3-Hydroxykynurenic Acid and Type 2 Diabetes: Implications for Aging, Obesity, Depression, Parkinson’s Disease, and Schizophrenia

Oxenkrug, Gregory F.

doi:10.1007/978-3-319-15630-9_8

Cited by 6 publications

(5 citation statements)

References 181 publications

(172 reference statements)

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“…The mechanisms of such association are not clear. Dysregulation of Trp-Kyn pathway in obesity was suggested [3,6] and supported by clinical and experimental data [27–29]. It is noteworthy that in Drosophila HSD induces not only IR/T2D but obesity as well [11].…”

Section: Discussionmentioning

confidence: 88%

Attenuation of high sucrose diet–induced insulin resistance in tryptophan 2,3-dioxygenase deficient Drosophila melanogaster vermilion mutants

Navrotskaya¹,

Oxenkrug²,

Vorobyova³

et al. 2015

Integr Obesity Diabetes

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Exposure to high sugar diet (HSD) serves as an experimental model of insulin resistance (IR) and type 2 diabetes (T2D) in mammals and insects. Peripheral IR induced by HSD delays emergence of pupae from larvae and decreases body weight of Drosophila imago. Understanding of mechanisms of IR/T2D is essential for refining T2D prevention and treatment strategies. Dysregulation of tryptophan (TRP) – kynurenine (KYN) pathway was suggested as one of the mechanisms of IR development. Rate-limiting enzyme of TRP – KYN pathway in Drosophila is TRP 2,3-dioxygenase (TDO), an evolutionary conserved ortholog of human TDO. In insects TDO is encoded by vermilion gene. TDO is not active in vermilion mutants. In order to evaluate the possible impact of deficient formation of KYN from TRP on the inducement of IR by HSD, we compared the effect of HSD in wild type (Oregon) and vermilion mutants of Drosophila melanogaster by assessing the time of white pupae emergence from larva and body weight of imago. Delay of emergence of pupae from larvae induced by high sucrose diet was less pronounced in vermilion (1.4 days) than in Oregon flies (3.3 days) in comparison with flies maintained on standard diet. Exposure to high sucrose diet decreased body weight of Oregon (but not vermilion) imago. Attenuation of high sucrose diet–induced IR/T2D in vermilion flies might depend on deficiency of TRP – KYN pathway. Besides IR/T2D, HSD induces obesity in Drosophila. Future studies of HSD-induced obesity and IR/T2D in TDO deficient vermilion mutants of Drosophila might help to understand the mechanisms of high association between IR/T2D and obesity. Modulation of TRP – KYN metabolism might be utilized for prevention and treatment of IR/T2D.

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Section: Discussionmentioning

confidence: 88%

Attenuation of high sucrose diet–induced insulin resistance in tryptophan 2,3-dioxygenase deficient Drosophila melanogaster vermilion mutants

Navrotskaya¹,

Oxenkrug²,

Vorobyova³

et al. 2015

Integr Obesity Diabetes

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“…Chronic stress or chronic low grade inflammation – induced up-regulation of upstream steps of KP combined with P5P deficiency, resulting in shifting of down-stream KYN metabolism from formation of NAD toward production of diabetogenic KYN derivatives, might contribute to increased association of IR (and T2D) with aging, neurodegenerative diseases (e.g., Parkinson’s, Alzheimer’s and Huntington’s), and schizophrenia and treatment by antipsychotic medications; viral infections (e.g., HIV and HCV), and depression [32, 33]. …”

Section: Discussionmentioning

confidence: 99%

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

Oxenkrug

2015

Mol Neurobiol

129

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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 cofactor 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 down-stream 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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“…Peripherally produced Kyn, ANA and 3-HK (but not KYNA) might contribute to central pathology by crossing blood brain barrier (BBB) [ 37 ] and entering a pool of centrally formed Kyn metabolites [ 38 ]. Dysregulation of Trp – Kyn pathway was suggested as a common signaling pathway for schizophrenia and Metabolic Syndrome in schizophrenia [ 9 , 13 , 15 ]. Elevated serum concentrations of KYNA, indicative of KMO deficiency, were observed in ZFR [ 13 ], and associated with weight gain in humans [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, in clinical studies, only elevated ANA and decreased 3-HK concentrations were observed in serum of SP without concurrent increase of Kyn and KYNA [ 15 , 31 ]. Therefore, we were interested to expand our previous study [ 9 ] by assessing serum KP metabolites in a subgroup of SP with elevated KYNA.…”

Section: Introductionmentioning

confidence: 99%

Peripheral kynurenine-3-monooxygenase deficiency as a potential risk factor for metabolic syndrome in schizophrenia patients

Oxenkrug

Hart²,

Roeser³

et al. 2017

Int Clin Med

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Increased predisposition of schizophrenia patients (SP) to development of obesity and insulin resistance suggested common signaling pathway between metabolic syndrome (MetS) and schizophrenia. Deficiency of kynurenine-3-monooxygenase (KMO), enzyme catalyzing formation of 3-hydroxykynurenine (3-HK) from kynurenine (Kyn), a tryptophan (Trp) metabolite, might contribute to development of MetS as suggested by non-expression of KMO genes in human fat tissue and elevated serum concentrations of Kyn and its metabolites, kynurenic (KYNA) and anthranilic (ANA) acids, in diabetic patients and Zucker fatty rats (ZFR). Markers of KMO deficiency: decreased 3-HK and elevated Kyn, KYNA and ANA, were observed in brains and spinal fluids of SP, and in brains and serum of experimental animals with genetically- or pharmacologically-induced KMO deficiency. However, elevated concentrations of ANA and decreased 3-HK were reported in serum of SP without concurrent increase of Kyn and KYNA. Present study aimed to re-assess serum Kyn metabolites (HPLC-MS) in a sub-group of SP with elevated KYNA. We found increased Kyn concentrations (by 30%) and Kyn:Trp ratio (by 20%) in serum of SP with elevated KYNA concentrations (by 40%). Obtained results and our previous data suggest that peripheral KMO deficiency might be manifested by, at least, two different patterns: elevated ANA with decreased 3-HK; and elevated KYNA and KYN. The latter pattern was previously described in type 2 diabetes patients and might underline increased predisposition of SP to development of MetS. Assessment of peripheral KMO deficiency might identify SP predisposed to MetS. Attenuation of the consequences of peripheral KMO deficiency might be a new target for prevention/treatment of obesity and diabetes in SP.

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3-Hydroxykynurenic Acid and Type 2 Diabetes: Implications for Aging, Obesity, Depression, Parkinson’s Disease, and Schizophrenia

Cited by 6 publications

References 181 publications

Attenuation of high sucrose diet–induced insulin resistance in tryptophan 2,3-dioxygenase deficient Drosophila melanogaster vermilion mutants

Attenuation of high sucrose diet–induced insulin resistance in tryptophan 2,3-dioxygenase deficient Drosophila melanogaster vermilion mutants

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

Peripheral kynurenine-3-monooxygenase deficiency as a potential risk factor for metabolic syndrome in schizophrenia patients

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