{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T06:54:28Z","timestamp":1772607268613,"version":"3.50.1"},"reference-count":50,"publisher":"American Diabetes Association","issue":"10","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2006,10,1]]},"abstract":"<jats:p>We previously demonstrated that insulin has a neuroprotective role against oxidative stress, a deleterious condition associated with diabetes, ischemia, and age-related neurodegenerative diseases. In this study, we investigated the effect of insulin on neuronal glucose uptake and metabolism after oxidative stress in rat primary cortical neurons. On oxidative stress, insulin stimulates neuronal glucose uptake and subsequent metabolism into pyruvate, restoring intracellular ATP and phosphocreatine. Insulin also increases intracellular and decreases extracellular adenosine, counteracting the effect of oxidative stress. Insulin effects are apparently mediated by phosphatidylinositol 3-K and extracellular signal\u2013regulated kinase signaling pathways. Extracellular adenosine under oxidative stress is largely inhibited after blockade of ecto-5\u2032-nucleotidase, suggesting that extracellular adenosine results preferentially from ATP release and catabolism. Moreover, insulin appears to interfere with the ATP release induced by oxidative stress, regulating extracellular adenosine levels. In conclusion, insulin neuroprotection against oxidative stress\u2013mediated damage involves 1) stimulation of glucose uptake and metabolism, increasing energy levels and intracellular adenosine and, ultimately, uric acid formation and 2) a decrease in extracellular adenosine, which may reduce the facilitatory activity of adenosine receptors.<\/jats:p>","DOI":"10.2337\/db06-0030","type":"journal-article","created":{"date-parts":[[2006,9,26]],"date-time":"2006-09-26T19:57:52Z","timestamp":1159300672000},"page":"2863-2870","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":82,"title":["Insulin Restores Metabolic Function in Cultured Cortical Neurons Subjected to Oxidative Stress"],"prefix":"10.2337","volume":"55","author":[{"given":"Ana I.","family":"Duarte","sequence":"first","affiliation":[{"name":"Department of Zoology, Center for Neuroscience and Cell Biology, Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal"}]},{"given":"Teresa","family":"Proenc\u0327a","sequence":"additional","affiliation":[{"name":"Department of Neurology, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal"}]},{"given":"Catarina R.","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal"}]},{"given":"Maria S.","family":"Santos","sequence":"additional","affiliation":[{"name":"Department of Zoology, Center for Neuroscience and Cell Biology, Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal"}]},{"given":"A. Cristina","family":"Rego","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal"}]}],"member":"1167","reference":[{"key":"2022031209365118500_R1","doi-asserted-by":"crossref","unstructured":"Gerozissis K: Brain insulin and feeding: a bi-directional communication. Eur J Pharmacol\u2008490:59\u201370,2004","DOI":"10.1016\/j.ejphar.2004.02.044"},{"key":"2022031209365118500_R2","doi-asserted-by":"crossref","unstructured":"Sankar R, Thamotharan S, Shin D, Moley KH, Devaskar SU: Insulin-responsive glucose transporters-GLUT8 and GLUT4 are expressed in the developing mammalian brain. Brain Res Mol Brain Res\u2008107:157\u2013165,2002","DOI":"10.1016\/S0169-328X(02)00487-4"},{"key":"2022031209365118500_R3","doi-asserted-by":"crossref","unstructured":"Hoyer S: Glucose metabolism and insulin receptor signal transduction in Alzheimer disease. Eur J