Skip to main content
SpringerLink
Log in

Metabolomic Analysis of the Improvements in Insulin Secretion and Resistance After Sleeve Gastrectomy: Implications of the Novel Biomarkers

  • Original Contributions
  • Published:
Obesity Surgery Aims and scope Submit manuscript

Abstract

Background

Large neutral amino acids (LNAAs) and gut microbial metabolites have been linked to insulin secretion and resistance. We investigated whether baseline LNAAs and kynurenine pathway metabolites and changes in tryptophan-derived gut microbial metabolites (TDGMs), such as indole compounds, were associated with improvements in insulin secretion and resistance after sleeve gastrectomy.

Methods

In this prospective single-arm longitudinal study, 23 patients with type 2 diabetes underwent sleeve gastrectomy. Twelve diabetes-related amino acid metabolites were quantified before surgery, and the following three indices were assessed as outcome measures: insulinogenic index, homeostasis model assessment–insulin resistance (HOMA-IR), and quantitative insulin sensitivity check index (QUICKI). We also measured changes in TDGMs, including four indole compounds, 3 months after bariatric surgery. A linear regression model and receiver operating characteristic curves were assessed.

Results

The mean age and body mass index of study participants were 41.8 years (standard deviation (SD), 13.1 years) and 38.9 kg/m2 (SD, 5.2 kg/m2), respectively. Several baseline amino acid metabolites were significantly associated with a change in insulin secretion or resistance 3 months after bariatric surgery. Phenylalanine and LNAAs showed superior performance for predicting improvements in insulin secretion and resistance. Among the TDGMs, Δindole-3-propionic acid was significantly associated with the Δinsulinogenic index, and Δindole-3-acetic acid was significantly associated with the ΔHOMA-IR and ΔQUICKI.

Conclusions

Our findings underscore the importance of baseline amino acid profiles, especially those of LNAAs and phenylalanine, and alterations in TDGMs for improving insulin secretion and resistance in the early postoperative period after sleeve gastrectomy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med. 2012;366(17):1577–85.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  PubMed Central  Google Scholar 

  3. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Saeidi N, Meoli L, Nestoridi E, et al. Reprogramming of intestinal glucose metabolism and glycemic control in rats after gastric bypass. Science. 2013;341(6144):406–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Rizzello M, Abbatini F, Casella G, et al. Early postoperative insulin-resistance changes after sleeve gastrectomy. Obes Surg. 2010;20(1):50–5.

    PubMed  Google Scholar 

  6. Abbatini F, Rizzello M, Casella G, et al. Long-term effects of laparoscopic sleeve gastrectomy, gastric bypass, and adjustable gastric banding on type 2 diabetes. Surg Endosc. 2010;24(5):1005–10.

    CAS  PubMed  Google Scholar 

  7. Basso N, Capoccia D, Rizzello M, et al. First-phase insulin secretion, insulin sensitivity, ghrelin, GLP-1, and PYY changes 72 h after sleeve gastrectomy in obese diabetic patients: the gastric hypothesis. Surg Endosc. 2011;25(11):3540–50.

    CAS  PubMed  Google Scholar 

  8. Nannipieri M, Baldi S, Mari A, et al. Roux-en-Y gastric bypass and sleeve gastrectomy: mechanisms of diabetes remission and role of gut hormones. J Clin Endocrinol Metab. 2013;98(11):4391–9.

    CAS  PubMed  Google Scholar 

  9. Honka H, Koffert J, Hannukainen JC, et al. The effects of bariatric surgery on pancreatic lipid metabolism and blood flow. J Clin Endocrinol Metab. 2015;100(5):2015–23.

    CAS  PubMed  Google Scholar 

  10. Wang TJ, Larson MG, Vasan RS, et al. Metabolite profiles and the risk of developing diabetes. Nat Med. 2011;17(4):448–53.

    PubMed  PubMed Central  Google Scholar 

  11. Roberts LD, Koulman A, Griffin JL. Towards metabolic biomarkers of insulin resistance and type 2 diabetes: progress from the metabolome. Lancet Diabetes Endocrinol. 2014;2(1):65–75.

