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Fasting serum bile acids concentration is associated with insulin resistance independently of diabetes status

  • Sang-Guk Lee , Yong-ho Lee , Eunhye Choi , Yonggeun Cho and Jeong-Ho Kim EMAIL logo
Published/Copyright: April 9, 2019
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Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 57 Issue 8

Abstract

Background

Bile acids (BAs) have been demonstrated to exert a variety of metabolic effects and alterations in BAs have been reported in patients with obesity, insulin resistance (IR) and type 2 diabetes mellitus (T2DM). However, it is unclear which metabolic condition is the main contributor to alterations in BAs. In this study, we investigate the associations between different BA profiles with glycemia, obesity or IR status.

Methods

Fasting serum concentrations of 15 BA species were determined in a total of 241 individuals (71 drug-naïve patients with T2DM, 95 patients with impaired fasting glucose [IFG], and 75 healthy controls.

Results

A comparison of the mean values of the BAs revealed no significant differences between normoglycemic controls and patients with IFG or T2DM. However, when the entire cohort was divided according to the presence of IR as determined by a homeostasis model assessment of insulin resistance (HOMA-IR) value >2.5, the levels of total BA and most species of BAs were significantly higher in patients with IR than in patients without. In the correlation analysis, most species of BAs, as well as total BA, were significantly associated with HOMA-IR levels. Furthermore, when the subjects were divided into four groups according to IR and diabetic status, subjects with IR had significantly higher total BAs than participants without IR both in diabetic and non-diabetic groups. Ultimately, multiple linear regression analysis identified HOMA-IR as the only significant contributor to most serum BA species.

Conclusions

Our findings support the essential role of IR in regulating BA metabolism and that this effect is independent of diabetic status.

Keywords: bile acids profile; GLP-1; insulin resistance; obesity; type 2 diabetes mellitus
Corresponding author: Jeong-Ho Kim, MD, PhD, Department of Laboratory Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea, Phone: +82-2-2228-2448, Fax: +82-2-313-0956

  1. Author contributions: S-G. L. designed the study, analyzed all data and wrote the manuscript. Y. L. recruited the patients and contributed critical discussions. E. C. performed experiments and researched the data. Y. C. contributed critical discussions and produced the illustrations. J-H. K. researched data, contributed statistical analysis and edited the manuscript. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: This work was supported by the National Research Foundation of Korea (NRF) Grant funded by the Ministry of Science, ICT and Future Planning, Republic of Korea (NRF-2017R1C1B5015044) and the faculty research grant of Yonsei University College of Medicine (6-2017-0051).

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. Competing interests: The funding organizations played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

References

1. Kuipers F, Bloks VW, Groen AK. Beyond intestinal soap – bile acids in metabolic control. Nat Rev Endocrinol 2014;10:488–98.10.1038/nrendo.2014.60Search in Google Scholar PubMed

2. Chavez-Talavera O, Tailleux A, Lefebvre P, Staels B. Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease. Gastroenterology 2017;152:1679–94.e3.10.1053/j.gastro.2017.01.055Search in Google Scholar PubMed

3. Zarrinpar A, Loomba R. Review article: the emerging interplay among the gastrointestinal tract, bile acids and incretins in the pathogenesis of diabetes and non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2012;36:909–21.10.1111/apt.12084Search in Google Scholar PubMed PubMed Central

4. Ferslew BC, Xie G, Johnston CK, Su M, Stewart PW, Jia W, et al. Altered bile acid metabolome in patients with nonalcoholic steatohepatitis. Dig Dis Sci 2015;60:3318–28.10.1007/s10620-015-3776-8Search in Google Scholar PubMed PubMed Central

5. Sonne DP, Hansen M, Knop FK. Bile acid sequestrants in type 2 diabetes: potential effects on GLP1 secretion. Eur J Endocrinol 2014;171:R47–65.10.1530/EJE-14-0154Search in Google Scholar PubMed

6. Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 2009;89:147–91.10.1152/physrev.00010.2008Search in Google Scholar PubMed

7. Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA, et al. Bile acids: natural ligands for an orphan nuclear receptor. Science 1999;284:1365–8.10.1126/science.284.5418.1365Search in Google Scholar PubMed

8. Kawamata Y, Fujii R, Hosoya M, Harada M, Yoshida H, Miwa M, et al. A G protein-coupled receptor responsive to bile acids. J Biol Chem 2003;278:9435–40.10.1074/jbc.M209706200Search in Google Scholar PubMed

9. Wewalka M, Patti ME, Barbato C, Houten SM, Goldfine AB. Fasting serum taurine-conjugated bile acids are elevated in type 2 diabetes and do not change with intensification of insulin. J Clin Endocrinol Metab 2014;99:1442–51.10.1210/jc.2013-3367Search in Google Scholar PubMed PubMed Central

