Abstract
AbstractAging, 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. Proinflammatory 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 first 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 deficiency, associated with inflammation, 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 deficiency. Pharmacological regulation of up- and 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.Keywords3-hydroxykynurenic (xanthurenic) acidDiabetesAgingObesityDepressionNeurodegenerationParkinson’sSchizophrenia
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