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Increased Plasma Levels of Xanthurenic and Kynurenic Acids in Type 2 Diabetes

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Abstract

About 350 million people worldwide have type 2 diabetes (T2D). The major risk factor of T2D is impaired glucose tolerance (pre-diabetes) with 10 % of pre-diabetes subjects develop T2D every year. Understanding of mechanisms of development of T2D from pre-diabetes is important for prevention and treatment of T2D. Chronic stress and chronic low-grade inflammation are prominent risk factors for T2D development in pre-diabetic subjects. However, molecular mechanisms mediating effect of stress and inflammation on development of T2D from pre-diabetes remain unknown. One of such mechanisms might involve kynurenine (KYN) pathway (KP) of tryptophan (TRP) metabolism. We suggested that chronic stress- or chronic low-grade inflammation-induced upregulation of formation of upstream KTP metabolites, KYN and 3-hydroxyKYN, combined with chronic stress- or chronic low-grade inflammation-induced deficiency of pyridoxal 5′-phosphate, a co-factor of downstream enzymes of KTP, triggers overproduction of diabetogenic downstream KYN metabolites, kynurenic acid (KYNA) and 3-hydroxyKYNA (also known as xanthurenic acid (XA)). As the initial assessment of our working hypothesis, we evaluated plasma levels of up- and downstream KP metabolites in the same samples of T2D patients. KYN, XA, and KYNA levels in plasma samples of T2D patients were higher than in samples of non-diabetic subjects. Our results provide further support of “kynurenine hypothesis of insulin resistance and its progression to T2D” that suggested that overproduction of diabetogenic KP metabolites, induced by chronic stress or chronic low-grade inflammation, is one of the mechanisms promoting development of T2D from pre-diabetes. Downstream metabolites of KP might serve as biomarkers of T2D and targets for clinical intervention.

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Abbreviations

T2D:

Type 2 diabetes

IR:

Insulin resistance

TRP:

Tryptophan

NAD:

Nicotinamide adenine dinucleotide

IFNG:

Interferon gamma

LPS:

Lipopolysaccharide

KP:

Kynurenine pathway of TRP metabolism

KYN:

Kynurenine

KYNA:

Kynurenic acid

3-HKYN:

3-hydroxykynurenine

3-HKYNA:

3-hydroxykynurenic acid

XA:

Xanthurenic acid

3-HAA:

3-hydroxyanthranilic acid

KMO:

Kynurenine 3-monooxygenase

P5P:

Pyridoxal 5′-phosphate

KAT:

Kynurenine aminotransferase

KYNase:

Kynureninase

IDO:

Indoleamine-2,3-dioxygenase

TDO:

Tryptophan-2,3-dioxygenase

HIV:

Human immunodeficiency virus

HCV:

Hepatitis C virus

HOMA:

Homeostatic model assessment

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Acknowledgments

This study is supported by NIMH104810. The author highly appreciates BioreclamationIVT, NY, USA, for providing plasma samples and Marieke van der Hart, PhD, for the excellent help with biochemical analyses

Conflict of Interest

The author declares that he has no competing interests.

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Authors and Affiliations

  1. Psychiatry and Inflammation Program, Department of Psychiatry, Tufts University School of Medicine and Tufts Medical Center, 800 Washington St, #1107, Boston, MA, 02111, USA

    Gregory F. Oxenkrug

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Correspondence to Gregory F. Oxenkrug.

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Oxenkrug, G.F. Increased Plasma Levels of Xanthurenic and Kynurenic Acids in Type 2 Diabetes. Mol Neurobiol 52, 805–810 (2015). https://doi.org/10.1007/s12035-015-9232-0

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