Introduction and Objective: Insulin-deficient diabetes in the absence of islet autoantibodies (Ab) remains poorly understood, with unclear mechanisms and limited guidance for clinical management. We aimed to characterize this entity using data from the RADIANT cohort. Methods: We evaluated 237 RADIANT participants with non-secondary diabetes who initiated continuous insulin therapy within 1 yr of diagnosis and tested negative for GAD65, IA-2 and ZnT8 Ab. Participants who completed both genetic (e.g., type 1 diabetes genetic risk score-2, T1D GRS2) and metabolic testing (n=92) were stratified into those who tested Ab-negative 5 yrs since diabetes diagnosis (Group 1, n=47) or ≥5 yrs (Group 2, n=45). Each group was further stratified by maximum OGTT-stimulated C-peptide (A: 0.3, B: 0.3-0.7, or C: 0.7 nmol/L). Group 1 included 9, 6, and 32 and Group 2 included 14, 6, and 25 participants in strata A, B, and C, respectively. Results: At enrollment, mean ±SD age was 36.0 ±16.9 yrs and diabetes duration 10.3 ±13.1 yrs; 54% were female, 68.4% White, 8.9% Black, and 7.6% Asian. Diabetic ketoacidosis was reported in 34.2% of participants (23.6% at diagnosis), and personal or family histories of autoimmunity in 6.8% and 35.4%, respectively.The lowest C-peptide group had the longest diabetes duration (A: 2.9, B: 2.8, C: 1.3 yrs; p=0.011) and the lowest BMI at diagnosis (18.4, 20.9, 23.6; p=0.018) in Group 1; the lowest neck acanthosis severity (0.08, 0.50, 1.05; p=0.024) in Group 2; and the highest T1D-GRS2 percentile in both groups (Group 1: 0.84, 0.72, 0.51; p=0.017; Group 2: 0.86, 0.59, 0.40; p0.001). Conclusion: The clinical phenotype of autoantibody-negative insulin-deficient diabetes includes subgroups with divergent genetic risk and beta-cell function that traditional criteria cannot distinguish. Incorporating C-peptide and genetic risk scores into evaluation may improve etiologic classification and guide treatment decisions in atypical diabetes. Disclosure K.R. Klein: Consultant; Current; Roche Pharmaceuticals, Novo Nordisk A/S. Advisory Panel; Current; vTv Therapeutics. Consultant; Current; Antag Therapeutics, Metsera. H. Parikh: None. A. Balasubramanyam: None. S.D. Gage: None. I. Hirsch: Research Support; Current; MannKind Corporation, Sequel Tech. Consultant; Current; Abbott Diabetes, Roche Diabetes Care, Hagar. C. Kirk: None. R.J. Kreienkamp: None. E.A. Kubota-Mishra: None. R. Naylor: None. L. Philipson: Research Support; Current; Novo Nordisk, Novo Nordisk Foundation. Research Support; Ended; Dompé. Research Support; Current; Vertex Pharmaceuticals Incorporated. Consultant; Current; Abbott. Research Support; Current; Zucara Therapeutics. Research Support; Ended; Diasome. Other - Data safety committee; Current; Cour. Consultant; Ended; Ono Pharmaceuticals. J.E. Posey: None. M. Tosur: None. M. Udler: Advisory Panel; Ended; Novo Nordisk. Research Support; Current; Novo Nordisk. C. Pihoker: None. M.J. Redondo: Advisory Panel; Current; Sanofi. Other - Data Safety Monitoring committee; Current; Lilly. Funding The RADIANT Study is funded by U54 DK118638 and U54 DK118612 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Klein et al. (Fri,) studied this question.