    CAS  PubMed  Google Scholar 

  12. Floegel A, Stefan N, Yu Z, et al. Identification of serum metabolites associated with risk of type 2 diabetes using a targeted metabolomic approach. Diabetes. 2013;62(2):639–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Wurtz P, Soininen P, Kangas AJ, et al. Branched-chain and aromatic amino acids are predictors of insulin resistance in young adults. Diabetes Care. 2013;36(3):648–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Oxenkrug G. Insulin resistance and dysregulation of tryptophan-kynurenine and kynurenine-nicotinamide adenine dinucleotide metabolic pathways. Mol Neurobiol. 2013;48(2):294–301.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Le Floc'h N, Otten W, Merlot E. Tryptophan metabolism, from nutrition to potential therapeutic applications. Amino Acids. 2011;41(5):1195–205.

    CAS  PubMed  Google Scholar 

  16. Pedersen ER, Tuseth N, Eussen SJ, et al. Associations of plasma kynurenines with risk of acute myocardial infarction in patients with stable angina pectoris. Arterioscler Thromb Vasc Biol. 2015;35(2):455–62.

    CAS  PubMed  Google Scholar 

  17. Roager HM, Licht TR. Microbial tryptophan catabolites in health and disease. Nat Commun. 2018;9(1):3294.

    PubMed  PubMed Central  Google Scholar 

  18. de Mello VD, Paananen J, Lindstrom J, et al. Indolepropionic acid and novel lipid metabolites are associated with a lower risk of type 2 diabetes in the Finnish diabetes prevention study. Sci Rep. 2017;7:46337.

    PubMed  PubMed Central  Google Scholar 

  19. Parrott J, Frank L, Rabena R, et al. American Society for Metabolic and Bariatric Surgery integrated health nutritional guidelines for the surgical weight loss patient 2016 update: micronutrients. Surg Obes Relat Dis. 2017;13(5):727–41.

    PubMed  Google Scholar 

  20. Tura A, Kautzky-Willer A, Pacini G. Insulinogenic indices from insulin and C-peptide: comparison of beta-cell function from OGTT and IVGTT. Diabetes Res Clin Pract. 2006;72(3):298–301.

    CAS  PubMed  Google Scholar 

  21. Chen H, Sullivan G, Quon MJ. Assessing the predictive accuracy of QUICKI as a surrogate index for insulin sensitivity using a calibration model. Diabetes. 2005;54(7):1914–25.

    CAS  PubMed  Google Scholar 

  22. Newgard CB, An J, Bain JR, et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 2009;9(4):311–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Shaham O, Wei R, Wang TJ, et al. Metabolic profiling of the human response to a glucose challenge reveals distinct axes of insulin sensitivity. Mol Syst Biol. 2008;4:214.

    PubMed  PubMed Central  Google Scholar 

  24. Huffman KM, Shah SH, Stevens RD, et al. Relationships between circulating metabolic intermediates and insulin action in overweight to obese, inactive men and women. Diabetes Care. 2009;32(9):1678–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Krebs M, Krssak M, Bernroider E, et al. Mechanism of amino acid-induced skeletal muscle insulin resistance in humans. Diabetes. 2002;51(3):599–605.

    CAS  PubMed  Google Scholar 

  26. Lynch CJ, Adams SH. Branched-chain amino acids in metabolic signalling and insulin resistance. Nat Rev Endocrinol. 2014;10(12):723–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Liu R, Hong J, Xu X, et al. Gut microbiome and serum metabolome alterations in obesity and after weight-loss intervention. Nat Med. 2017;23(7):859–68.

    CAS  PubMed  Google Scholar 

  28. Gralka E, Luchinat C, Tenori L, et al. Metabolomic fingerprint of severe obesity is dynamically affected by bariatric surgery in a procedure-dependent manner. Am J Clin Nutr. 2015;102(6):1313–22.

    CAS  PubMed  Google Scholar 

  29. Modesitt SC, Hallowell PT, Slack-Davis JK, et al. Women at extreme risk for obesity-related carcinogenesis: baseline endometrial pathology and impact of bariatric surgery on weight, metabolic profiles and quality of life. Gynecol Oncol. 2015;138(2):238–45.

    PubMed  Google Scholar 

  30. Schwarcz R. The kynurenine pathway of tryptophan degradation as a drug target. Curr Opin Pharmacol. 2004;4(1):12–7.

    CAS  PubMed  Google Scholar 

  31. Brandacher G, Hoeller E, Fuchs D, et al. Chronic immune activation underlies morbid obesity: is IDO a key player? Curr Drug Metab. 2007;8(3):289–95.

    CAS  PubMed  Google Scholar 

  32. Oxenkrug G, van der Hart M, Summergrad P. Elevated anthranilic acid plasma concentrations in type 1 but not type 2 diabetes mellitus. Integr Mol Med. 2015;2(5):365–8.

