Plasma FGF-19 Levels are Increased in Patients with Post-Bariatric Hypoglycemia

  • Christopher M. Mulla
  • Allison B. Goldfine
  • Jonathan M. Dreyfuss
  • Sander Houten
  • Hui Pan
  • David M. Pober
  • Nicolai J. Wewer Albrechtsen
  • Maria S. Svane
  • Julie B. Schmidt
  • Jens Juul Holst
  • Colleen M. Craig
  • Tracey L. McLaughlin
  • Mary-Elizabeth PattiEmail author
Original Contributions



Hypoglycemia is an increasingly recognized complication of bariatric surgery. Mechanisms contributing to glucose lowering remain incompletely understood. We aimed to identify differentially abundant plasma proteins in patients with post-bariatric hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB), compared to asymptomatic post-RYGB.


Proteomic analysis of blood samples collected after overnight fast and mixed meal challenge in individuals with PBH, asymptomatic RYGB, severe obesity, or overweight recruited from outpatient hypoglycemia or bariatric clinics.


The top-ranking differentially abundant protein at 120 min after mixed meal was fibroblast growth factor 19 (FGF-19), an intestinally derived hormone regulated by bile acid-FXR signaling; levels were 2.4-fold higher in PBH vs. asymptomatic post-RYGB (mean + SEM, 1094 ± 141 vs. 428 ± 45, P < 0.001, FDR < 0.01). FGF-19 ELISA confirmed 3.5-fold higher concentrations in PBH versus asymptomatic (360 ± 70 vs. 103 ± 18, P = 0.025). To explore potential links between increased FGF-19 and GLP-1, residual samples from other human studies in which GLP-1 was modulated were assayed. FGF-19 levels did not change in response to infusion of GLP-1 and PYY in overweight/obese individuals. Infusion of the GLP-1 receptor antagonist exendin 9–39 in recently operated asymptomatic post-RYGB did not alter FGF-19 levels after mixed meal. By contrast, GLP-1 receptor antagonist infusion yielded a significant increase in FGF-19 levels after oral glucose in individuals with PBH. While plasma bile acids did not differ between PBH and asymptomatic post-RYGB, these data suggest unique interrelationships between GLP-1 and FGF-19 in PBH.


Taken together, these data support FGF-19 as a potential contributor to insulin-independent pathways driving postprandial hypoglycemia in PBH.


Gastric bypass Hypoglycemia FGF-19 Bile acids 



We thank the authors of references [13, 14] for providing surplus plasma samples from these studies to measure FGF-19. We would also like to acknowledge support from the Joslin Clinical Research Center and thank its philanthropic donors.

Funding information

This study received research grant funding from the American Society of Metabolic and Bariatric Surgery and Medimmune (both to MEP), a pilot award for plasma proteomic assay from SomaLogic (to MEP), T32 DK007260 and Hearst Fellowship (to CMM), American Diabetes Association 7–13-CE-17 (to ABG), RC1 DK086918 (to ABG), R56 DK095451 (to ABG), and P30 DK036836 (Joslin DRC). This work was conducted with support from Harvard Catalyst|The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102). NNF Center for Basic Metabolic Research, University of Copenhagen, NNF application number: 13563 (Novo Nordisk Foundation, Denmark), EliteForsk Rejsestipendiat (2016), The Danish Council for Independent Research (DFF–1333-00206A), European Research Council (Grant no.695069), Augustinus Foundation, and Aase og Ejnar Danielsens Fond. The following are the Stanford study funding sources: KL2 TR 001083, UL1 TR001085, and L30 TR001569-01 (to CMC), and a Fellow Pilot Award from the Stanford Translational Research and Applied Medicine (TRAM) Program of Stanford University School of Medicine (to CMC).

