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Role of Kynurenine Pathway in Insulin Resistance: Toward Kynurenine Hypothesis of Insulin Resistance and Diabetes

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Targeting the Broadly Pathogenic Kynurenine Pathway

Abstract

Diabetogenic effect of kynurenine (KYN) derivative of tryptophan (TRP), xanthurenic acid (XA), has been suggested last century. Recent interest to this hypothesis was stimulated by data revealing that TRP–KYN pathway can be upregulated by both chronic low-grade inflammation and stress, the two conditions involved in the pathogenesis of insulin resistance (IR), diabetes type 2 (T2D), and, probably, type 1 (T1D). Pro-inflammatory factors (e.g., interferons) and stress hormones (e.g., cortisol) activate enzymes catalyzing first two steps of TRP–KYN pathway: indoleamine- or tryptophan-2,3-dioxygenases and kynurenine 3-monooxygenase (KMO), resulting in increased formation of KYN and 3-hydroxyKYN (3-HK), respectively. In addition to overproduction of 3-HK, inflammation/stress-induced increased demand for pyridoxal 5′-phosphate (P5P) leads to functional deficiency of P5P. 3-HK is a substrate for two competing pathways dependent on P5P: formation of 3-hydroxyanthranilic acid (3-HAA) catalyzed by kynureninase (KYNase) and formation of xanthurenic acid (XA) catalyzed by 3-HK-transaminase (3-HKT). Since KYNase is more sensitive to P5P deficiency than 3-HKT, inflammation/stress-induced P5P deficiency inhibits KYNase and shifts downstream metabolism of overproduced 3-HK from formation of 3-HAA toward excessive formation of XA. Recent data revealed additional mechanisms of diabetogenic effects of XA, 3-HK, and their derivatives. This chapter suggests that dysregulation of KYN metabolism is one of the mechanisms mediating the impact of chronic low-grade inflammation and/or stress on pathogenesis of IR, T2D, and T1D. Up- and downstream 3-HK derivatives might be used as biomarkers predicting inflammation and/or stress-induced progression from IR to T2D. TRP–KYN pathway might be a new target for prevention and treatment of IR and diabetes.

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Abbreviations

3-HAA:

3-Hydroxyanthranilic acid

3-HK:

3-Hydroxykynurenine

3-HKT:

3-HK transaminase

HCV:

Hepatitis C virus

IDO:

Indoleamine 2,3-dioxygenase

IFN-γ:

Interferon-gamma

IR:

Insulin resistance

KAT:

Kynurenine aminotransferase

KMO:

Kynurenine 3-aminooxygenase

KYN:

Kynurenine

KYNA:

Kynurenic acid

KYNase:

Kynureninase

NAD:

Nicotinamide adenine dinucleotide

P5P:

Pyridoxal 5′-phosphate

TDO:

Tryptophan 2,3-dioxygenase

T1D:

Type 1 diabetes

T2D:

Type 2 diabetes

TRP:

Tryptophan

XA:

Xanthurenic acid

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Acknowledgments

G. F. Oxenkrug is recipient of NIMH099517 and NIMH104810 grants.

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Author reports no conflict of interest.

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  1. Psychiatry and Inflammation Program, Department of Psychiatry, Tufts Medical Center, Tufts University School of Medicine, 800 Washington St. #1077, Boston, MA, 02111, USA

    Gregory F. Oxenkrug

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  1. Chairman, Department of Neurosurgery, Wayne State University, Detroit, Michigan, USA

    Sandeep Mittal

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Oxenkrug, G.F. (2015). Role of Kynurenine Pathway in Insulin Resistance: Toward Kynurenine Hypothesis of Insulin Resistance and Diabetes. In: Mittal, S. (eds) Targeting the Broadly Pathogenic Kynurenine Pathway. Springer, Cham. https://doi.org/10.1007/978-3-319-11870-3_13

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