title: Expression of the kynurenine pathway enzymes in the pancreatic islet cells. Activation by cytokines and glucolipotoxicity.
abstract: The tryptophan/kynurenine pathway (TKP) is the main route of tryptophan degradation and generates several neuroactive and immunomodulatory metabolites. Experimental and clinical data have clearly established that besides fat, muscle and liver, pancreatic islet tissue itself is a site of inflammation during obesity and type 2 diabetes. Therefore it is conceivable that pancreatic islet exposure to increased levels of cytokines may induce upregulation of islet kynurenine metabolism in a way resembling that seen in the brain in many neurodegenerative disorders. Using normal rat islets and the INS-1 β-cell line, we have demonstrated for the first time that: 1/only some TKP genes are constitutively expressed, both in β-cells as well as non β-cells; 2/ the regulatory enzyme indoleamine 2,3-dioxygenase (IDO1) is not constitutively expressed; 3/ IDO1 and kynurenine 3-monoxygenase (KMO) expression are potently activated by proinflammatory cytokines (IFN-γ, IL-1β) and glucolipotoxicity respectively, rather in β-cells than in non β-cells; 4/ Islet kynurenine/kynurenic acid production ratio is enhanced following IFN-γ and glucolipotoxicity; 5/ acute exposure to KYN potentiates glucose-induced insulin secretion by normal islets; and 6/ oxidative stress or glucocorticoid modulates TKP genes only marginally. Pancreatic islets may represent a new target tissue for inflammation and glucolipotoxicity to activate the TKP. Since inflammation is now recognized as a crucial mechanism in the development of the metabolic syndrome and more specifically at the islet level, it is needed to evaluate the potential induction of the TKP in the endocrine pancreas during obesity and/or diabetes and its relationship to the islet cell functional alterations.
authors: UnivParisDiderot, Sorbonne-Paris-Cité, Laboratoire B2PE (Biologie et Pathologie du Pancréas Endocrine), Unité BFA (Biologie Fonctionnelle et Adaptive), CNRS UMR 8251 CNRS, Paris, France; MetaBrain Research, Chilly-Mazarin, France.
authors: J J
authors: JJ
authors: Liu
authors: MetaBrain Research, Chilly-Mazarin, France.
authors: S
authors: S
authors: Raynal
authors: UnivParisDiderot, Sorbonne-Paris-Cité, Laboratoire B2PE (Biologie et Pathologie du Pancréas Endocrine), Unité BFA (Biologie Fonctionnelle et Adaptive), CNRS UMR 8251 CNRS, Paris, France.
authors: D
authors: D
authors: Bailbé
authors: UnivParisDiderot, Sorbonne-Paris-Cité, Laboratoire B2PE (Biologie et Pathologie du Pancréas Endocrine), Unité BFA (Biologie Fonctionnelle et Adaptive), CNRS UMR 8251 CNRS, Paris, France.
authors: B
authors: B
authors: Gausseres
authors: MetaBrain Research, Chilly-Mazarin, France.
authors: C
authors: C
authors: Carbonne
authors: MetaBrain Research, Chilly-Mazarin, France.
authors: V
authors: V
authors: Autier
authors: UnivParisDiderot, Sorbonne-Paris-Cité, Laboratoire B2PE (Biologie et Pathologie du Pancréas Endocrine), Unité BFA (Biologie Fonctionnelle et Adaptive), CNRS UMR 8251 CNRS, Paris, France.
authors: J
authors: J
authors: Movassat
authors: MetaBrain Research, Chilly-Mazarin, France.
authors: M
authors: M
authors: Kergoat
authors: UnivParisDiderot, Sorbonne-Paris-Cité, Laboratoire B2PE (Biologie et Pathologie du Pancréas Endocrine), Unité BFA (Biologie Fonctionnelle et Adaptive), CNRS UMR 8251 CNRS, Paris, France. Electronic address: portha@univ-paris-diderot.fr.
authors: B
authors: B
authors: Portha
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D016207:Cytokines / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D007515:Islets of Langerhans / Q000378:metabolism*; D007737:Kynurenine / Q000378:metabolism*; D050601:Kynurenine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D016877:Oxidants / Q000494:pharmacology; D010168:Palmitates / Q000494:pharmacology; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014364:Tryptophan / Q000378:metabolism
chemical_list: D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007328:Insulin; D053583:Interleukin-1beta; D016877:Oxidants; D010168:Palmitates; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan; D006861:Hydrogen Peroxide; D050601:Kynurenine 3-Monooxygenase; D005947:Glucose
keywords: Glucolipotoxicity; IFN-γ; IL-1β; Kynurenine pathway; Non β-cells; β-cells