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Diabetologia
Published in: Diabetologia 9/2017

Open Access 01-09-2017 | Article

The kynurenine:tryptophan ratio as a predictor of incident type 2 diabetes mellitus in individuals with coronary artery disease

Authors: Eirik W. Rebnord, Elin Strand, Øivind Midttun, Gard F.T. Svingen, Monika H.E. Christensen, Per M. Ueland, Gunnar Mellgren, Pål R. Njølstad, Grethe S. Tell, Ottar K. Nygård, Eva R. Pedersen

Published in: Diabetologia | Issue 9/2017

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Abstract

Aims/hypothesis

The tryptophan metabolite kynurenine has potent immune modulatory and vasoactive properties. Experimental data implicate kynurenine in obesity-related morbidities. Epidemiological studies are, however, sparse. We evaluated associations of the plasma and urine kynurenine:tryptophan ratio (KTR) to incident type 2 diabetes.

Methods

We followed 2519 individuals with coronary artery disease (CAD; 73.1% men) without diabetes at baseline for a median of 7.6 years, during which 173 (6.9%) new incidences of type 2 diabetes were identified. Multivariate Cox regression analyses were applied to investigate the prospective relationships of plasma and urine KTR with new onset type 2 diabetes.

Results

At inclusion, mean (SD) age was 61.3 (10.4) years, BMI was 25.9 (3.71) kg/m2 and median (interquartile range) HbA1c was 5.6% (5.0%–6.0%) (38 [31–42] mmol/mol). Plasma KTR was not significantly related to type 2 diabetes risk. By contrast, urine KTR showed a strong positive association. Comparing quartile 4 with quartile 1, the HRs (95% CIs) were 2.59 (1.56, 4.30) and 2.35 (1.39, 3.96) in the age- and sex-adjusted and multivariate models, respectively.

