adult type 1 diabetes cases.Funding Statement: NJT is funded by a Wellcome Trust funded GW4 PhD (220601/Z/20/Z). M.N.W. is supported by the Wellcome Trust Institutional Support Fund (WT097835MF). KAP is a Wellcome Trust fellow (219606/Z/19/Z) and the genetic risk score analysis in ADDRESS-2 was funded by Diabetes wellness Research foundation pump priming grant. ADDRESS-2 is co-funded by Diabetes UK (grant numbers 09-0003919, 15-005234 & 19/0006119) and the Juvenile Diabetes Research Foundation (grant numbers 9-2010-407 & 3-SRA-2015-35-A-N), supported by the NIHR Clinical Research Network and hosted by Imperial College London. S.M. is currently supported by a Future Leaders Mentorship award from the European Federation for the Study of Diabetes. NO is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College London. DJ is funded by the NIHR CRN.Declaration of Interests: We declare no competing interest.Ethics Approval Statement:Ethics for the ADDRESS2 study was granted by the South Central –Berkshire NHS Research Ethics Committee on the 03/10/2010, ref:10/H0505/85.Ethics for monogenic testing in the ADDRESS2 cohort by the East ofEngland – Essex Research Ethics Committee on the 14/7/2016, ref16/EE/0306