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26-12-2023 | Mood Disorders | Original Article

Circulating biomarkers of upstream kynurenine pathway and brain-derived neurotropic factor in the diagnosis of type 2 and gestational diabetes mellitus with depression

Authors: Prasanth Subramanian, Venkataraman Prabhu, Kumar J. S, Anuradha M, Arul Saravanan Ramachandran

Published in: Comparative Clinical Pathology | Issue 2/2024

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Abstract

The kynurenine pathway (KP) is the main catabolic pathway for the essential amino acid tryptophan (TRP). The imbalance between beneficial and harmful kynurenines was concerned with the pathogenesis and biological mechanisms of various disorders such as diabetes mellitus (DM), obesity, dyslipidemia, hypertension, depression, and schizophrenia. The present study aimed to determine the levels of biomarkers—TRP, indoleamine-2,3-dioxygenase (IDO), kynurenine (KYN) and brain-derived neurotrophic factor (BDNF) in type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM) to find their association with relevant clinical parameters. Further, aimed to shed light on how coordination amongst the metabolites of KP and BDNF may influence the diagnosis of T2DM and GDM comorbid with depression. One hundred eighty participants were divided into six groups based on glycemic index and depression state. TRP, IDO, KYN and BDNF were determined using enzyme-linked immunosorbent assay (ELISA), and their association was examined. The biochemical parameters were analysed by fully automated equipment. The levels of TRP, IDO and KYN were significantly higher in diabetic patients when compared to non-diabetic, whereas the BDNF level was lower. Correlation analyses showed that TRP, IDO and KYN were positively associated, whereas BDNF was negatively associated with glycemic index (p < 0.01). Our study correlated the overall association between KYN metabolites and BDNF in the aetiology of T2DM and GDM with depression as a cofactor. According to our findings, TRP, IDO, KYN and BDNF either individually or in combination have the potential to be an effective diagnostic tool for both diabetes and depression.

