Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Bariatric Surgery

Altered bile acid kinetics contribute to postprandial hypoglycaemia after Roux-en-Y gastric bypass surgery

International Journal of Obesity volume 45, pages 619–630 (2021)Cite this article

Subjects

Abstract

Background/objectives

Bile acids (BA) act as detergents in intestinal fat absorption and as modulators of metabolic processes via activation of receptors such as FXR and TGR5. Elevated plasma BA as well as increased intestinal BA signalling to promote GLP-1 release have been implicated in beneficial health effects of Roux-en-Y gastric bypass surgery (RYGB). Whether BA also contribute to the postprandial hypoglycaemia that is frequently observed post-RYGB is unknown.

Methods

Plasma BA, fibroblast growth factor 19 (FGF19), 7α-hydroxy-4-cholesten-3-one (C4), GLP-1, insulin and glucose levels were determined during 3.5 h mixed-meal tolerance tests (MMTT) in subjects after RYGB, either with (RYGB, n = 11) or without a functioning gallbladder due to cholecystectomy (RYGB-CC, n = 11). Basal values were compared to those of age, BMI and sex-matched obese controls without RYGB (n = 22).

Results

Fasting BA as well as FGF19 levels were elevated in RYGB and RYGB-CC subjects compared to non-bariatric controls, without significant differences between RYGB and RYGB-CC. Postprandial hypoglycaemia was observed in 8/11 RYGB-CC and only in 3/11 RYGB. Subjects who developed hypoglycaemia showed higher postprandial BA levels coinciding with augmented GLP-1 and insulin responses during the MMTT. The nadir of plasma glucose concentrations after meals showed a negative relationship with postprandial BA peaks. Plasma C4 was lower during MMTT in subjects experiencing hypoglycaemia, indicating lower hepatic BA synthesis. Computer simulations revealed that altered intestinal transit underlies the occurrence of exaggerated postprandial BA responses in hypoglycaemic subjects.

Conclusion

Altered BA kinetics upon ingestion of a meal, as frequently observed in RYGB-CC subjects, appear to contribute to postprandial hypoglycaemia by stimulating intestinal GLP-1 release.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Glucose, insulin, GLP-1, total bile acids, FGF19 and C4 over time in response to a mixed meal in patients after Roux-en-Y gastric bypass surgery, subdivided between subjects with hypoglycemia (black) and without hypoglycemia (grey).
Fig. 2: Relationships between postprandial elevations of plasma bile acids and plasma glucose responses.
Fig. 3: . Mathematical modelling analysis of the bile acid and GLP-1 response to RYGB.

Similar content being viewed by others

References

  1. Angrisani L, Santonicola A, Iovino P, Vitiello A, Zundel N, Buchwald H, et al. Bariatric surgery and endoluminal procedures: IFSO Worldwide Survey 2014. Obes Surg. 2017;27:2279–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Rubino F, Gagner M, Gentileschi P, Kini S, Fukuyama S, Feng J, et al. The early effect of the Roux-en-Y gastric bypass on hormones involved in body weight regulation and glucose metabolism. Ann Surg. 2004;240:236–42.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Nakatani H, Kasama K, Oshiro T, Watanabe M, Hirose H, Itoh H. Serum bile acid along with plasma incretins and serum high-molecular weight adiponectin levels are increased after bariatric surgery. Metabolism. 2009;58:1400–07.

    Article  CAS  PubMed  Google Scholar 

  4. Nemati R, Lu J, Dokpuang D, Booth M, Plank LD, Murphy R. 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.

    Article  PubMed  Google Scholar 

  5. Albaugh VL, Banan B, Antoun J, Xiong Y, Guo Y, Ping J, et al. Role of bile acids and GLP-1 in mediating the metabolic improvements of bariatric surgery. Gastroenterology. 2019;156:1041–51.

    Article  CAS  PubMed  Google Scholar 

  6. Nielsen S, Svane MS, Kuhre RE, Clausen TR, Kristiansen VB, Rehfeld JF, et al. Chenodeoxycholic acid stimulates glucagon-like peptide-1 secretion in patients after Roux-en-Y gastric bypass. Physiol Rep. 2017;5:e13140.

  7. Aron-Wisnewsky J, Prifti E, Belda E, Ichou F, Kayser BD, Dao MC, et al. Major microbiota dysbiosis in severe obesity: fate after bariatric surgery. Gut. 2019;68:70–82.