10. Haeusler RA, Astiarraga B, Camastra S, Accili D, Ferrannini E. Human insulin resistance is associated with increased plasma levels of 12alpha-hydroxylated bile acids. Diabetes 2013;62:4184–91.10.2337/db13-0639Search in Google Scholar PubMed PubMed Central

11. Steiner C, Othman A, Saely CH, Rein P, Drexel H, von Eckardstein A, et al. Bile acid metabolites in serum: intraindividual variation and associations with coronary heart disease, metabolic syndrome and diabetes mellitus. PLoS One 2011;6:e25006.10.1371/journal.pone.0025006Search in Google Scholar PubMed PubMed Central

12. Cariou B, Chetiveaux M, Zair Y, Pouteau E, Disse E, Guyomarc’h-Delasalle B, et al. Fasting plasma chenodeoxycholic acid and cholic acid concentrations are inversely correlated with insulin sensitivity in adults. Nutr Metab (Lond) 2011;8:48.10.1186/1743-7075-8-48Search in Google Scholar PubMed PubMed Central

13. Brufau G, Stellaard F, Prado K, Bloks VW, Jonkers E, Boverhof R, et al. Improved glycemic control with colesevelam treatment in patients with type 2 diabetes is not directly associated with changes in bile acid metabolism. Hepatology 2010;52:1455–64.10.1002/hep.23831Search in Google Scholar PubMed

14. Sun W, Zhang D, Wang Z, Sun J, Xu B, Chen Y, et al. Insulin resistance is associated with total bile acid level in type 2 diabetic and nondiabetic population: a cross-sectional study. Medicine (Baltimore) 2016;95:e2778.10.1097/MD.0000000000002778Search in Google Scholar PubMed PubMed Central

15. Sonne DP, van Nierop FS, Kulik W, Soeters MR, Vilsboll T, Knop FK. Postprandial plasma concentrations of individual bile acids and FGF-19 in patients with type 2 diabetes. J Clin Endocrinol Metab 2016;101:3002–9.10.1210/jc.2016-1607Search in Google Scholar PubMed

16. American Diabetes Association. Classification and diagnosis of diabetes. Sec. 2. In Standards of Medical Care in Diabetes—2015. Diabetes Care 2015;38(Suppl. 1):S8–16.10.2337/dc15-S005Search in Google Scholar PubMed

17. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412–9.10.1007/BF00280883Search in Google Scholar PubMed

18. World Health Organization Western Pacific Region IAftSoO. The Asia-Pacific perspective: redefining obesity and its treatment. Sydney: Health Communications Australia, 2000:15–21.Search in Google Scholar

19. Yamada C, Mitsuhashi T, Hiratsuka N, Inabe F, Araida N, Takahashi E. Optimal reference interval for homeostasis model assessment of insulin resistance in a Japanese population. J Diabetes Investig 2011;2:373–6.10.1111/j.2040-1124.2011.00113.xSearch in Google Scholar PubMed PubMed Central

20. Marksteiner J, Blasko I, Kemmler G, Koal T, Humpel C. Bile acid quantification of 20 plasma metabolites identifies lithocholic acid as a putative biomarker in Alzheimer’s disease. Metabolomics 2018;14:1.10.1007/s11306-017-1297-5Search in Google Scholar PubMed PubMed Central

21. Pham HT, Arnhard K, Asad YJ, Deng L, Felder TK, Williams LS, et al. Inter-laboratory robustness of next-generation bile acid study in mice and humans: international ring trial involving 12 laboratories. J Appl Lab Med 2016;1:129–42.10.1373/jalm.2016.020537Search in Google Scholar PubMed

22. Vincent RP, Omar S, Ghozlan S, Taylor DR, Cross G, Sherwood RA, et al. Higher circulating bile acid concentrations in obese patients with type 2 diabetes. Ann Clin Biochem 2013;50:360–4.10.1177/0004563212473450Search in Google Scholar PubMed

23. Legry V, Francque S, Haas JT, Verrijken A, Caron S, Chavez-Talavera O, et al. Bile acid alterations are associated with insulin resistance, but not with NASH, in obese subjects. J Clin Endocrinol Metab 2017;102:3783–94.10.1210/jc.2017-01397Search in Google Scholar PubMed

24. Li T, Francl JM, Boehme S, Ochoa A, Zhang Y, Klaassen CD, et al. Glucose and insulin induction of bile acid synthesis: mechanisms and implication in diabetes and obesity. J Biol Chem 2012;287:1861–73.10.1074/jbc.M111.305789Search in Google Scholar PubMed PubMed Central

25. Nakae J, Kitamura T, Silver DL, Accili D. The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression. J Clin Invest 2001;108:1359–67.10.1172/JCI200112876Search in Google Scholar

26. Li T, Kong X, Owsley E, Ellis E, Strom S, Chiang JY. Insulin regulation of cholesterol 7 alpha-hydroxylase expression in human hepatocytes: roles of forkhead box O1 and sterol regulatory element-binding protein 1c. J Biol Chem 2006;281:28745–54.10.1074/jbc.M605815200Search in Google Scholar PubMed PubMed Central