Compliance with Ethical Standards

Conflict of Interest Statement

Dr. Patti has consulted for Eiger Pharmaceuticals; has received investigator-initiated grant support from Janssen Pharmaceuticals, Medimmune, Sanofi, Astra-Zeneca, Jenesis, and Nuclea; has been a site investigator for XOMA; and acknowledges clinical trial research trial product support from Ethicon, Covidien, NovoNordisk, Nestle, and Dexcom within the past 5 years. Dr. Patti and Dr. Goldfine disclose a patent application for plasma proteins contributing to hypoglycemia. Dr. Mulla, Dr. Dreyfuss, Dr. Houten, Dr. Pan, Dr. Pober, Dr. Wewer Albrechtsen, Dr. Svane, Dr. Schmidt, Dr. Holst, Dr. Craig, and Dr. McLaughlin declare no potential competing interests.

Supplementary material

11695_2019_3845_MOESM1_ESM.pptx (2.9 mb)
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  1. 1.
    Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric-metabolic surgery versus conventional medical treatment in obese patients with type 2 diabetes: 5 year follow-up of an open-label, single-centre, randomised controlled trial. Lancet. 2015;386(9997):964–73.CrossRefGoogle Scholar
  2. 2.
    Schauer PR, Bhatt DL, Kirwan JP, et al. Bariatric surgery versus intensive medical therapy for diabetes - 5-year outcomes. N Engl J Med. 2017;376(7):641–51.CrossRefGoogle Scholar
  3. 3.
    Halperin F, Ding SA, Simonson DC, et al. Roux-en-Y gastric bypass surgery or lifestyle with intensive medical management in patients with type 2 diabetes: feasibility and 1-year results of a randomized clinical trial. JAMA Surg. 2014;149(7):716–26.CrossRefGoogle Scholar
  4. 4.
    Adams TD, Davidson LE, Litwin SE, et al. Weight and metabolic outcomes 12 years after gastric bypass. N Engl J Med. 2017;377(12):1143–55.CrossRefGoogle Scholar
  5. 5.
    Patti ME, Goldfine AB. The rollercoaster of post-bariatric hypoglycaemia. Lancet Diabetes Endocrinol. 2016;4(2):94–6.CrossRefGoogle Scholar
  6. 6.
    Goldfine AB, Patti ME. How common is hypoglycemia after gastric bypass? Obesity (Silver Spring). 2016;24(6):1210–1.CrossRefGoogle Scholar
  7. 7.
    Goldfine AB, Mun EC, Devine E, et al. Patients with neuroglycopenia after gastric bypass surgery have exaggerated incretin and insulin secretory responses to a mixed meal. J Clin Endocrinol Metab. 2007;92(12):4678–85.CrossRefGoogle Scholar
  8. 8.
    Craig CM, Liu LF, Deacon CF, et al. Critical role for GLP-1 in symptomatic post-bariatric hypoglycaemia. Diabetologia. 2017;60(3):531–40.CrossRefGoogle Scholar
  9. 9.
    Salehi M, Gastaldelli A, D'Alessio DA. Beta-cell sensitivity to glucose is impaired after gastric bypass surgery. Diabetes Obes Metab. 2018;20(4):872–8.CrossRefGoogle Scholar
  10. 10.
    Salehi M, Gastaldelli A, D'Alessio DA. Altered islet function and insulin clearance cause hyperinsulinemia in gastric bypass patients with symptoms of postprandial hypoglycemia. J Clin Endocrinol Metab. 2014;99(6):2008–17.CrossRefGoogle Scholar
  11. 11.
    Patti ME, Li P, Goldfine AB. Insulin response to oral stimuli and glucose effectiveness increased in neuroglycopenia following gastric bypass. Obesity (Silver Spring). 2015;23(4):798–807.CrossRefGoogle Scholar
  12. 12.
    Gavin III JR, Alberti KG, Davidson MB, et al. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 1997;20(7):1183–97.CrossRefGoogle Scholar
  13. 13.
    Schmidt JB, Gregersen NT, Pedersen SD, et al. Effects of PYY3-36 and GLP-1 on energy intake, energy expenditure, and appetite in overweight men. Am J Physiol Endocrinol Metab. 2014;306(11):E1248–56.CrossRefGoogle Scholar