    Article  CAS  PubMed  Google Scholar 

  8. Baud G, Daoudi M, Hubert T, Raverdy V, Pigeyre M, Hervieux E, et al. Bile diversion in Roux-en-Y gastric bypass modulates sodium-dependent glucose intestinal uptake. Cell Metab. 2016;23:547–53.

    Article  CAS  PubMed  Google Scholar 

  9. Isbell JM, Tamboli RA, Hansen EN, Saliba J, Dunn JP, Phillips SE, et al. The importance of caloric restriction in the early improvements in insulin sensitivity after Roux-en-Y gastric bypass surgery. Diabetes Care. 2010;33:1438–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Emous M, Wolffenbuttel BHR, Totté E, van Beek AP. The short- to mid-term symptom prevalence of dumping syndrome after primary gastric-bypass surgery and its impact on health-related quality of life. Surg Obes Relat Dis. 2017;13:1489–1500.

    Article  PubMed  Google Scholar 

  11. Emous M, van den Broek M, Wijma RB, de Heide LJM, van Dijk G, Laskewitz A, et al. Prevalence of hypoglycaemia in a random population after Roux-en-Y gastric bypass after a meal test. Endocr Connect. 2019;8:969–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. le Roux CW, Welbourn R, Werling M, Osborne A, Kokkinos A, Laurenius A, et al. Gut hormones as mediators of appetite and weight loss after Roux-en-Y gastric bypass. Ann Surg. 2007;246:780–5.

    Article  PubMed  Google Scholar 

  13. Berr F, Stellaard F, Pratschke E, Paumgartner G. Effects of cholecystectomy on the kinetics of primary and secondary bile acids. J Clin Investig. 1989;83:1541–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Barrera F, Azocar L, Molina H, Schalper KA, Ocares M, Liberona J, et al. Effect of cholecystectomy on bile acid synthesis and circulating levels of fibroblast growth factor 19. Ann Hepatol. 2015;14:710–21.

    Article  CAS  PubMed  Google Scholar 

  15. Erlinger S. Gallstones in obesity and weight loss. Eur J Gastroenterol Hepatol. 2000;12:1347–52.

    Article  CAS  PubMed  Google Scholar 

  16. Amstutz S, Michel JM, Kopp S, Egger B. Potential benefits of prophylactic cholecystectomy in patients undergoing bariatric bypass surgery. Obes Surg. 2015;25:2054–60.

    Article  PubMed  Google Scholar 

  17. Wanjura V, Sandblom G, Österberg J, Enochsson L, Ottosson J, Szabo E. Cholecystectomy after gastric bypass—incidence and complications. Surg Obes Relat Dis. 2017;13:979–87.

    Article  PubMed  Google Scholar 

  18. Wijma RB, Emous M, van den Broek M, Laskewitz A, Kobold ACM, van Beek AP. Prevalence and pathophysiology of early dumping in patients after primary Roux-en-Y gastric bypass during a mixed-meal tolerance test. Surg Obes Relat Dis. 2018;15:73–81.

    Article  PubMed  Google Scholar 

  19. Soenen S, Bonomi AG, Lemmens SG, Scholte J, Thijssen MA, van Berkum F. Relatively high-protein or ‘low-carb’ energy-restricted diets for body weight loss and body weight maintenance? Physiol Behav. 2012;107:374–80.

    Article  CAS  PubMed  Google Scholar 

  20. Out C, Dikkers A, Laskewitz A, Boverhof R, van der Ley C, Kema IP, et al. Prednisolone increases enterohepatic cycling of bile acids by induction of Asbt and promotes reverse cholesterol transport. J Hepatol. 2014;61:351–7.

    Article  CAS  PubMed  Google Scholar 

  21. Eggink HM, Tambyrajah LL, van den Berg R, Mol IM, van den Heuvel JK, Koehorst M, et al. Chronic infusion of taurolithocholate into the brain increases fat oxidation in mice. J Endocrinol. 2018;236:85–97.

    Article  CAS  PubMed  Google Scholar 

  22. Sips FLP, Eggink HM, Hilbers PAJ, Soeters MR, Groen AK, van Riel NAW. In silico analysis identifies intestinal transit as a key determinant of systemic bile acid metabolism. Front Physiol. 2018;9:631.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Horowitz M, Harding PE, Maddox A, Maddern GJ, Collins PJ, Chatterton BE, et al. Gastric and oesophageal emptying in insulin-dependent diabetes mellitus. J Gastroenterol Hepatol. 1986;1:97–113.

