Background: Plasma levels of tryptophan (TRP) metabolites have not been measured extensively in patients of type 2 diabetes mellitus (T2DM). Methods: Metabolites analysis was performed by a liquid chromatograph tandem mass spectrometer, the LCMS-8060 quadrupole mass spectrometer combined with Nexera X2 liquid chromatograph system (Shimadzu Corporation, Kyoto, Japan). Body mass index (BMI) and TRP metabolites have been measured in healthy old men (n = 20) and patients of T2DM (n = 20). TRP metabolites were measured by using the ultrahigh speed liquid chromatography-mass spectros-copy (Shimadzu Corporation). Results: The plasma levels of 5-hydroxytryptophan (5-HTRP), 5-hydroxyindoleacetic acid (5-HIAA), kynurenic acid (KNA), 3-hydroxykynurenine (3-HKN), and 3-hydroxyanthranilic acid (3-HAA) were higher in patients of T2DM than healthy old men. Since 5HTRP and 5-HIAA belong to the serotonin pathway, and KNA, 3-HKN, and 3-HAA belong to the KN pathway of TRP metabolism, these pathways were activated more in the patients of T2DM. Since plasma levels of Indole-3-acetic acid were not elevated in T2DM, that pathway was not activated more in T2DM. Serotonin levels were not increased but 5-HIAA levels were increased in the plasma of T2DM patients, which may mean that serotonin was quickly metabolized to 5-HIAA in the patients of T2DM. Conclusion: Plasma levels of tryptophan metabolites in serotonin and kynurenine pathways increased in T2DM patients. Obesity expressed by BMI may not influence tryptophan metabolism in healthy old men and T2DM patients. These results indicate that our new method of the simultaneous measurements of all the tryptophan metabolites is the powerful measure to identify factor related to endogenous stresses seen in DM.
[1] Cervenka, I., Agudelo, L.Z. and Ruas, J.L. (2017) Kynurenines: Tryptophan’s Metabolites in Exercise, Inflammation, and Mental Health. Science, 357, pii: eaaf9794. https://doi.org/10.1126/science.aaf9794
Yates, C.A. and Herbert, J. (1976) Differential Circadian Rhythms in Pineal and Hypothalamic 5-HT Induced by Artificial Photoperiods or Melatonin. Nature, 262, 219-220. https://doi.org/10.1038/262219a0
Stone, T.W., Stoy, N. and Darlington, L.G. (2013) An Expanding Range of Targets for Kynurenine Metabolites of Tryptophan. Trends in Pharmacological Sciences, 34, 136-143. https://doi.org/10.1016/j.tips.2012.09.006
Malyszko, J., Urano, T., Yan, D., Serizawa, K., Kozima, Y., Takada, Y. and Takada, A. (1994) Foot Shock-Induced Changes in Blood and Brain Serotonin and Related Substances in Rats. The Japanese Journal of Physiology, 44, 35-47. https://doi.org/10.2170/jjphysiol.44.35
Malyszko, J., Urano, T., Takada, Y. and Takada, A. (1995) Amino Acids, Serotonin, and 5-Hydroxyindoleacetic Acid Following Foot Shock in Rats. Brain Research Bulletin, 36, 137-140. https://doi.org/10.1016/0361-9230(94)00178-4
Pawlak, D., Takada, Y., Urano, T. and Takada, A. (2000) Serotonergic and Kynurenic Pathways in Rats Exposed to Foot Shock. Brain Research Bulletin, 53, 197-205. https://doi.org/10.1016/S0361-9230(00)00252-5
Okuno, E., Nishikawa, T. and Nakamura, M. (1996) Kynurenine Aminotransferases in the Rat. Localization and Characterization. Advances in Experimental Medicine and Biology, 398, 455-464. https://doi.org/10.1007/978-1-4613-0381-7_71
Nakagami, Y., Saito, H. and Katsuki, H. (1996) 3-Hydroxykynurenine Toxicity on the Rat Striatum in Vivo. The Japanese Journal of Pharmacology, 2, 183-186. https://doi.org/10.1254/jjp.71.183
Price, L.H., Charney, D.S., Delgado, P.L., Goodman, W.K., Krystal, J.H., Woods, S.W. and Heninger, G.R. (1990) Clinical Studies of 5-HT Function Using i.v. L-Tryptophan. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 14, 459-472.