Conclusions/interpretation

Urine KTR is a strong predictor of incident type 2 diabetes in individuals with CAD. Potential clinical implications and possible pathogenic roles of renal kynurenine excretion in type 2 diabetes development should be further elucidated.
Appendix
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Literature
1.
Kahn SE, Cooper ME, Del Prato S (2014) Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet 383:1068–1083CrossRefPubMed
2.
Donath MY, Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11:98–107CrossRefPubMed
3.
Oxenkrug GF (2010) Metabolic syndrome, age-associated neuroendocrine disorders, and dysregulation of tryptophan-kynurenine metabolism. Ann N Y Acad Sci 1199:1–14CrossRefPubMed
4.
Schrocksnadel K, Wirleitner B, Winkler C, Fuchs D (2006) Monitoring tryptophan metabolism in chronic immune activation. Clin Chim Acta 364:82–90CrossRefPubMed
5.
Oxenkrug GF (2011) Interferon-gamma-inducible kynurenines/pteridines inflammation cascade: implications for aging and aging-associated psychiatric and medical disorders. J Neural Transm 118:75–85CrossRefPubMed
6.
Oxenkrug G (2011) Interferon-gamma–inducible inflammation: contribution to aging and aging-associated psychiatric disorders. Aging Dis 2:474–486PubMedPubMedCentral
7.
Oxenkrug G (2013) Insulin resistance and dysregulation of tryptophan-kynurenine and kynurenine-nicotinamide adenine dinucleotide metabolic pathways. Mol Neurobiol 48:294–301CrossRefPubMedPubMedCentral
8.
Mellor AL, Munn DH (2004) IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 4:762–774CrossRefPubMed
9.
Lapin IP (1976) Depressor effect of kynurenine and its metabolites in rats. Life Sci 19:1479–1483CrossRefPubMed
10.
11.
Favennec M, Hennart B, Caiazzo R et al (2015) The kynurenine pathway is activated in human obesity and shifted toward kynurenine monooxygenase activation. Obesity 23:2066–2074CrossRefPubMed
12.
Liu JJ, Raynal S, Bailbe D et al (2015) Expression of the kynurenine pathway enzymes in the pancreatic islet cells. Activation by cytokines and glucolipotoxicity. Biochim Biophys Acta 1852:980–991CrossRefPubMed
13.
Oxenkrug G, Cornicelli J, van der Hart M, Roeser J, Summergrad P (2016) Kynurenic acid, an aryl hydrocarbon receptor ligand, is elevated in serum of Zucker fatty rats. Integr Mol Med 3:761–763PubMedPubMedCentral
14.
15.
Oxenkrug G, Tucker KL, Requintina P, Summergrad P (2011) Neopterin, a marker of interferon-gamma-inducible inflammation, correlates with pyridoxal-5′-phosphate, waist circumference, HDL-cholesterol, insulin resistance and mortality risk in adult Boston community dwellers of Puerto Rican origin. Am J Neuroprot Neuroregen 3:48–52CrossRefPubMedPubMedCentral
16.
Oxenkrug GF, Turski WA, Zgrajka W, Weinstock JV, Summergrad P (2013) Tryptophan-kynurenine metabolism and insulin resistance in hepatitis C patients. Hepat Res Treat 2013:149247PubMedPubMedCentral
17.
Pedersen ER, Tuseth N, Eussen SJPM et al (2015) Associations of plasma kynurenines with risk of acute myocardial infarction in patients with stable angina pectoris. Arterioscler Thromb Vasc Biol 35:455–462CrossRefPubMed
18.
Cheng S, Rhee EP, Larson MG et al (2012) Metabolite profiling identifies pathways associated with metabolic risk in humans. Circulation 125:2222–2231CrossRefPubMedPubMedCentral
19.
Pedersen ER, Svingen GFT, Schartum-Hansen H et al (2013) Urinary excretion of kynurenine and tryptophan, cardiovascular events, and mortality after elective coronary angiography. Eur Heart J 34:2689–2696CrossRefPubMed
20.
Ebbing M, Bleie O, Ueland PM et al (2008) Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. JAMA 300:795–804CrossRefPubMed
21.
Midttun O, Hustad S, Ueland PM (2009) Quantitative profiling of biomarkers related to B-vitamin status, tryptophan metabolism and inflammation in human plasma by liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 23:1371–1379CrossRefPubMed
22.
Rebnord EW, Pedersen ER, Strand E et al (2015) Glycated hemoglobin and long-term prognosis in patients with suspected stable angina pectoris without diabetes mellitus: a prospective cohort study. Atherosclerosis 240:115–120CrossRefPubMed
23.
Levy JC, Matthews DR, Hermans MP (1998) Correct homeostasis model assessment (HOMA) evaluation uses the computer program. Diabetes Care 21:2191–2192CrossRefPubMed
24.
Sulo G, Igland J, Vollset SE, Nygård O, Øyen N, Tell GS (2013) Cardiovascular disease and diabetes mellitus in Norway during 1994-2009 CVDNOR—a nationwide research project. Nor J Epidemiol 21:101–107
25.
van Buuren S (2007) Multiple imputation of discrete and continuous data by fully conditional specification. Stat Methods Med Res 16:219–242CrossRefPubMed
26.
Hastie T, Tibshirani R (1986) Generalized additive models. Stat Sci 1:297–318CrossRef
27.
Pencina MJ, D'Agostino RB Sr, Steyerberg EW (2011) Extensions of net reclassification improvement calculations to measure usefulness of new biomarkers. Stat Med 30:11–21CrossRefPubMed
