1129-OR: Youth with Type 2 Diabetes Have Diminished Citrulline Availability for Arginine and Nitric Oxide Synthesis

Introduction and Objective: Arginine (Arg) stimulates insulin secretion and is the sole precursor for nitric oxide (NO). Citrulline (Cit) is the primary substrate for de novo Arg synthesis. We previously showed lower circulating Arg, Cit and glutamine (primary Cit precursor) concentrations in youth with type 2 diabetes (T2D). Here, we aimed to characterize whole-body kinetics of Arg-related metabolic pathways using stable isotope tracers and mass spectrometry. Methods: We studied 13 adolescents with well-controlled T2D (on metformin or lifestyle management alone) and 13 age- and sex-matched healthy controls (HC). Body composition including lean body mass (LBM) was assessed by DXA. After an overnight fast, participants underwent a 5-hour multi-tracer infusion protocol, with sampling of blood and breath at isotopic plateau. Isotopic enrichments were measured by LC-MS/MS, and amino acid kinetics were compared between groups. Results: The overall cohort was 62% female, mean age 15.5 ± 1.5 years, 35% Hispanic and 46% non-Hispanic Black. Mean HbA1c was 6.1 ± 0.7% in T2D and 5.4 ± 0.2% in HC, with mean BMI percentiles 98.8 ± 1.2 and 60.9 ± 28, respectively. The T2D group had lower Cit flux (8.3 ± 1.8 vs. 10.9 ± 2.7 µmol/kg-LBM/h, p=0.009) than HC, with a corresponding trend to lower de novo Arg synthesis (5.5 ± 1 vs. 6.7 ± 2.1 µmol/kg-LBM/h, p=0.059). Arg flux, Arg oxidation, Arg hydrolysis, total Arg availability, NO synthesis and ornithine flux did not differ between the groups. Total phenylalanine flux and Arg from protein breakdown were similar. Conclusion: Youth with well-controlled T2D exhibit reduced citrulline flux in the fasted state compared to HC, and hence a diminished supply of primary substrate for de novo Arg synthesis. This lower substrate availability may reflect impaired conversion of glutamine to citrulline in gut enterocytes, with implications for blunted Arg and NO synthesis during stressful conditions such as chronic hyperglycemia. Disclosure M. Tosur: None. J.W. Hsu: None. A. DannerDeArmas: None. S.K. Chacko: None. M. Redondo: Advisory Panel; Current; Sanofi. Other - Data Safety Monitoring committee; Current; Lilly.