The role of kynurenines in diabetes mellitus

Connick, J.H.; Stone, T.W.

doi:10.1016/0306-9877(85)90104-5

Cited by 28 publications

(25 citation statements)

References 7 publications

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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: 89%

“…Therefore, understanding of mechanisms of IR is essential for developing T2D prevention and treatment strategies. Dysregulation of kynurenine (Kyn) pathway of tryptophan (Trp) metabolism was suggested as one of the mechanisms of development of IR and T2D [3–8]. We found IR correlation with activity of Trp-Kyn pathway in Hepatitis C virus (HCV) patients [9], and elevation of plasma concentrations of Kyn downstream metabolites in T2D patients [10].…”

Section: Introductionmentioning

confidence: 99%

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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: 89%

Section: Introductionmentioning

confidence: 99%

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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show abstract

“…It was considered that TRP-KYN metabolism might contribute to mechanisms of diabetes [11]. Recent review of clinical and experimental data suggested the involvement of KYN pathway of TRP metabolism in the development of IR since KYN and some of its derivatives affect biosynthesis, release, and activity of insulin [12].…”

Section: Discussionmentioning

confidence: 99%

“…Upregulated IDO expression in the dendritic cells [9] and in the liver [10] and increased serum KYN : TRP ratio (KTR) [10] were reported for HCV patients. Review of clinical and experimental data suggested that KYN and some of its derivatives affect biosynthesis, release, and activity of insulin [11]. We suggested that upregulated TRP-KYN metabolism might be one of the mechanisms of IR in HCV patients [12].…”

Section: Introductionmentioning

confidence: 99%

Tryptophan-Kynurenine Metabolism and Insulin Resistance in Hepatitis C Patients

Oxenkrug

Turski

Zgrajka

et al. 2013

Hepatitis Research and Treatment

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Chronic hepatitis C virus (HCV) infection is associated with 50% incidence of insulin resistance (IR) that is fourfold higher than that in non-HCV population. IR impairs the outcome of antiviral treatment. The molecular mechanisms of IR in HCV are not entirely clear. Experimental and clinical data suggested that hepatitis C virus per se is diabetogenic. However, presence of HCV alone does not affect IR. It was proposed that IR is mediated by proinflammatory cytokines, mainly by TNF-alpha. TNF-alpha potentiates interferon-gamma-induced transcriptional activation of indoleamine 2,3-dioxygenase, the rate-limiting enzyme of tryptophan- (TRP-) kynurenine (KYN) metabolism. Upregulation of TRP-KYN metabolism was reported in HCV patients. KYN and some of its derivatives affect insulin signaling pathways. We hypothesized that upregulation of TRP-KYN metabolism might contribute to the development of IR in HCV. To check this suggestion, we evaluated serum concentrations of TRP and KYN and HOMA-IR and HOMA-beta in 60 chronic HCV patients considered for the treatment with IFN-alpha. KYN and TRP concentrations correlated with HOMA-IR and HOMA-beta scores. Our data suggest the involvement of KYN and its metabolites in the development of IR in HCV patients. TRP-KYN metabolism might be a new target for prevention and treatment of IR in HCV patients.

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“…Apart from a specifi c role for 3H-KYNA in the signaling cascade resulting in gamete maturation in mosquitoes (Billker et al 1998 ), nothing was known about its functions in other species including mammals, except it pro-convulsive effect (Lapin 1978 ). 3H-KYNA was reported to induce experimental diabetes in rats (Kotake et al 1975 ), and its elevated urinary excretion was found in alloxan-and streptozotocin-induced diabetic rats (Okamoto 2003 ;Ikeda and Kotake 1986 ;Hattori et al 1984 ;Connick and Stone 1985 ), while decreased activity of P5P-dependent KYNase was observed in alloxan-induced diabetic rabbits (Allegri et al 2003 ). Increased urine excretion of 3H-KYNA was found in diabetic patients (Kotake et al 1975 ) and in subjects with prediabetes (Manusadzhian et al 1974 ).…”

Section: H-kynamentioning

confidence: 96%

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

Oxenkrug

2015

Tryptophan Metabolism: Implications for Biological Processes, Health and Disease

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Aging, obesity, depression, Parkinson's and other neurodegenerative diseases, schizophrenia, and treatment with antipsychotic drugs are highly associated with insulin resistance (IR) and type 2 diabetes mellitus (T2D). Molecular mechanisms of increased associations remain uncertain. Current review of literature and our data suggest that one such mechanism is the overproduction of diabetogenic factors resulting from dysregulation of upstream and downstream pathways of tryptophan (TRP)-kynurenine (KYN) metabolism. Proinfl ammatory factors and stress hormones activate two upstream steps of TRP-KYN pathway: TRP conversion into KYN, a substrate for formation of kynurenic acid (KYNA), and KYN conversion into 3-hydroxyKYN (3-HK). The fi rst step of downstream pathway of 3-HK metabolism, formation of 3-hydroxyanthranilic acid (3-HAA), is catalyzed by pyridoxal-5-phosphate (P5P)-dependent kynureninase (KYNase). P5P defi ciency, associated with infl ammation, stress, and treatment with antipsychotic drugs, diverts metabolism of overproduced 3-HK from formation of 3-HAA to the excessive formation of 3-hydroxykynurenic acid (3H-KYNA). Human and experimental studies suggested diabetogenic (e.g., impairment of production, release, and biological activity of insulin) effect of KYN, 3H-KYNA, KYNA, and their metabolites. We propose that one of the mechanisms of increased association of IR (and T2D) with aging, obesity, depression, neurodegenerative diseases, schizophrenia, and treatment with antipsychotic drugs is overproduction of 3H-KYNA resulting from upregulated formation of 3-HK augmented by P5P defi ciency. Pharmacological regulation of upand downstream TRP-KYN metabolic pathways might be a new approach for prevention and treatment of IR (and IR progression to T2D) associated with aging, obesity, depression, neurodegenerative diseases, schizophrenia, and treatment with antipsychotic drugs.

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The role of kynurenines in diabetes mellitus

Cited by 28 publications

References 7 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

Tryptophan-Kynurenine Metabolism and Insulin Resistance in Hepatitis C Patients

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

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