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

Abstract

ObjectiveWe investigated whether further characterisation of full-length (f-) GADA responses could identify early insulin requirement in adult-onset diabetes.Research Design and MethodsIn 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 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.Resultst-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=1×10-7), 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).ConclusionsThe 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.Article HighlightsProgression to insulin therapy is highly variable in adult-onset GADA positive diabetes.We further characterised GADA characteristics in adult-onset diabetes and assessed whether these are associated with early insulin requirement.Truncated GADA positivity was associated with a type 1 diabetes like phenotype and stratified risk of early insulin requirement. Those GADA positive who were negative for truncated GADA had the characteristics and progression of classical type 2 diabetes. Assessing full-length GADA IgG subclass and affinity did not further stratify risk of progression.t-GADA assessment remains underutilised in clinical practice, but could assist correct therapy allocation in adult-onset diabetes.