2638-P: Muscle Fat Accumulation Is Linked to Glycemic Dysregulation Not Fully Explained by Insulin Resistance

Introduction and Objective: Individuals with organ-related fat accumulation have an increased risk of diabetes, with the largest risk observed with liver fat and comparable risk observed across pancreas fat, visceral fat, and muscle fat. However, the pathophysiological mechanisms linking fat accumulation in these depots to dysglycemia remain unclear. Methods: We investigated associations of fat distribution with insulin resistance (triglyceride-glucose index (TyG)) in 19,132 individuals without diabetes from the UK Biobank. Archetype analysis was used to identify 4 groups of individuals (N = 2882) with isolated forms of fat accumulation in the liver, pancreas, visceral adipose tissue, and thigh muscles, respectively. Associations were compared to individuals without significant fat accumulation in any depot and were adjusted for age, sex, and fasting time. Results: The TyG was significantly elevated in all four fat distribution groups (adj.p 0.001), with the greatest elevation in hepatic steatosis (ß = 0.289 mg/dL, CI = 0.257-0.321) and the smallest in thigh myosteatosis (ß = 0.108 mg/dL, CI = 0.081-0.135). In contrast, elevations in blood glucose (adj.p 0.05 vs controls) were similar between individuals with hepatic steatosis and thigh myosteatosis (adj.p = 1). Conclusion: These results indicate that isolated muscle fat accumulation is characterized by moderate insulin resistance but disproportionate elevations in glycemia. This dissociation suggests that dysglycemia associated with muscle fat may not be fully explained by insulin resistance and indicates depot-specific mechanisms affecting glucose regulation. Disclosure M. Ennis: None. H. Yamazaki: Speaker's Bureau; Ended; Mundipharma, Mitsubishi Tanabe Pharma Corporation, AstraZeneca, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited. Consultant; Ended; Takeda Pharmaceutical Company Limited, Magmitt Pharmaceutical Co. Ltd. Speaker's Bureau; Ended; Janssen Pharmaceuticals, Inc. R. Wagner: Advisory Panel; Current; Sanofi. Speaker's Bureau; Ended; Daiichi Sankyo, Novo Nordisk. M. Heni: Advisory Panel; Ended; Chiesi USA, Inc. Speaker's Bureau; Ended; Chiesi USA, Inc. Advisory Panel; Ended; Boehringer Ingelheim International GmbH. Speaker's Bureau; Ended; Boehringer Ingelheim International GmbH, AstraZeneca, Lilly, Novartis AG, Novo Nordisk, Bayer AG. Funding European Research Council (101125605), Japan Society for the Promotion of Science KAKENHI (JP24K21305 and JP25K10709).