Stone, T.W. (1993) Neuropharmacology of Quinolinic and Kynurenic Acids. Pharmacological Reviews, 45, 309-379.
Matsuoka, K., Kato, K., Takao, T., Ogawa, M., Ishii, Y., Shimizu, F., Masuda, J. and Takada, A. (2016) Concentrations of Various Tryptophan Metabolites Increase in Patients of Diabetes Mellitus Compared to Healthy Aged Male Adults. Diabetology International.
Hervè, E., Beyne, E., Jamault, H. and Delacoux, E. (1996) Determination of Tryptophan and Its Kynurenine Pathway Metabolites in Human Serum by High-Performance Liquid Chromatography with Simultaneous Ultraviolet and Fluorimetric Detection. Journal of Chromatography B, 675, 157-161. https://doi.org/10.1016/0378-4347(95)00341-X
Marklová, E., Makovicková, H. and Krákorova, I. (2000) Screening for Defects in Tryptophan Metabolism. Journal of Chromatography A, 870, 289-293. https://doi.org/10.1016/S0021-9673(99)00973-5
Zhu, W., Stevens, A.P., Dettmer, K., Gottfried, E., Hoves, S., Kreutz, M., Holler, E., Canelas, A.B., Kema, I. and Oefner, P.J. (2011) Quantitative Profiling of Tryptophan Metabolites in Serum, Urine, and Cell Culture Supernatants by Liquid Chromatography-Tandem Mass Spectrometry. Analytical and Bioanalytical Chemistry, 401, 3249-3261. https://doi.org/10.1007/s00216-011-5436-y
Zhang, A., Rijal, K., Kah, S., Ravid, K. and Chitalia, V. (2017) A Mass Spectrometric Method for Quantification of Tryptophan-Derived Uremic Solutes in Human Serum. Journal of Biological Methods, 4, e75. https://doi.org/10.14440/jbm.2017.182
Canli, T. and Lesch, K.P. (2001) Long Story Short: The Serotonin Transporter in Emotion Regulation and Social Cognition. Nature Neuroscience, 10, 1103-1109. https://doi.org/10.1038/nn1964
Cantó, C., Menzies, K.J. and Auwerx, J. (2015) NAD+ Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus. Cell Metabolism, 22, 31-53. https://doi.org/10.1016/j.cmet.2015.05.023
Felig, P. (1975) Amino Acid Metabolism in Man. Annual Review of Biochemistry, 44, 933-955. https://doi.org/10.1146/annurev.bi.44.070175.004441
Jefferson, L.S., Li, J.B. and Rannels, S.R. (1977) Regulation by Insulin of Amino Acid Release and Protein Turnover in the Perfused rat Hemicorpus. The Journal of Biological Chemistry, 252, 1476-1483.