27. Li T, Chanda D, Zhang Y, Choi HS, Chiang JY. Glucose stimulates cholesterol 7 alpha-hydroxylase gene transcription in human hepatocytes. J Lipid Res 2010;51:832–42.10.1194/jlr.M002782Search in Google Scholar PubMed PubMed Central

28. Jones BV, Begley M, Hill C, Gahan CG, Marchesi JR. Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome. Proc Natl Acad Sci USA 2008;105:13580–5.10.1073/pnas.0804437105Search in Google Scholar PubMed PubMed Central

29. Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008;57:1470–81.10.2337/db07-1403Search in Google Scholar PubMed

30. Prinz P, Hofmann T, Ahnis A, Elbelt U, Goebel-Stengel M, Klapp BF, et al. Plasma bile acids show a positive correlation with body mass index and are negatively associated with cognitive restraint of eating in obese patients. Front Neurosci 2015;9:199.10.3389/fnins.2015.00199Search in Google Scholar PubMed PubMed Central

Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/cclm-2018-0741).

Received: 2018-07-16
Accepted: 2018-12-20
Published Online: 2019-04-09
Published in Print: 2019-07-26

©2019 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/cclm-2018-0741
Keywords for this article
bile acids profile; GLP-1; insulin resistance; obesity; type 2 diabetes mellitus

Articles in the same Issue

  1. Frontmatter
  2. Editorials
  3. CCLM Award for the Most Cited Paper
  4. Folate and vitamin B12 assays after recalibration to the WHO International Standard 03/178: making the interpretation as simple as possible, but not simpler
  5. Reviews
  6. Blood contamination in salivary diagnostics: current methods and their limitations
  7. Central adrenal insufficiency: open issues regarding diagnosis and glucocorticoid treatment
  8. Genetics and Molecular Diagnostics
  9. Measuring the chronology of the translational process of molecular genetic discoveries
  10. Development and interlaboratory evaluation of a NIST Reference Material RM 8366 for EGFR and MET gene copy number measurements
  11. General Clinical Chemistry and Laboratory Medicine
  12. Post-translational modification-derived products are associated with frailty status in elderly subjects
  13. Urine chloride self-measurement to monitor sodium chloride intake in patients with chronic kidney disease
  14. Estimated urinary osmolality based on combined urinalysis parameters: a critical evaluation
  15. Measurement of S100B protein: evaluation of a new prototype on a bioMérieux Vidas® 3 analyzer
  16. Measuring thyroglobulin in patients with thyroglobulin autoantibodies: evaluation of the clinical impact of BRAHMS Kryptor® Tg-minirecovery test in a large series of patients with differentiated thyroid carcinoma
  17. Human chorionic gonadotropin suspected heterophile interference investigations in immunoassays: a recommended approach
  18. Certified reference material against PR3 ANCA IgG autoantibodies. From development to certification
  19. Diagnostic accuracy of a fully automated multiplex celiac disease antibody panel for serum and plasma
  20. Fasting serum bile acids concentration is associated with insulin resistance independently of diabetes status
  21. Hematology and Coagulation
  22. The association between activated protein C ratio and Factor V Leiden are gender-dependent
  23. Reference Values and Biological Variations
  24. Determination of sigma score based on biological variation for haemostasis assays: fit-for-purpose for daily practice?
  25. Calcitonin measurement in pediatrics: reference ranges are gender-dependent, validation in medullary thyroid cancer and thyroid diseases
  26. Cancer Diagnostics
  27. Uncovering the clinical impact of kallikrein-related peptidase 5 (KLK5) mRNA expression in the colorectal adenoma-carcinoma sequence
  28. Cardiovascular Diseases
  29. Performance of a novel high sensitivity cardiac troponin I assay in asymptomatic hemodialysis patients – evidence for sex-specific differences
  30. Infectious Diseases
  31. Rapid susceptibility testing of multi-drug resistant Escherichia coli and Klebsiella by glucose metabolization monitoring
  32. Letters to the Editor
  33. Vitamin B12 and folate levels in a healthy population: establishing reference intervals
  34. Reference values of a new serum folate assay traceable to the WHO International Standard
  35. Serum protein electrophoresis and complement deficiencies: a veteran but very versatile test in clinical laboratories
  36. Introduction of a novel ELISA assay for serum AMH determination
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  38. Evaluation of the MULTISURE HIV Rapid Test in a Korean population with low human immunodeficiency virus prevalence
  39. Vancomycin immunoassay: does the Advia Centaur XPT underestimate the exposure of patients? A method comparison study
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  43. Congress Abstracts
  44. Proceedings of ACBI 2018 41ST Annual Conference Association of Clinical Biochemists in Ireland
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