1642-P: Sex-Specific Mechanisms of Weight Loss-Induced Prediabetes Remission

Introduction and Objective: The German Prediabetes Lifestyle Intervention Study (PLIS) demonstrated that weight loss-induced prediabetes remission is driven by improved insulin sensitivity and reduced visceral adipose tissue (VAT) mass. This analysis aims to investigate potential sex differences in these mechanisms, which remains underexplored. Methods: Of 908 PLIS participants with prediabetes who completed a 12-months lifestyle intervention, 298 achieved a clinically significant weight loss of ≥5%. Linear mixed models were used to compare within- and between-sex changes in body fat distribution (whole body MRI), insulin sensitivity (Matsuda index) and secretion (AUCcₚept0-30 divided by AUCglu0-30), and glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) from baseline to 12 months. Kaplan-Meier analyses evaluated the 9-year type 2 diabetes survival risk by sex. Results: Among those who reached weight loss targets, 69 females and 59 males achieved prediabetes remission. Both sexes showed similar reduction in overall fat mass (p=0. 35) and VAT (p=0. 99). Sex-specific differences included muscle insulin sensitivity, which increased in males only (0. 019±0. 014 AU in females p=0. 19 vs. 0. 067±0. 016 in males p0. 0001, p=0. 015), accompanied by greater improvements in maximal aerobic capacity (0. 019±0. 015 ml min kg−1 p=0. 020 vs. 0. 067±0. 016 p0. 0001, p=0. 019). In contrast, females showed enhanced insulin secretion (14. 85±6. 14 pmol mmol-1 p=0. 016 vs. -5. 17±6. 87 p=0. 45, p=0. 014). At 12 months, which may be explained by significantly stronger GLP-1 (p=0. 012) and GIP (p=0. 007) responses during OGTT compared to males. Both sexes showed comparable 9-year diabetes prevention (p=0. 51). Conclusion: Weight loss-induced prediabetes remission exhibits sex-specific pathways, with males uniquely increasing muscle insulin sensitivity paralleled by aerobic fitness and females enhancing β-cell function associated with improved incretin responses. Disclosure Y. Wang: None. L. Sandforth: None. M. Roden: Advisory Panel; Current; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly, Madrigal Pharmaceuticals, Inc. , Novo Nordisk, Sanofi, Echosens. N. Stefan: Speaker's Bureau; Current; AstraZeneca. Advisory Panel; Ended; Boehringer Ingelheim International GmbH. Speaker's Bureau; Ended; Boehringer Ingelheim International GmbH. Advisory Panel; Ended; Lilly. Speaker's Bureau; Current; Lilly. Advisory Panel; Ended; Pfizer Inc. , Madrigal Pharmaceuticals, Inc. Speaker's Bureau; Ended; Madrigal Pharmaceuticals, Inc. Research Support; Ended; Sanofi. Speaker's Bureau; Current; Sanofi. A. Fritsche: None. A. L. Birkenfeld: None. Funding German Federal Ministry for Education and Research via the German Center for Diabetes Research