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Cited by 12Bariatric Surgery and OutcomesDiabetes Management and ResearchMetabolomics and Mass Spectrometry Studies

Postprandial Metabolomics Analysis Reveals Disordered Serotonin Metabolism in Post-Bariatric Hypoglycemia

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Ferraz-Bannitz, Rafael, Ozturk, Berkcan, Cummings, Cameron, Efthymiou, Vissarion, Casanova Querol, Pilar, Poulos, Lindsay, Wang, Hanna, Navarrete, Valerie +7 more·2024·Journal of Clinical Investigation
DOI 10.1172/jci180157PMC PMC11527454
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Abstract

BACKGROUND: Bariatric surgery is a potent therapeutic 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. METHODS: To identify mediators of disordered metabolism in PBH, we analyzed the plasma metabolome in the fasting state and 30 and 120 minutes after mixed meal in 3 groups: PBH ( n = 13), asymptomatic post–Roux-en-Y gastric bypass (post-RYGB) ( n = 10), and nonsurgical controls ( n = 8). RESULTS: In the fasting state, multiple tricarboxylic acid cycle intermediates and the ketone β-hydroxybutyrate were increased by 30%–80% in PBH versus asymptomatic. Conversely, multiple amino acids (branched-chain amino acids, tryptophan) and polyunsaturated lipids were reduced by 20%–50% in PBH versus asymptomatic. Tryptophan-related metabolites, including kynurenate, xanthurenate, and serotonin, were reduced 2- to 10-fold in PBH in the fasting state. Postprandially, plasma serotonin was uniquely increased 1.9-fold in PBH versus asymptomatic post-RYGB. In mice, serotonin administration lowered glucose and increased plasma insulin and GLP-1. Moreover, serotonin-induced hypoglycemia in mice was blocked by the nonspecific serotonin receptor antagonist cyproheptadine and the specific serotonin receptor 2 antagonist ketanserin. CONCLUSION: Together these data suggest that increased postprandial serotonin may contribute to the pathophysiology of PBH and provide a potential therapeutic target. FUNDING: National Institutes of Health (NIH) grant R01-DK121995, NIH grant P30-DK036836 (Diabetes Research Center grant, Joslin Diabetes Center), and Fundação de Amparo à Pesquisa do Estado de São Paulo grant 2018/22111-2.

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  • Decreased insulin clearance, blunted glucagon responses, increased serotonin levels, altered bile acid metabolism, and changes in microbiome composition have been implicated in PBH pathophysiology.

    “Decreased insulin clearance, blunted glucagon responses, increased serotonin levels, altered bile acid metabolism, and changes in microbiome composition have also been implicated in the complex pathophysiology of PBH [49,53,54].”

    From Non-Diabetic Hypoglycemia: Evaluation and Management in Adults (2025) · cites this paper as [54]

    The Discussion reports increased meal-stimulated serotonin in PBH and says reduced counterregulatory responses may contribute to hypoglycemia. The Results report higher fasting taurocholate, but the Discussion says PBH-specific microbiome differences require further study. Our copy does not establish decreased insulin clearance or specifically blunted glucagon responses, so it supports only part of the attributed list. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Ferraz-Bannitz, R., Ozturk, B., Cummings, C., Efthymiou, V., Casanova Querol, P., Poulos, L., Wang, H., Navarrete, V., Saeed, H., Mulla, C. M., Pan, H., Dreyfuss, J. M., Simonson, D. C., Sandoval, D. A., & Patti, M.-E.
Affiliations
  • Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.
  • Joslin Diabetes Center (US)
  • Brigham and Women's Hospital (US)
  • University of Colorado Anschutz (US)
Corresponding author
Patti, Mary-Elizabeth
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2024-09-12
Volume
134
Issue
21
ISSN
  • 0021-9738 (ISSN-L)
  • 1558-8238
DOI
10.1172/jci180157
PMC
PMC11527454
OpenAlex
W4402479615
Cited by
12
References
9
Citations by year
2026: 3 · 2025: 7 · 2024: 2
FWCI
5.05
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Clinical Investigation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (R01 DK121995, P30 DK036836)
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (2018/22111-2)
Topics
  • Health Sciences › Medicine › Surgery › Bariatric Surgery and Outcomes
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
Keywords
post-bariatric hypoglycemia, serotonin, postprandial metabolism, bariatric surgery, Roux-en-Y gastric bypass, tryptophan metabolism, kynurenine pathway, tricarboxylic acid cycle intermediates, beta-hydroxybutyrate, branched-chain amino acids, polyunsaturated fatty acids, glucagon-like peptide-1, insulin, serotonin antagonists, cyproheptadine, ketanserin, obesity, type 2 diabetes
MeSH terms
Adult, Animals, Female, Humans, Hypoglycemia, Male, Middle Aged, Serotonin, Gastric Bypass, Postprandial Period, Mice, Metabolomics

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