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Literature
go back to reference Abedi S, Vessal M, Asadian F, Takhshid MA (2021) Association of serum kynurenine/tryptophan ratio with poor glycemic control in patients with type 2 diabetes. J Diabetes Metab Disord 20:1521–1527CrossRefPubMedPubMedCentral Abedi S, Vessal M, Asadian F, Takhshid MA (2021) Association of serum kynurenine/tryptophan ratio with poor glycemic control in patients with type 2 diabetes. J Diabetes Metab Disord 20:1521–1527CrossRefPubMedPubMedCentral
go back to reference Atlas ID. Diabetes around the world in (2021) International Diabetes Federation Atlas ID. Diabetes around the world in (2021) International Diabetes Federation
go back to reference Badawy AA (2017) Kynurenine pathway of tryptophan metabolism: regulatory and functional aspects. Int J Tryptophan Res 9(10):1178646917691938 Badawy AA (2017) Kynurenine pathway of tryptophan metabolism: regulatory and functional aspects. Int J Tryptophan Res 9(10):1178646917691938
go back to reference Bakker L, Ramakers IH, van Boxtel MP, Schram MT, Stehouwer CD, van der Kallen CJ, Dagnelie PC, Van Greevenbroek MM, Wesselius A, Midttun Ø, Ueland PM (2021) Associations between plasma kynurenines and cognitive function in individuals with normal glucose metabolism, prediabetes and type 2 diabetes: the Maastricht Study. Diabetologia 64:2445–2457CrossRefPubMedPubMedCentral Bakker L, Ramakers IH, van Boxtel MP, Schram MT, Stehouwer CD, van der Kallen CJ, Dagnelie PC, Van Greevenbroek MM, Wesselius A, Midttun Ø, Ueland PM (2021) Associations between plasma kynurenines and cognitive function in individuals with normal glucose metabolism, prediabetes and type 2 diabetes: the Maastricht Study. Diabetologia 64:2445–2457CrossRefPubMedPubMedCentral
go back to reference Campayo A, De Jonge P, Roy JF, Saz P, De la Cámara C, Quintanilla MA, Marcos G, Santabárbara J, Lobo A (2010) Depressive disorder and incident diabetes mellitus: the effect of characteristics of depression. Am J Psychiatry 167(5):580–588CrossRefPubMed Campayo A, De Jonge P, Roy JF, Saz P, De la Cámara C, Quintanilla MA, Marcos G, Santabárbara J, Lobo A (2010) Depressive disorder and incident diabetes mellitus: the effect of characteristics of depression. Am J Psychiatry 167(5):580–588CrossRefPubMed
go back to reference Chen T, Zheng X, Ma X, Bao Y, Ni Y, Hu C, Rajani C, Huang F, Zhao A, Jia W, Jia W (2016) Tryptophan predicts the risk for future type 2 diabetes. PLoS ONE 11(9):e0162192CrossRefPubMedPubMedCentral Chen T, Zheng X, Ma X, Bao Y, Ni Y, Hu C, Rajani C, Huang F, Zhao A, Jia W, Jia W (2016) Tryptophan predicts the risk for future type 2 diabetes. PLoS ONE 11(9):e0162192CrossRefPubMedPubMedCentral
go back to reference Eyileten C, Mirowska-Guzel D, Milanowski L, Zaremba M, Rosiak M, Cudna A, Kaplon-Cieslicka A, Opolski G, Filipiak KJ, Malek L, Postula M (2019) Serum brain-derived neurotrophic factor is related to platelet reactivity and metformin treatment in adult patients with type 2 diabetes mellitus. Can J Diabetes 43(1):19–26CrossRefPubMed Eyileten C, Mirowska-Guzel D, Milanowski L, Zaremba M, Rosiak M, Cudna A, Kaplon-Cieslicka A, Opolski G, Filipiak KJ, Malek L, Postula M (2019) Serum brain-derived neurotrophic factor is related to platelet reactivity and metformin treatment in adult patients with type 2 diabetes mellitus. Can J Diabetes 43(1):19–26CrossRefPubMed
go back to reference Fiore V, Marci M, Poggi A, Giagulli VA, Licchelli B, Iacoviello M, Guastamacchia E, De Pergola G, Triggiani V (2015) The association between diabetes and depression: a very disabling condition. Endocrine 48:14–24CrossRefPubMed Fiore V, Marci M, Poggi A, Giagulli VA, Licchelli B, Iacoviello M, Guastamacchia E, De Pergola G, Triggiani V (2015) The association between diabetes and depression: a very disabling condition. Endocrine 48:14–24CrossRefPubMed
