Ismail, Heba M.Cuthbertson, DavidGalderisi, AlfonsoLibman, IngridJacobsen, LauraMoran, AntoinettePetrelli, AlessandraAtkinson, MarkRedondo, Maria J.Hannon, TamaraMather, Kieren J.Sosenko, Jay M.2025-07-152025-07-152025Ismail HM, Cuthbertson D, Galderisi A, et al. The Disposition Index in Autoantibody-Positive Individuals at Risk for Type 1 Diabetes. Diabetes. 2025;74(7):1196-1204. doi:10.2337/db24-1000https://hdl.handle.net/1805/49477Since little is known about the disposition index (DI) in autoantibody-positive individuals, we have assessed whether DI has a similar association between insulin secretion and sensitivity to the association observed in other populations. In TrialNet Pathway to Prevention (TNPTP; n = 6,620) and Diabetes Prevention Trial-Type 1 (DPT-1; n = 704) study participants, two secretion-sensitivity pairs, each representing a DI, were analyzed cross-sectionally at baseline: area under the curve (AUC) C-peptide/AUC glucose (AUC ratio) and Matsuda index (MI) from TNPTP oral glucose tolerance tests (oral DI), first-phase insulin response (FPIR), and 1 / fasting insulin (1/FI) from DPT-1 from intravenous glucose tolerance tests (DI). Participants were followed for progression to type 1 diabetes (T1D). Within the normal and diabetes glucose ranges, associations of AUC ratio with MI in TNPTP and FPIR with 1/FI in DPT-1 had inverse curvilinear patterns with convexities to the origin. After logarithmic transformations to linearize the secretion and sensitivity measures, the inverse slope was steeper for the diabetes range (P < 0.0001). In a Cox regression model including the AUC ratio and MI as variables and another model including FPIR and 1/FI, the interaction terms of secretion × sensitivity (i.e., the DI/oral DI) predicted stage 3 T1D in both (P < 0.0001). The DI remained significantly predictive (P < 0.0001) when the DPT-1 risk score was added as a covariate in regression models. In autoantibody-positive populations, insulin secretion is inversely related to sensitivity in a quasi-hyperbolic relationship in normal and diabetes ranges of glucose. The DI can be represented by a statistical and physiologic interaction between secretion and sensitivity that is predictive of stage 3 T1D. Article highlights: Little is known about the relationship between secretion and sensitivity in individuals at risk for type 1 diabetes (T1D). This study examined the relationship between secretion and sensitivity in antibody-positive relatives at risk for T1D and the predictive value of the disposition index (DI) as a measure of β-cell function. Secretion and sensitivity measures in two independent antibody-positive populations at risk for T1D had an inverse relationship across different glycemic ranges. The DI using different measures of secretion and sensitivity was predictive of T1D. The DI is a useful biomarker of β-cell function in individuals at risk for T1D.en-USPublisher PolicyAutoantibodiesBlood glucoseType 1 diabetes mellitusGlucose tolerance testInsulin resistanceInsulin secretionArticle