title: Increased oxidative stress and apoptosis in the hypothalamus of diabetic male mice in the insulin receptor substrate-2 knockout model.
abstract: Insulin receptor substrate-2-deficient (IRS2(-/-)) mice are considered a good model to study the development of diabetes because IRS proteins mediate the pleiotropic effects of insulin-like growth factor-I (IGF-I) and insulin on metabolism, mitogenesis and cell survival. The hypothalamus might play a key role in the early onset of diabetes, owing to its involvement in the control of glucose homeostasis and energy balance. Because some inflammatory markers are elevated in the hypothalamus of diabetic IRS2(-/-) mice, our aim was to analyze whether the diabetes associated with the absence of IRS2 results in hypothalamic injury and to analyze the intracellular mechanisms involved. Only diabetic IRS2(-/-) mice showed increased cell death and activation of caspase-8 and -3 in the hypothalamus. Regulators of apoptosis such as FADD, Bcl-2, Bcl-xL and p53 were also increased, whereas p-IκB and c-FLIPL were decreased. This was accompanied by increased levels of Nox-4 and catalase, enzymes involved in oxidative stress. In summary, the hypothalamus of diabetic IRS2(-/-) mice showed an increase in oxidative stress and inflammatory markers that finally resulted in cell death via substantial activation of the extrinsic apoptotic pathway. Conversely, non-diabetic IRS2(-/-) mice did not show cell death in the hypothalamus, possibly owing to an increase in the levels of circulating IGF-I and in the enhanced hypothalamic IGF-IR phosphorylation that would lead to the stimulation of survival pathways. In conclusion, diabetes in IRS2-deficient male mice is associated with increased oxidative stress and apoptosis in the hypothalamus.
authors.affiliation: Department of Paediatrics, Universidad Autónoma de Madrid, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Instituto de Investigación Sanitaria Princesa, IIS-IP, Madrid E-28006, Spain Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid E-28029, Spain.
authors.forename: Eva
authors.identifier: 0000-0002-3934-2134
authors.initials: E
authors.lastname: Baquedano
authors.affiliation: Department of Paediatrics, Universidad Autónoma de Madrid, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Instituto de Investigación Sanitaria Princesa, IIS-IP, Madrid E-28006, Spain Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid E-28029, Spain.
authors.forename: Emma
authors.identifier: 0000-0002-6942-3023
authors.initials: E
authors.lastname: Burgos-Ramos
authors.affiliation: Department of Paediatrics, Universidad Autónoma de Madrid, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Instituto de Investigación Sanitaria Princesa, IIS-IP, Madrid E-28006, Spain Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid E-28029, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Canelles
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas/Universidad Autónoma de Madrid, Madrid E-28029, Spain Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid E-28029, Spain.
authors.forename: Agueda
authors.identifier: 0000-0001-6559-0847
authors.initials: A
authors.lastname: González-Rodríguez
authors.affiliation: Department of Paediatrics, Universidad Autónoma de Madrid, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Instituto de Investigación Sanitaria Princesa, IIS-IP, Madrid E-28006, Spain Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid E-28029, Spain.
authors.forename: Julie A
authors.identifier: 0000-0002-4770-2291
authors.initials: JA
authors.lastname: Chowen
authors.affiliation: Department of Paediatrics, Universidad Autónoma de Madrid, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Instituto de Investigación Sanitaria Princesa, IIS-IP, Madrid E-28006, Spain Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid E-28029, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Argente
authors.affiliation: Department of Paediatrics, Universidad Autónoma de Madrid, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Instituto de Investigación Sanitaria Princesa, IIS-IP, Madrid E-28006, Spain Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid E-28029, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Barrios
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas/Universidad Autónoma de Madrid, Madrid E-28029, Spain Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid E-28029, Spain.
authors.forename: Angela M
authors.identifier: 0000-0003-1192-9045
authors.initials: AM
authors.lastname: Valverde
authors.affiliation: Department of Paediatrics, Universidad Autónoma de Madrid, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Instituto de Investigación Sanitaria Princesa, IIS-IP, Madrid E-28006, Spain Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid E-28029, Spain laura.frago@uam.es.
authors.forename: Laura M
authors.identifier: 0000-0002-5927-9240
authors.initials: LM
authors.lastname: Frago
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D007031:Hypothalamus / Q000473:pathology*; D007249:Inflammation / Q000473:pathology; D055504:Insulin Receptor Substrate Proteins / Q000172:deficiency* / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism
chemical_list: D015415:Biomarkers; D016207:Cytokines; D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D020169:Caspases
keywords: Apoptosis; Cell death; Diabetes; Hypothalamus; IRS2; Oxidative stress