    PubMed  PubMed Central  Google Scholar 

  33. Muzik O, Burghardt P, Yi Z, et al. Successful metformin treatment of insulin resistance is associated with down-regulation of the kynurenine pathway. Biochem Biophys Res Commun. 2017;488(1):29–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Oxenkrug GF. Increased plasma levels of xanthurenic and kynurenic acids in type 2 diabetes. Mol Neurobiol. 2015;52(2):805–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Christensen MHE, Fadnes DJ, Rost TH, et al. Inflammatory markers, the tryptophan-kynurenine pathway, and vitamin B status after bariatric surgery. PLoS One. 2018;13(2):e0192169.

    PubMed  PubMed Central  Google Scholar 

  36. Krause D, Suh HS, Tarassishin L, et al. The tryptophan metabolite 3-hydroxyanthranilic acid plays anti-inflammatory and neuroprotective roles during inflammation: role of hemeoxygenase-1. Am J Pathol. 2011;179(3):1360–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Yu E, Papandreou C, Ruiz-Canela M, et al. Association of tryptophan metabolites with incident type 2 diabetes in the PREDIMED trial: a case-cohort study. Clin Chem. 2018;64(8):1211–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Pedersen HK, Gudmundsdottir V, Nielsen HB, et al. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature. 2016;535(7612):376–81.

    CAS  PubMed  Google Scholar 

  39. Le Chatelier E, Nielsen T, Qin J, et al. Richness of human gut microbiome correlates with metabolic markers. Nature. 2013;500(7464):541–6.

    PubMed  Google Scholar 

  40. Furet JP, Kong LC, Tap J, et al. Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers. Diabetes. 2010;59(12):3049–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Heianza Y, Sun D, Li X, et al. Gut microbiota metabolites, amino acid metabolites and improvements in insulin sensitivity and glucose metabolism: the POUNDS Lost trial. Gut. 2019;68(2):263–70.

    CAS  PubMed  Google Scholar 

  42. Tuomainen M, Lindstrom J, Lehtonen M, et al. Associations of serum indolepropionic acid, a gut microbiota metabolite, with type 2 diabetes and low-grade inflammation in high-risk individuals. Nutr Diabetes. 2018;8(1):35.

    PubMed  PubMed Central  Google Scholar 

  43. Fontana L, Cummings NE, Arriola Apelo SI, et al. Decreased consumption of branched-chain amino acids improves metabolic health. Cell Rep. 2016;16(2):520–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhang Y, Guo K, LeBlanc RE, et al. Increasing dietary leucine intake reduces diet-induced obesity and improves glucose and cholesterol metabolism in mice via multimechanisms. Diabetes. 2007;56(6):1647–54.

    CAS  PubMed  Google Scholar 

  45. Nicholson JK, Holmes E, Kinross J, et al. Host-gut microbiota metabolic interactions. Science. 2012;336(6086):1262–7.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Sinhyung Kim for research support; Seona Lee for administrative support; Korea Basic Science Institute for technical support; and STARDOM Biobank for the storage service of study samples.

Funding

This research was supported by a grant of Korea University Anam Hospital, Seoul, Republic of Korea (Grant No. O1904941) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2020R1I1A1A01070106).

Author information

Author notes

  1. Yeongkeun Kwon and Mi Jang contributed equally to this work.

Authors and Affiliations

  1. Division of Foregut Surgery, Korea University College of Medicine, Seoul, South Korea

    Yeongkeun Kwon, Jane Ha & Sungsoo Park

  2. Center for Obesity and Metabolic Diseases, Korea University Anam Hospital, Seoul, South Korea

    Yeongkeun Kwon, Jane Ha & Sungsoo Park

  3. Department of Biotechnology and Food Science, Norwegian University of Science and Technology, Trondheim, Norway

    Mi Jang

  4. Advanced Analysis Center, Korea Institute of Science and Technology, Seoul, South Korea

    Youngsun Lee

Authors
  1. Yeongkeun Kwon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mi Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Youngsun Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jane Ha
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sungsoo Park
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sungsoo Park.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Statement

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher’s Note

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

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kwon, Y., Jang, M., Lee, Y. et al. Metabolomic Analysis of the Improvements in Insulin Secretion and Resistance After Sleeve Gastrectomy: Implications of the Novel Biomarkers. OBES SURG 31, 43–52 (2021). https://doi.org/10.1007/s11695-020-04925-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11695-020-04925-2

Keywords

Search

Navigation