28.
Zinman B, Kahn SE, Haffner SM, O’Neill MC, Heise MA, Freed MI (2004) Phenotypic characteristics of GAD antibody-positive recently diagnosed patients with type 2 diabetes in North America and Europe. Diabetes 53:3193–3200CrossRefPubMed
29.
Ix JH, de Boer IH, Wassel CL, Criqui MH, Shlipak MG, Whooley MA (2010) Urinary creatinine excretion rate and mortality in persons with coronary artery disease: the Heart and Soul Study. Circulation 121:1295–1303CrossRefPubMedPubMedCentral
30.
Clarke R, Shipley M, Lewington S et al (1999) Underestimation of risk associations due to regression dilution in long-term follow-up of prospective studies. Am J Epidemiol 150:341–353CrossRefPubMed
31.
Geeraerts F, Schimpfessel L, Crokaert R (1980) The stability of tryptophan metabolites prior to urine analysis. Clin Chim Acta 102:247–251CrossRefPubMed
32.
Haffner SM (1999) Epidemiology of insulin resistance and its relation to coronary artery disease. Am J Cardiol 84:11J–14JCrossRefPubMed
33.
Pedersen ER, Midttun O, Ueland PM et al (2011) Systemic markers of interferon-gamma-mediated immune activation and long-term prognosis in patients with stable coronary artery disease. Arterioscler Thromb Vasc Biol 31:698–704CrossRefPubMed
34.
Sulo G, Vollset SE, Nygård O et al (2013) Neopterin and kynurenine-tryptophan ratio as predictors of coronary events in older adults, the Hordaland Health Study. Int J Cardiol 168:1435–1440CrossRefPubMed
35.
Zhang Y, Ruan Y, Zhang P, Wang L (2016) Increased indoleamine 2,3-dioxygenase activity in type 2 diabetic nephropathy. J Diabetes Complicat 31:223–227CrossRefPubMed
36.
Fu H, Liu X, Yu W, Zhu L, Zheng D, Wang J (2013) Screening of urinary biomarkers in patients with type 2 diabetes mellitus. Wei Sheng Yan Jiu 42:907–914PubMed
37.
38.
Sarkar SA, Wong R, Hackl SI et al (2007) Induction of indoleamine 2,3-dioxygenase by interferon-gamma in human islets. Diabetes 56:72–79CrossRefPubMed
39.
Baban B, Liu JY, Mozaffari S (2013) Endoplasmic reticulum stress response and inflammatory cytokines in type 2 diabetic nephropathy: role of indoleamine 2,3-dioxygenase and programmed death-1. Exp Mol Pathol 94:343–351CrossRefPubMed
40.
Mohib K, Guan Q, Diao H, Du C, Jevnikar AM (2007) Proapoptotic activity of indoleamine 2,3-dioxygenase expressed in renal tubular epithelial cells. Am J Physiol Renal Physiol 293:F801–F812CrossRefPubMed
41.
Wolowczuk I, Hennart B, Leloire A et al (2012) Tryptophan metabolism activation by indoleamine 2,3-dioxygenase in adipose tissue of obese women: an attempt to maintain immune homeostasis and vascular tone. Am J Physiol Regul Integr Comp Physiol 303:R135–R143CrossRefPubMed
42.
Poulain-Godefroy O, Eury E, Leloire A et al (2013) Induction of TDO2 and IDO2 in liver by high-fat feeding in mice: discrepancies with human obesity. Int J Tryptophan Res 6:29–37CrossRefPubMedPubMedCentral
43.
Moller SE (1981) Pharmacokinetics of tryptophan, renal handling of kynurenine and the effect of nicotinamide on its appearance in plasma and urine following L-tryptophan loading of healthy subjects. Eur J Clin Pharmacol 21:137–142CrossRefPubMed
44.
Sallee M, Dou L, Cerini C, Poitevin S, Brunet P, Burtey S (2014) The aryl hydrocarbon receptor-activating effect of uremic toxins from tryptophan metabolism: a new concept to understand cardiovascular complications of chronic kidney disease. Toxins 6:934–949CrossRefPubMedPubMedCentral
45.
Eleftheriadis T, Pissas G, Antoniadi G, Liakopoulos V, Stefanidis I (2016) Indoleamine 2,3-dioxygenase depletes tryptophan, activates general control non-derepressible 2 kinase and down-regulates key enzymes involved in fatty acid synthesis in primary human CD4+ T cells. Immunology 146:292–300CrossRef
46.
Eleftheriadis T, Tsogka K, Pissas G, Antoniadi G, Liakopoulos V, Stefanidis I (2016) Activation of general control nonderepressible 2 kinase protects human glomerular endothelial cells from harmful high-glucose-induced molecular pathways. Int Urol Nephrol 48:1731–1739CrossRefPubMed
47.
48.
49.
Ryden L, Grant PJ, Anker SD et al (2013) ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 34:3035–3087CrossRefPubMed
50.
Sattar N, Wannamethee SG, Forouhi NG (2008) Novel biochemical risk factors for type 2 diabetes: pathogenic insights or prediction possibilities? Diabetologia 51:926–940CrossRefPubMed
Metadata
Title
The kynurenine:tryptophan ratio as a predictor of incident type 2 diabetes mellitus in individuals with coronary artery disease
Authors
Eirik W. Rebnord
Elin Strand
Øivind Midttun
Gard F.T. Svingen
Monika H.E. Christensen
Per M. Ueland
Gunnar Mellgren
Pål R. Njølstad
Grethe S. Tell
Ottar K. Nygård
Eva R. Pedersen
Publication date
01-09-2017
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 9/2017
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-017-4329-9

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