2821-LB: Semaglutide Improves Tissue-Specific Insulin Action and Reduces Liver Fat in Type 2 Diabetes with Spinal Cord Injury

Introduction and Objective: Individuals with spinal cord injury (SCI) develop type 2 diabetes (T2D) at higher rates than the general population due to severe denervation-induced muscle loss below the injury, adverse fat redistribution, and metabolic dysfunction-associated steatotic liver disease. However, the relative contributions of muscle versus hepatic/adipose insulin resistance in SCI remain unclear. We examined the effects of semaglutide-induced weight loss on tissue-specific insulin action, body composition, and hepatic fat in individuals with SCI and T2D. Methods: Insulin kinetics were assessed using a two-step hyperinsulinemic-euglycemic clamp (15 and 80 mU/m²/min) in five men with T2D and SCI (duration 11±4 years; age 53±3 years; BMI 35±3 kg/m²; HbA1c 7±0.5%) at baseline and after 6 months of semaglutide (2 mg weekly). Body composition and hepatic fat and fibrosis were measured using dual-energy X-ray absorptiometry and Fibroscan. Results: Semaglutide reduced body weight by 10±2 kg and waist circumference by 9±2 cm (p<0.05). Total fat, abdominal fat, and lean mass decreased by 13±2%, 17±2%, and 8±2%, respectively (p<0.05), without changes in bone density. Liver fat decreased by 19±3.5% (p<0.05) without changes in liver stiffness. Insulin-stimulated glucose disposal (M/I) during the high-dose insulin clamp and free-fatty-acid suppression during the low-dose insulin clamp increased by 38±17% and 65±9% (p<0.05), indicating improved skeletal muscle and adipocyte insulin action, while hepatic insulin sensitivity measured by M/I during the low-dose insulin clamp showed modest improvement. Conclusion: Our novel findings demonstrate that semaglutide improves tissue-specific insulin resistance in SCI, particularly skeletal muscle and adipocyte insulin action, while reducing hepatic steatosis. These findings provide new insight into metabolic dysfunction after SCI and support GLP-1 receptor agonists as a promising strategy to reduce cardiometabolic risk in this high-risk population. Disclosure A. Alamdari: None. M.E. Trbovich: None. S. Hoekstra: None. A. Gastaldelli: Consultant; Current; Boehringer Ingelheim International GmbH. Speaker's Bureau; Current; Boehringer Ingelheim International GmbH. Other - educational grant; Ended; Boehringer Ingelheim International GmbH. Other - educational grant; Current; Eli Lilly and Company. Consultant; Ended; Merck Sharp & Dohme Corp. Speaker's Bureau; Ended; Merck Sharp & Dohme Corp. Other - grant reviewer; Ended; Pfizer Inc. Advisory Panel; Ended; Novo Nordisk Global Business Services. Speaker's Bureau; Ended; Novo Nordisk Global Business Services. Advisory Panel; Ended; Regeneron Pharmaceuticals Inc. Other - educational grant; Current; Madrigal Pharmaceuticals, Inc. Speaker's Bureau; Ended; Madrigal Pharmaceuticals, Inc. M. Salehi: Advisory Panel; Ended; Vognex. Advisory Panel; Current; Amylyx.