Autoantibodies to truncated GAD(96-585) antigen stratify risk of early insulin requirement in adult-onset diabetes

Objective We investigated whether further characterisation of full-length (f-) GADA responses could identify early insulin requirement in adult-onset diabetes. Research Design and Methods In 179 f-GADA positive participants diagnosed with type 2 diabetes, we assessed the association of truncated (t-)GADA positivity, f-GADA IgG subclasses, and f-GADA IgG affinity with early insulin requirement (<5 years), type 1 diabetes genetic risk score (T1D GRS), and C-peptide. These characteristics were compared to f-GADA positive type 1 diabetes (n=141) and f-GADA negative type 2 diabetes (n=6420) cohorts. Results t-GADA positivity was lower in f-GADA positive without early insulin in comparison to f-GADA positive type 2 diabetes requiring insulin within 5 years, and type 1 diabetes (75% vs. 91% and 95% respectively, p<0.0001). t-GADA positivity (in those f-GADA positive) identified a group with a higher type 1 diabetes genetic susceptibility (mean T1D GRS 0.248 vs. 0.225, p=0.003), lower C-peptide (1156 pmol/L vs. 4289 pmol/L, p=1x10-7), and increased IA-2A positivity (23% vs. 6%, p=0.03). In survival analysis, t-GADA positivity was associated with early insulin requirement compared with those only positive for f-GADA, independently from age of diagnosis, f-GADA titre and duration of diabetes [adjusted HR 5.7 (95% CI 1.4, 23.5), p=0.017]. Early insulin requirement was not associated with an IgG1-restricted f-GADA response (p=0.81) or a high affinity f-GADA response (p=0.89). Conclusions The testing of t-GADA in f-GADA positive individuals with type 2 diabetes identifies those who have genetic and clinical characteristics comparable to type 1 diabetes and stratifies those at higher risk of early insulin requirement. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by a grant from The NovoNordisk UK Research Foundation. SLG was funded by an E3 PhD Studentship. AEL is jointly funded as a Diabetes UK & JDRF RD Lawrence Fellow (18/0005778 and 3-APF-2018-591-A-N). CLW was funded by Diabetes UK (16/0005556 and 21/0006332). AGJ was supported for this work by an NIHR Clinician Scientist award (CS-2015-15-018). TJM is an NIHR Senior Clinical Senior Lecturer. ERP is a Wellcome Trust New Investigator (102820/Z/13/Z). StartRight study is funded by Diabetes UK (17/0005624) and the UK National Institute of Health and Social Care Research (CS-2015-15-018). GADA assessment in GoDARTS was funded by EU Innovative Medicines Initiative 115317 (DIRECT) resources of which are composed of financial contributions from the European Unions Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations companies in kind contribution. The DARE study was funded by the Wellcome Trust and supported by the Exeter NIHR Clinical Research Facility. The MASTERMIND study was funded by the U.K. Medical Research Council (MR/N00633X/) and supported by the Exeter NIHR Clinical Research Facility. The PRIBA study was funded by the National Institute for Health Research (NIHR; U.K. DRF-2010-03-72) and supported by the Exeter NIHR Clinical Research Facility. Genotyping for generation of the type 1 genetic risk score was supported by the European Foundation for the Study of Diabetes (2016 Rising Star Fellowship). This study was supported by the National Institute for Health and Care Research Exeter Biomedical Research Centre and National Institute for Health and Care Research Exeter Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: StartRight study was approved by the South West- Cornwall & Plymouth NHS Research Ethics Committee on the 06/06/2016, ref: 16/SW/0130. PRIBA, DARE and MRC Progressors were ethically approved by the South West Research Ethics committee (UK). The GoDARTS study was approved by the Tayside Medical Ethics Committee (UK). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The StartRight dataset generated during and/or analysed in the current study is available from the corresponding author upon reasonable request. Data pertaining to the other Exeter studies (DARE, PRIBA and MRX Progressors) can be accessed via application to the Penninsula Research Bank; and for GoDARTs via application to the GoDARTs study committee.