2336-P: Divergent Risk Profiles of Diabetes Progression in Lean and Obese Prediabetes

Introduction and Objective: Understanding the risk differences could enhance early risk stratification and targeted interventions. This study aimed to determine the incidence and risks associations of T2DM progression among prediabetes, stratified by BMI. Methods: A prospective cohort was conducted between 2019 and 2024 at Siriraj Hospital, Thailand. Participants with prediabetes were stratified into obese (BMI≥25 kg/m²) and lean (BMI<23 kg/m²) groups. T2DM incidence rates and prognostic factors were evaluated using Cox proportional hazards regression. Genetic associations for selected SNPs were analyzed using multivariable logistic regression. Results: 297 were included in the analyses (101 lean, 196 obese). Mean age was 58.39±9.94 years, 68.7% were women, and the median follow-up was 2.32 years. T2DM incidence did not differ significantly between obese and lean groups (incidence rates 4.37vs.4.76 per 100 person-years;p=0.7). In the obese group, higher BMI (HR1.16,1.05-1.28, p=0.003), elevated HbA1c (22.7,2.93-175.7, p=0.003), and 2-hour OGTT glucose (1.02,1.01-1.03, p<0.001) independently predict progression. In the lean group, 2-hOGTT glucose (1.04,1.02-1.06, p<0.001) and liver stiffness measured (2.35,1.01-5.47, p=0.04) predicted progression. Genetic analysis revealed that only in the lean individuals KCNQ1 rs2237895 and TLE4 rs13292136 variants were associated with increased progression risk, while BCL11A rs243021 was protective. Conclusion: T2DM incidence was similar between lean and obese. The 2-hOGTT glucose was a universal predictor of progression in both groups. Additional predictors included BMI and HbA1c in obese and liver stiffness in lean individuals. The distinct genetic associations in lean prediabetes suggest divergent mechanisms of diabetes risk by body phenotype. These findings support tailored preventive strategies in prediabetes management.