  14. 14.
    Svane MS, Jorgensen NB, Bojsen-Moller KN, et al. Peptide YY and glucagon-like peptide-1 contribute to decreased food intake after Roux-en-Y gastric bypass surgery. Int J Obes. 2016;40(11):1699–706.CrossRefGoogle Scholar
  15. 15.
    Gold L, Ayers D, Bertino J, et al. Aptamer-based multiplexed proteomic technology for biomarker discovery. PLoS One. 2010;5(12):e15004.CrossRefGoogle Scholar
  16. 16.
    Argmann CA, Houten SM, Champy MF, Auwerx J. Lipid and bile acid analysis. Curr Protoc Mol Biol. 2006; Chapter 29:Unit 29B.2.
  17. 17.
    Patti ME, Houten SM, Bianco AC, et al. Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism. Obesity (Silver Spring). 2009;17(9):1671–7.CrossRefGoogle Scholar
  18. 18.
    Ritchie ME, Phipson B, Wu D, et al. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43(7):e47.CrossRefGoogle Scholar
  19. 19.
    Team RDC. R: a language and environment for statistical computing: R Foundation for Statistical Computing; 2007.
  20. 20.
    Makishima M, Okamoto AY, Repa JJ, et al. Identification of a nuclear receptor for bile acids. Science. 1999;284(5418):1362–5.CrossRefGoogle Scholar
  21. 21.
    Parks DJ, Blanchard SG, Bledsoe RK, et al. Bile acids: natural ligands for an orphan nuclear receptor. Science. 1999;284(5418):1365–8.CrossRefGoogle Scholar
  22. 22.
    Wang H, Chen J, Hollister K, et al. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell. 1999;3(5):543–53.CrossRefGoogle Scholar
  23. 23.
    Schirra J, Sturm K, Leicht P, et al. Exendin(9-39)amide is an antagonist of glucagon-like peptide-1(7-36)amide in humans. J Clin Invest. 1998;101(7):1421–30.CrossRefGoogle Scholar
  24. 24.
    Salehi M, Gastaldelli A, D'Alessio DA. Blockade of glucagon-like peptide 1 receptor corrects postprandial hypoglycemia after gastric bypass. Gastroenterology. 2014;146(3):669–80 e2.CrossRefGoogle Scholar
  25. 25.
    Xie MH, Holcomb I, Deuel B, et al. FGF-19, a novel fibroblast growth factor with unique specificity for FGFR4. Cytokine. 1999;11(10):729–35.CrossRefGoogle Scholar
  26. 26.
    Fu L, John LM, Adams SH, et al. Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. Endocrinology. 2004;145(6):2594–603.CrossRefGoogle Scholar
  27. 27.
    Tomlinson E, Fu L, John L, et al. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology. 2002;143(5):1741–7.CrossRefGoogle Scholar
  28. 28.
    Morton GJ, Matsen ME, Bracy DP, et al. FGF19 action in the brain induces insulin-independent glucose lowering. J Clin Invest. 2013;123(11):4799–808.CrossRefGoogle Scholar
  29. 29.
    Ryan KK, Tremaroli V, Clemmensen C, et al. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature. 2014;509(7499):183–8.CrossRefGoogle Scholar
  30. 30.
    Hu X, Xiong Q, Xu Y, et al. Association of serum fibroblast growth factor 19 levels with visceral fat accumulation is independent of glucose tolerance status. Nutr Metab Cardiovasc Dis. 2018;28(2):119–25.CrossRefGoogle Scholar
  31. 31.
    Pournaras DJ, Glicksman C, Vincent RP, et al. The role of bile after Roux-en-Y gastric bypass in promoting weight loss and improving glycaemic control. Endocrinology. 2012;153(8):3613–9.CrossRefGoogle Scholar
  32. 32.
    Jansen PL, van Werven J, Aarts E, et al. Alterations of hormonally active fibroblast growth factors after Roux-en-Y gastric bypass surgery. Dig Dis. 2011;29(1):48–51.CrossRefGoogle Scholar