Biolo, G., Williams, B.D., Fleming, R.Y. and Wolfe, R.R. (1999) Insulin Action on Muscle Protein Kinetics and Amino Acid Transport during Recovery after Resistance Exercise. Diabetes, 48, 949-957. https://doi.org/10.2337/diabetes.48.5.949
Robinson, M.M., Soop, M., Sohn, T.S., Morse, D.M., Schimke, J.M., Klaus, K.A. and Nair, K.S. (2014) High Insulin Combined with Essential Amino Acids Stimulates Skeletal Muscle Mitochondrial Protein Synthesis While Decreasing Insulin Sensitivity in Healthy Humans. The Journal of Clinical Endocrinology & Metabolism, 99, E2574-E2583. https://doi.org/10.1210/jc.2014-2736
Stancáková, A., Civelek, M., Saleem, N.K., Soininen, P., Kangas, A.J., Cederberg, H., Paananen, J., Pihlajamaki, J., Bonnycastle, L.L., Morken, M.A., Boehnke, M., Pajukanta, P., Lusis, A.J., Collins, F.S., Kuusisto, J., Ala-Korpela, M. and Laakso, M. (2012) Hyperglycemia and a Common Variant of GCKR Are Associated with the Levels of Eight Amino Acids in 9,369 Finnish Men. Diabetes, 61, 1895-1902. https://doi.org/10.2337/db11-1378
Crane, J.D., Palanivel, R., Mottillo, E.P., Bujak, A.L., Wang, H., Ford, R.J., Collins, A., Blümer, R.M., Fullerton, M.D., Yabut, J.M., Kim, J.J., Ghia, J.E., Hamza, S.M., Morrison, K.M., Schertzer, J.D., Dyck, J.R., Khan, W.I. and Steinberg, G.R. (2015) Inhibiting Peripheral Serotonin Synthesis Reduces Obesity and Metabolic Dysfunction by Promoting Brown Adipose Tissue Thermogenesis. Nature Medicine, 21, 166-172. https://doi.org/10.1038/nm.3766
Bach-Mizrachi, H., Underwood, M.D., Kassir, S.A., Bakalian, M.J., Sibille, E., Tamir, H., Mann, J.J. and Arango, V. (2006) Neuronal Tryptophan Hydroxylase mRNA Expression in the Human Dorsal and Median Raphe Nuclei: Major Depression and Suicide. Neuropsychopharmacology, 31, 814-824. https://doi.org/10.1038/sj.npp.1300897
Patterson, A.D., Bonzo, J.A., Li, F., Krausz, K.W., Eichler, G.S., Aslam, S., Tigno, X., Weinstein, J.N., Hansen, B.C., Idle, J.R. and Gonzalez, F.J. (2011) Metabolomics Reveals Attenuation of the SLC6A20 Kidney Transporter in Nonhuman Primate and Mouse Models of Type 2 Diabetes Mellitus. The Journal of Biological Chemistry, 286, 19511-19522. https://doi.org/10.1074/jbc.M111.221739
Hattori, M., Kotake, Y. and Kotake, Y. (1984) Studies on the Urinary Excretion of Xanthurenic Acid in Diabetics. Acta Vitaminologica et Enzymologica, 6, 221-228.
Rogers, K.S. and Evangelista, S.J. (1985) 3-Hydroxykynurenine, 3-Hydroxyanthranilic Acid, and o-Aminophenol Inhibit Leucine-Stimulated Insulin Release from Rat Pancreatic Islets. Proceedings of the Society for Experimental Biology and Medicine, 178, 275-278.
Pedersen, E.R., Tuseth, N., Eussen, S.J., Ueland, P.M., Strand, E., Svingen, G.F., Midttun, Ø., Meyer, K., Mellgren, G., Ulvik, A., Nordrehaug, J.E., Nilsen, D.W. and Nygard, O. (2015) Associations of Plasma Kynurenines with Risk of Acute Myocardial Infarction in Patients with Stable Angina Pectoris. Arteriosclerosis, Thrombosis, and Vascular Biology, 35, 455-462. https://doi.org/10.1161/ATVBAHA.114.304674
Swardfager, W., Herrmann, N., Dowlati, Y., Oh, P.I., Kiss, A., Walker, S.E. and Lanctot, K.L. (2009) Indoleamine 2,3-Dioxygenase Activation and Depressive Symptoms in Patients with Coronary Artery Disease. Psychoneuroendocrinology, 34, 1560-1566. https://doi.org/10.1016/j.psyneuen.2009.05.019
Shimizu, F., Ishii, Y., Ogawa, M., Takao, T., Matsuoka, K., Kato, K. and Takada, Ａ. (2017) Plasma Levels of Various Amino Acids and Their Changes upon Protein Uptakes in Japanese 1 Young and Old Men and Women. Integrative Food, Nutrition and Metabolism, 4, 1-5.