go back to reference Kiluk M, Lewkowicz J, Pawlak D, Tankiewicz-Kwedlo A (2021) Crosstalk between tryptophan metabolism via kynurenine pathway and carbohydrate metabolism in the context of cardio-metabolic risk. J Clin Med 10(11):2484CrossRefPubMedPubMedCentral Kiluk M, Lewkowicz J, Pawlak D, Tankiewicz-Kwedlo A (2021) Crosstalk between tryptophan metabolism via kynurenine pathway and carbohydrate metabolism in the context of cardio-metabolic risk. J Clin Med 10(11):2484CrossRefPubMedPubMedCentral
go back to reference Kubacka J, Staniszewska M, Sadok I, Sypniewska G, Stefanska A (2022) The kynurenine pathway in obese middle aged women with normoglycemia and type 2 diabetes. Metabolites 12(6):492CrossRefPubMedPubMedCentral Kubacka J, Staniszewska M, Sadok I, Sypniewska G, Stefanska A (2022) The kynurenine pathway in obese middle aged women with normoglycemia and type 2 diabetes. Metabolites 12(6):492CrossRefPubMedPubMedCentral
go back to reference Malina HZ, Richter C, Mehl M, Hess OM (2001) Pathological apoptosis by xanthurenic acid, a tryptophan metabolite: activation of cell caspases but not cytoskeleton breakdown. BMC Physiol 1:1–8CrossRef Malina HZ, Richter C, Mehl M, Hess OM (2001) Pathological apoptosis by xanthurenic acid, a tryptophan metabolite: activation of cell caspases but not cytoskeleton breakdown. BMC Physiol 1:1–8CrossRef
go back to reference Meyramov G, Korchin V, Kocheryzkina N (1998) Diabetogenic activity of xanthurenic acid determined by its chelating properties. InTransplantation proceedings 30(6):2682-2684 Meyramov G, Korchin V, Kocheryzkina N (1998) Diabetogenic activity of xanthurenic acid determined by its chelating properties. InTransplantation proceedings  30(6):2682-2684
go back to reference Musselman DL, Betan E, Larsen H, Phillips LS (2003) Relationship of depression to diabetes types 1 and 2: epidemiology, biology, and treatment. Biol Psychiat 54(3):317–329CrossRefPubMed Musselman DL, Betan E, Larsen H, Phillips LS (2003) Relationship of depression to diabetes types 1 and 2: epidemiology, biology, and treatment. Biol Psychiat 54(3):317–329CrossRefPubMed
go back to reference Noto Y, Okamoto H (1978) Inhibition by kynurenine metabolites of proinsulin synthesis in isolated pancreatic islets. Acta Diabetol Lat 15:273–282CrossRefPubMed Noto Y, Okamoto H (1978) Inhibition by kynurenine metabolites of proinsulin synthesis in isolated pancreatic islets. Acta Diabetol Lat 15:273–282CrossRefPubMed
go back to reference Nurjono M, Lee J, Chong SA (2012) A review of brain-derived neurotrophic factor as a candidate biomarker in schizophrenia. Clin Psychopharmacol Neurosci Nurjono M, Lee J, Chong SA (2012) A review of brain-derived neurotrophic factor as a candidate biomarker in schizophrenia. Clin Psychopharmacol Neurosci
go back to reference Okuda S, Nishiyama N, Saito H, Katsuki H (1998) 3- Hydroxykynurenine, an endogenous oxidative stress generator, causes neuronal cell death with apoptotic features and region selectivity. J Neurochem 70(1):299–307CrossRefPubMed Okuda S, Nishiyama N, Saito H, Katsuki H (1998) 3- Hydroxykynurenine, an endogenous oxidative stress generator, causes neuronal cell death with apoptotic features and region selectivity. J Neurochem 70(1):299–307CrossRefPubMed
go back to reference Oxenkrug GF (2015b) Role of kynurenine pathway in insulin resistance: toward kynurenine hypothesis of insulin resistance and diabetes. Targeting the broadly pathogenic kynurenine pathway. 169–78 Oxenkrug GF (2015b) Role of kynurenine pathway in insulin resistance: toward kynurenine hypothesis of insulin resistance and diabetes. Targeting the broadly pathogenic kynurenine pathway. 169–78
go back to reference Pillai A, Kale A, Joshi S, Naphade N, Raju MS, Nasrallah H, Mahadik SP (2010) Decreased BDNF levels in CSF of drug-naive first-episode psychotic subjects: correlation with plasma BDNF and psychopathology. Int J Neuropsychopharmacol 13(4):535–539CrossRefPubMed Pillai A, Kale A, Joshi S, Naphade N, Raju MS, Nasrallah H, Mahadik SP (2010) Decreased BDNF levels in CSF of drug-naive first-episode psychotic subjects: correlation with plasma BDNF and psychopathology. Int J Neuropsychopharmacol 13(4):535–539CrossRefPubMed