  33. 33.
    Jorgensen NB, Dirksen C, Bojsen-Moller KN, et al. Improvements in glucose metabolism early after gastric bypass surgery are not explained by increases in total bile acids and fibroblast growth factor 19 concentrations. J Clin Endocrinol Metab. 2015;100(3):E396–406.CrossRefGoogle Scholar
  34. 34.
    Nemati R, Lu J, Dokpuang D, et al. Increased bile acids and FGF19 after sleeve gastrectomy and Roux-en-Y gastric bypass correlate with improvement in type 2 diabetes in a randomized trial. Obes Surg. 2018;28:2672–86.CrossRefGoogle Scholar
  35. 35.
    Gomez-Ambrosi J, Gallego-Escuredo JM, Catalan V, et al. FGF19 and FGF21 serum concentrations in human obesity and type 2 diabetes behave differently after diet- or surgically-induced weight loss. Clin Nutr. 2017;36(3):861–8.CrossRefGoogle Scholar
  36. 36.
    Harris LLS, Smith GI, Mittendorfer B, et al. Roux-en-Y gastric bypass surgery has unique effects on postprandial FGF21 but not FGF19 secretion. J Clin Endocrinol Metab. 2017;102(10):3858–64.CrossRefGoogle Scholar
  37. 37.
    Craig CM, Liu LF, Nguyen T, et al. Efficacy and pharmacokinetics of subcutaneous exendin (9-39) in patients with post-bariatric hypoglycaemia. Diabetes Obes Metab. 2018;20(2):352–61.CrossRefGoogle Scholar
  38. 38.
    Tremaroli V, Karlsson F, Werling M, et al. Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation. Cell Metab. 2015;22(2):228–38.CrossRefGoogle Scholar
  39. 39.
    Flynn CR, Albaugh VL, Cai S, et al. Bile diversion to the distal small intestine has comparable metabolic benefits to bariatric surgery. Nat Commun. 2015;6:7715.CrossRefGoogle Scholar
  40. 40.
    Sachdev S, Wang Q, Billington C, et al. FGF 19 and bile acids increase following Roux-en-Y gastric bypass but not after medical management in patients with type 2 diabetes. Obes Surg. 2016;26(5):957–65.CrossRefGoogle Scholar
  41. 41.
    Thoni V, Pfister A, Melmer A, et al. Dynamics of bile acid profiles, GLP-1, and FGF19 after laparoscopic gastric banding. J Clin Endocrinol Metab. 2017;102(8):2974–84.CrossRefGoogle Scholar
  42. 42.
    Zhang H, DiBaise JK, Zuccolo A, et al. Human gut microbiota in obesity and after gastric bypass. Proc Natl Acad Sci U S A. 2009;106(7):2365–70.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Christopher M. Mulla
    • 1
  • Allison B. Goldfine
    • 1
  • Jonathan M. Dreyfuss
    • 1
    • 2
  • Sander Houten
    • 3
  • Hui Pan
    • 1
    • 2
  • David M. Pober
    • 1
  • Nicolai J. Wewer Albrechtsen
    • 4
  • Maria S. Svane
    • 5
  • Julie B. Schmidt
    • 6
  • Jens Juul Holst
    • 4
  • Colleen M. Craig
    • 7
  • Tracey L. McLaughlin
    • 7
  • Mary-Elizabeth Patti
    • 1
    Email author
  1. 1.Research DivisionJoslin Diabetes Center, and Harvard Medical SchoolBostonUSA
  2. 2.Department of Biomedical EngineeringBoston UniversityBostonUSA
  3. 3.Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale BiologyIcahn School of Medicine at Mount SinaiNew YorkUSA
  4. 4.NNF Center for Basic Metabolic Research and Department of Biomedical SciencesUniversity of CopenhagenCopenhagenDenmark
  5. 5.Department of EndocrinologyCopenhagen University Hospital HvidovreCopenhagenDenmark
  6. 6.Department of Nutrition, Exercise and Sports, Faculty of ScienceUniversity of CopenhagenCopenhagenDenmark
  7. 7.Division of Endocrinology and MetabolismStanford University School of MedicineStanfordUSA

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