6817 Metabolomics Analysis Reveals Disordered Serotonin Metabolism as a Novel Therapeutic Target for Post-Bariatric Hypoglycemia

Abstract Disclosure: R. Ferraz-Bannitz: None. B. Ozturk: None. C. Cummings: None. V. Efthymiou: None. H. Wang: None. V. Navarrete: None. H. Saeed: None. C.M. Mulla: None. D. Sandoval: None. H. Pan: None. J.M. Dreyfuss: None. M. Patti: Advisory Board Member; Self; Fractyl Health. Consulting Fee; Self; AstraZeneca, Hamni, MBX Biosciences. Grant Recipient; Self; Dexcom. Bariatric surgery is a potent approach for obesity and type 2 diabetes but can be complicated by post-bariatric hypoglycemia (PBH). PBH typically occurs 1-3 hours after meals, in association with exaggerated postprandial levels of incretins and insulin. To identify mediators of disordered metabolism in PBH, we analyzed the plasma metabolome in the fasting state and 30 and 120 minutes after an oral mixed meal in 3 groups: PBH (n=13), asymptomatic post-RYGB (n=10), and non-surgical controls (n=8). In the fasting state, multiple tricarboxylic acid cycle intermediates and the ketone beta-hydroxybutyrate were increased by 30-80% in PBH vs. asymptomatic. Conversely, multiple amino acids (BCAA, tryptophan) and polyunsaturated lipids were reduced by 20-50% in PBH vs. asymptomatic. Tryptophan-related metabolites, including kynurenate, xanthurenate, and serotonin, were reduced by 2-10-fold in PBH in the fasting state (p<0.01 for all). Serotonin patterns in response to meal ingestion were distinct in PBH. ELISA analysis of serotonin levels revealed 1.9-fold increase at 120 minutes after the meal (p<0.001); by comparison, serotonin levels decreased by 1.6 to 1.4-fold over the same time course in asymptomatic and nonsurgical groups (p<0.001 for both). To determine whether serotonin could modulate glucose levels, we injected wild type C57BL/6J mice with serotonin (20 mg/kg, intraperitoneal) or vehicle. Glucose levels were 39-43% lower in serotonin-injected mice (p<0.01 at 15-60 minutes). Serotonin administration also significantly increased plasma insulin by up to 5-fold at 30 minutes (p=0.004) and increased plasma GLP1 by up to 2-fold (p<0.001). Moreover, serotonin-induced hypoglycemia after mixed meal in mice was blocked by the serotonin antagonist cyproheptadine. Together these data suggest that increased postprandial serotonin may contribute to the pathophysiology of PBH and provide a new therapeutic target. Presentation: 6/1/2024