go back to reference Pouwer F, Beekman AT, Nijpels G, Dekker JM, Snoek FJ, Kostense PJ, Heine RJ, Deeg DJ (2003) Rates and risks for co-morbid depression in patients with type 2 diabetes mellitus: results from a community-based study. Diabetologia 46:892–898CrossRefPubMed Pouwer F, Beekman AT, Nijpels G, Dekker JM, Snoek FJ, Kostense PJ, Heine RJ, Deeg DJ (2003) Rates and risks for co-morbid depression in patients with type 2 diabetes mellitus: results from a community-based study. Diabetologia 46:892–898CrossRefPubMed
go back to reference Rogers KS, Evangelista SJ (1985) 3-Hydroxykynurenine, 3-hydroxyanthranilic acid, and o-aminophenol inhibit leucine-stimulated insulin release from rat pancreatic islets. Proc Soc Exp Biol Med 178(2):275–278CrossRefPubMed Rogers KS, Evangelista SJ (1985) 3-Hydroxykynurenine, 3-hydroxyanthranilic acid, and o-aminophenol inhibit leucine-stimulated insulin release from rat pancreatic islets. Proc Soc Exp Biol Med 178(2):275–278CrossRefPubMed
go back to reference Spitzer RL, Williams JB, Kroenke KJ (2014) Test review: patient health questionnaire–9 (PHQ-9). Rehabil Couns Bull 57(4):246–248CrossRef Spitzer RL, Williams JB, Kroenke KJ (2014) Test review: patient health questionnaire–9 (PHQ-9). Rehabil Couns Bull 57(4):246–248CrossRef
go back to reference Tutakhail A, Boulet L, Khabil S, Nazari QA, Hamid H, Coudoré F (2020) Neuropathology of kynurenine pathway of tryptophan metabolism. Curr Pharmacol Rep 6:8–23CrossRef Tutakhail A, Boulet L, Khabil S, Nazari QA, Hamid H, Coudoré F (2020) Neuropathology of kynurenine pathway of tryptophan metabolism. Curr Pharmacol Rep 6:8–23CrossRef
go back to reference Williams MM, Clouse RE, Lustman PJ (2006) Treating depression to prevent diabetes and its complications: understanding depression as a medical risk factor. Clin Diabetes 24(2):79–86CrossRef Williams MM, Clouse RE, Lustman PJ (2006) Treating depression to prevent diabetes and its complications: understanding depression as a medical risk factor. Clin Diabetes 24(2):79–86CrossRef
go back to reference Yamanaka M, Itakura Y, Tsuchida A, Nakagawa T, Taiji M (2008) Brain-derived neurotrophic factor (BDNF) prevents the development of diabetes in prediabetic mice. Biomed Res 29(3):147–153CrossRefPubMed Yamanaka M, Itakura Y, Tsuchida A, Nakagawa T, Taiji M (2008) Brain-derived neurotrophic factor (BDNF) prevents the development of diabetes in prediabetic mice. Biomed Res 29(3):147–153CrossRefPubMed
go back to reference Yu E, Papandreou C, Ruiz-Canela M, Guasch-Ferre M, Clish CB, Dennis C, Liang L, Corella D, Fito M, Razquin C, Lapetra J (2018) Association of tryptophan metabolites with incident type 2 diabetes in the PREDIMED trial: a case–cohort study. Clin Chem 64(8):1211–1220CrossRefPubMedPubMedCentral Yu E, Papandreou C, Ruiz-Canela M, Guasch-Ferre M, Clish CB, Dennis C, Liang L, Corella D, Fito M, Razquin C, Lapetra J (2018) Association of tryptophan metabolites with incident type 2 diabetes in the PREDIMED trial: a case–cohort study. Clin Chem 64(8):1211–1220CrossRefPubMedPubMedCentral
go back to reference Zhen YF, Zhang J, Liu XY, Fang H, Tian LB, Zhou DH, Kosten TR, Zhang XY (2013) Low BDNF is associated with cognitive deficits in patients with type 2 diabetes. Psychopharmacology 227:93–100CrossRefPubMed Zhen YF, Zhang J, Liu XY, Fang H, Tian LB, Zhou DH, Kosten TR, Zhang XY (2013) Low BDNF is associated with cognitive deficits in patients with type 2 diabetes. Psychopharmacology 227:93–100CrossRefPubMed
Metadata
Title
Circulating biomarkers of upstream kynurenine pathway and brain-derived neurotropic factor in the diagnosis of type 2 and gestational diabetes mellitus with depression
Authors
Prasanth Subramanian
Venkataraman Prabhu
Kumar J. S
Anuradha M
Arul Saravanan Ramachandran
Publication date
26-12-2023
Publisher
Springer London
Published in
Comparative Clinical Pathology / Issue 2/2024
Print ISSN: 1618-5641
Electronic ISSN: 1618-565X
DOI
https://doi.org/10.1007/s00580-023-03546-2

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