title: Glucagon-like peptide-1 improves beta-cell antioxidant capacity via extracellular regulated kinases pathway and Nrf2 translocation.
abstract: Oxidative stress plays an important role in the development of beta-cell dysfunction and insulin resistance, two major pathophysiological abnormalities of type 2 diabetes. Expression levels of antioxidant enzymes in beta cells are very low, rendering them more susceptible to damage caused by reactive oxygen species (ROS). Although the antioxidant effects of glucagon-like peptide-1 (GLP-1) and its analogs have been previously reported, the exact mechanisms involved are still unclear. In this study, we demonstrated that GLP-1 was able to effectively inhibit oxidative stress and cell death of INS-1E beta cells induced by the pro-oxidant tert-butyl hydroperoxide (tert-BOOH). Incubation with GLP-1 enhanced cellular levels of glutathione and the activity of its related enzymes, glutathione-peroxidase (GPx) and -reductase (GR) in beta cells. However, inhibition of ERK, but not of the PI3K/AKT pathway abolished, at least in part, the antioxidant effect of GLP-1. Moreover, ERK activation seems to be protein kinase A (PKA)-dependent because inhibition of PKA with H-89 was sufficient to block the GLP-1-derived protective effect on beta cells. GLP-1 likewise increased the synthesis of GR and favored the translocation of the nuclear transcription factor erythroid 2p45-related factor (Nrf2), a transcription factor implicated in the expression of several antioxidant/detoxificant enzymes. Glucose-stimulated insulin secretion was also preserved in beta-cells challenged with tert-BOOH but pre-treated with GLP-1, probably through the down-regulation of the mitochondrial uncoupling-protein2 (UCP2). Thus, our results provide additional mechanisms of action of GLP-1 to prevent oxidative damage in beta cells through the modulation of signaling pathways involved in antioxidant enzyme regulation.
authors.affiliation: Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain. Electronic address: elfernan@ucm.es.
authors.forename: E
authors.initials: E
authors.lastname: Fernández-Millán
authors.affiliation: Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain; Departamento de Metabolismo y Nutrición, Instituto de Ciencia y Tecnología de Alimentos y Nutrición (ICTAN-CSIC), Calle Jose Antonio Novais 10, Madrid, Spain.
authors.forename: M A
authors.initials: MA
authors.lastname: Martín
authors.affiliation: Departamento de Metabolismo y Nutrición, Instituto de Ciencia y Tecnología de Alimentos y Nutrición (ICTAN-CSIC), Calle Jose Antonio Novais 10, Madrid, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Goya
authors.affiliation: Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain; Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Ciudad Universitaria s/n, Universidad Complutense de Madrid, 28040 Madrid, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Lizárraga-Mollinedo
authors.affiliation: Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain; Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Ciudad Universitaria s/n, Universidad Complutense de Madrid, 28040 Madrid, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Escrivá
authors.affiliation: Departamento de Metabolismo y Nutrición, Instituto de Ciencia y Tecnología de Alimentos y Nutrición (ICTAN-CSIC), Calle Jose Antonio Novais 10, Madrid, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Ramos
authors.affiliation: Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain; Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Ciudad Universitaria s/n, Universidad Complutense de Madrid, 28040 Madrid, Spain. Electronic address: calvarez@ucm.es.
authors.forename: C
authors.initials: C
authors.lastname: Álvarez
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics; D052216:Glucagon-Like Peptide 1 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D005978:Glutathione / Q000096:biosynthesis; D005980:Glutathione Reductase / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D007546:Isoquinolines / Q000494:pharmacology; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D000071246:Uncoupling Protein 2 / Q000235:genetics* / Q000378:metabolism; D020122:tert-Butylhydroperoxide / Q000378:metabolism
chemical_list: D000975:Antioxidants; D007328:Insulin; D007546:Isoquinolines; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D000071246:Uncoupling Protein 2; D052216:Glucagon-Like Peptide 1; D020122:tert-Butylhydroperoxide; D005980:Glutathione Reductase; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D005978:Glutathione; D005947:Glucose; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
keywords: Beta cell; GLP-1; Glutathione-related enzymes; Oxidative stress