    Article  Google Scholar 

  24. Dirksen C, Damgaard M, Bojsen-Møller KN, Jørgensen NB, Kielgast U, Jacobsen SH, et al. Fast pouch emptying, delayed small intestinal transit, and exaggerated gut hormone responses after Roux-en-Y gastric bypass. Neurogastroenterol Motil. 2013;25:346–55.

    Article  CAS  PubMed  Google Scholar 

  25. Ahmad TR, Haeusler RA. Bile acids in glucose metabolism and insulin signalling - mechanisms and research needs. Nat Rev Endocrinol. 2019;15:701–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Shapiro H, Kolodziejczyk AA, Halstuch D, Elinav E. Bile acids in glucose metabolism in health and disease. J Exp Med. 2018;215:383–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kreymann B, Williams G, Ghatei MA, Bloom SR. Glucagon-like peptide-1 7-36: a physiological incretin in man. Lancet. 1987;8571:1300–4.

    Article  Google Scholar 

  28. Zhang Y, Parajuli KR, Fava GE, Gupta R, Xu W, Nguyen LU, et al. GLP-1 receptor in pancreatic α-cells regulates glucagon secretion in a glucose-dependent bidirectional manner. Diabetes. 2019;68:34–44.

    Article  CAS  PubMed  Google Scholar 

  29. Chavez-Talavera O, Haas J, Grzych G, Tailleux A, Staels B. Bile acid alterations in nonalcoholic fatty liver disease, obesity, insulin resistance and type 2 diabetes: what do the human studies tel? Curr Opin Lipidol. 2019;30:244–54.

    Article  CAS  PubMed  Google Scholar 

  30. Mulla CM, Goldfine AB, Dreyfuss JM, Houten S, Pan H, Pober DM, et al. Plasma FGF-19 levels are increased in patients with post-bariatric hypoglycemia. Obes Surg. 2019;29:2092–9.

    Article  PubMed  PubMed Central  Google Scholar 

  31. van Furth AM, van den Broek M, Emous M, de Heide LJM, Kuipers F, van Beek AP. Cholecystectomy increases the risk of dumping syndrome andpost-bariatric hypoglycemia after bariatric surgery. Surg. Obes. Rel. Dis. 2020;16:1939−47.

Download references

Acknowledgements

University of Groningen Campus Fryslân (MvdB, TvZ), the Netherlands Heart Foundation (CVON2018-27) (AKG, FK) and EU’s Seventh Programme for Research, Technological Development and Demonstration under grant agreement No. 305707 (AKG, NAWvR). The study sponsor/funder was not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report.

Author information

Authors and Affiliations

  1. Center for Obesity North Netherlands (CON), Department of Surgery, MCL, Leeuwarden, The Netherlands

    Merel van den Broek, Loek J. M. de Heide, Marloes Emous & André P. van Beek

  2. Faculty Campus Fryslân, University of Groningen, Leeuwarden, The Netherlands

    Merel van den Broek & Tim van Zutphen

  3. Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands

    Fianne L. P. Sips & Natal A. W. van Riel

  4. Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Martijn Koehorst, Martijn van Faassen, Albert K. Groen, Jan F. de Boer & Folkert Kuipers

  5. Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Tim van Zutphen, Jan F. de Boer & Folkert Kuipers

  6. Department of Vascular Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands

    Albert K. Groen & Natal A. W. van Riel

  7. Department of Endocrinology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    André P. van Beek

Authors
  1. Merel van den Broek
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Loek J. M. de Heide
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fianne L. P. Sips
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martijn Koehorst
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tim van Zutphen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marloes Emous
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Martijn van Faassen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Albert K. Groen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Natal A. W. van Riel
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jan F. de Boer
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. André P. van Beek
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Folkert Kuipers
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Folkert Kuipers.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

van den Broek, M., de Heide, L.J.M., Sips, F.L.P. et al. Altered bile acid kinetics contribute to postprandial hypoglycaemia after Roux-en-Y gastric bypass surgery. Int J Obes 45, 619–630 (2021). https://doi.org/10.1038/s41366-020-00726-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41366-020-00726-w

This article is cited by

Search

Advanced search

Quick links