2587-P: Bariatric Metabolic Surgery for Type 2 Diabetes Reprograms DNA Methylation in Leukocytes to a Greater Extent than Medical/Lifestyle Therapy

Introduction and Objective: Bariatric/metabolic surgery induces sustained weight loss and improved glycemic control for Type 2 diabetes (T2D), yet the molecular mechanisms underlying its metabolic benefits and diabetes remission remain incompletely defined. Methods: We analyzed buffy coat samples previously collected during longitudinal followup for 3 years in the SLIMM-T2D trial, in which participants with T2D were randomized to Roux-en-Y gastric bypass (RYGB) (n:17) or nonsurgical medical/lifestyle intervention (MLI) (n:16). DNA was isolated from leukocytes collected at baseline and 3, 12 and 36 months and analyzed for DNA methylation (DNAm) using the Infinium MethylationEPIC array. Data were processed and analyzed using SeSAMe and Limma, with significance FDR<0.05. Results: DNAm analysis revealed progressive epigenetic remodeling over 36 months, with RYGB inducing a significantly greater effect than MLI. Both groups showed few differentially methylated CpG loci (DML) at 3 months. By 36 months, there were 27,961 DML in RYGB vs. baseline, with predominant hypermethylation (19,276 CpGs), in comparison with only 14821 vs. baseline in MLI. In weighted models, no significant DML associations with HbA1c or BMI were detected (FDR<0.05) and adjustment for these variables minimally altered the magnitude or trajectory of DNAm changes, suggesting that RYGB-associated epigenetics changes are largely independent of glycemic control or adiposity. Conclusion: Our findings demonstrate that RYGB induces a robust, progressive and durable reprogramming of DNAm that exceeds changes observed in MLI. Future analysis will seek to identify mechanisms contributing to surgery-induced alterations in DNAm. Disclosure R. Ferraz-Bannitz: None. L. Osterwalder: None. A. Goncalves da Cruz: None. B. Ozturk: None. D.C. Simonson: Board Member; Current; Phase V Technologies, Inc. Stock/Shareholder; Current; GI Windows. H. Pan: None. J. Dreyfuss: None. M. Patti: Other - My institution receives research funding for clinical trial.; Current; Recordati S.p.A, Amylyx. Other - Data Safety Monitoring Board; Current; Fractyl Health, Inc. Funding Joslin/BILH Epigenetics Initiative Grant