2388-P: BMI-Dependent Impact of Type 1 Diabetes Genetic Risk on β-Cell Function at Disease Onset

Introduction and Objective: Genetic risk scores for type 1 diabetes (T1D), such as T1D-GRS2, are used for risk stratification, but it remains unclear if they also predict β-cell function (βCF) at disease onset. This study investigated using gold-standard measures, whether T1D-GRS2 is associated with reduced βCF, diabetes symptoms and ketonuria at diagnosis and longitudinally with a faster decline of βCF. Methods: We performed a cohort analysis within the German Diabetes Study (GDS) including 360 genotyped adults with recent-onset T1D (1 year of diagnosis, age 36.9±12.0; 41% female; BMI 25.0±4 kg/m2). βCF was assessed from the C-peptide area under the curve (0-60 min) during intravenous glucose tolerance test and insulin sensitivity (M-value) from hyperinsulinemic-euglycemic clamp test. In a subset of N=149, repeated measurements were performed after a mean of 4.6 years. Analyses were conducted with linear and logistic regression models. Results: Male sex and higher BMI were associated with lower T1D-GRS2 at diagnosis independent of age (βmales=-0.21±0.10; p=0.04 and βBMI=-0.03±0.01; p=0.01). Higher T1D-GRS2 was associated with lower βCF at diagnosis, independent of sex, age, BMI and M-value. BMI showed a strong interaction with T1D-GRS (p0.001). When stratifying BMI into tertiles (low-BMI: 16-22.6, mid-BMI: 22.6-25.9, high-BMI: 26-42.9 kg/m2), T1D-GRS2 was inversely associated with βCF only in the high-BMI group (β =−0.46, SE = 0.10, 95% CI −0.67 to −0.26, p = 1.93×10−5). Among ketonuria, fatigue and nausea, T1D-GRS was associated with higher probability of ketonuria, but not after adjustment for sex, age and BMI. In the longitudinal analysis, T1D-GRS was not associated with changes of βCF (5.6 × 10-6, p=0.54). Conclusion: Within the first year after diagnosis, an association of genetic T1D risk with lower βCF is present only in overweight or obese adults, independent of age and sex. However, genetic T1D risk does not seem to predict the subsequent decline of βCF. Disclosure I. Yurchenko: None. C. Binsch: None. K. Prystupa: None. L. Szczerbinski: Research Support; Current; Novo Nordisk. Consultant; Current; Eli Lilly and Company. A. Kretowski: None. K.B. Bódis: Other - travel support; Ended; Sanofi. Other - lecture honoraria; Ended; Pfizer Inc. D.M. Mendez Cardenas: None. S. Trenkamp: None. B. Knebel: None. H. Al-Hasani: None. M. Roden: Advisory Panel; Current; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly, Madrigal Pharmaceuticals, Inc., Novo Nordisk, Sanofi, Echosens. R. Wagner: Advisory Panel; Current; Sanofi. Speaker's Bureau; Ended; Daiichi Sankyo, Novo Nordisk.