Pharmacol\u2008490:115\u2013125,2004","DOI":"10.1016\/j.ejphar.2004.02.049"},{"key":"2022031209365118500_R4","doi-asserted-by":"crossref","unstructured":"Schechter R, Beju D, Gaffney T, Schaefer F, Whetsell L: Preproinsulin I and II mRNAs and insulin electron microscopic immunoreaction are present within the rat fetal nervous system. Brain Res\u2008736:16\u201327,1996","DOI":"10.1016\/0006-8993(96)00664-6"},{"key":"2022031209365118500_R5","doi-asserted-by":"crossref","unstructured":"Gerozissis K: Brain insulin: regulation, mechanisms of action and functions. Cell Mol Neurobiol\u200823:1\u201325,2003","DOI":"10.1023\/A:1022598900246"},{"key":"2022031209365118500_R6","doi-asserted-by":"crossref","unstructured":"Pellerin L, Magistretti PJ: Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci U S A\u200891:10625\u201310629,1994","DOI":"10.1073\/pnas.91.22.10625"},{"key":"2022031209365118500_R7","doi-asserted-by":"crossref","unstructured":"Vannucci SJ, Maher F, Simpson IA: Glucose transporter proteins in brain: delivery of glucose to neurons and glia. Glia\u200821:2\u201321,1997","DOI":"10.1002\/(SICI)1098-1136(199709)21:1<2::AID-GLIA2>3.0.CO;2-C"},{"key":"2022031209365118500_R8","doi-asserted-by":"crossref","unstructured":"Choeiri C, Staines W, Messier C: Immunohistochemical localization and quantification of glucose transporters in the mouse brain. Neuroscience\u2008111:19\u201334,2002","DOI":"10.1016\/S0306-4522(01)00619-4"},{"key":"2022031209365118500_R9","doi-asserted-by":"crossref","unstructured":"Stockhorst U, de Fries D, Steingrueber HJ, Scherbaumb WA: Insulin and the CNS: effects on food intake, memory, and endocrine parameters and the role of intranasal insulin administration in humans. Physiol Behav\u200883:47\u201354,2004","DOI":"10.1016\/S0031-9384(04)00348-8"},{"key":"2022031209365118500_R10","doi-asserted-by":"crossref","unstructured":"Kokoszka JE, Coskun P, Esposito LA, Wallace DC: Increased mitochondrial oxidative stress in the Sod2 (+\/-) mouse results in the age-related decline of mitochondrial function culminating in increased apoptosis. Proc Natl Acad Sci U S A\u200898:2278\u20132283,2001","DOI":"10.1073\/pnas.051627098"},{"key":"2022031209365118500_R11","doi-asserted-by":"crossref","unstructured":"Chong ZZ, Li F, Maiese K: Oxidative stress in the brain: novel cellular targets that govern survival during neurodegenerative disease. Prog Neurobiol\u200875:207\u2013246,2005","DOI":"10.1016\/j.pneurobio.2005.02.004"},{"key":"2022031209365118500_R12","doi-asserted-by":"crossref","unstructured":"Butterfield AD, Castegna A, Lauderback CM, Drake J: Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer\u2019s disease brain contribute to neuronal death. Neurobiol Aging\u200823:655\u2013664,2002","DOI":"10.1016\/S0197-4580(01)00340-2"},{"key":"2022031209365118500_R13","doi-asserted-by":"crossref","unstructured":"Rabini RA, Tesei M, Galeazzi T, Dousset N, Ferretti G, Mazzanti L: Increased susceptibility to peroxidation of VLDL from non-insulin-dependent diabetic patients: a possible correlation with fatty acid composition. Mol Cell Biochem\u2008199:63\u201367,1999","DOI":"10.1023\/A:1006994931023"},{"key":"2022031209365118500_R14","doi-asserted-by":"crossref","unstructured":"Makar TK, Hungund BL, Cook GA, Kashfi K, Cooper AJ: Lipid metabolism and membrane composition are altered in the brains of type II diabetic mice. J Neurochem\u200864:2159\u20132168,1995","DOI":"10.1046\/j.1471-4159.1995.64052159.x"},{"key":"2022031209365118500_R15","doi-asserted-by":"crossref","unstructured":"de Courten-Myers GM, Kleinholz M, Wagner KR, Myers RE: Fatal strokes in hyperglycemic cats. Stroke\u200820:1707\u20131715,1989","DOI":"10.1161\/01.STR.20.12.1707"},{"key":"2022031209365118500_R16","doi-asserted-by":"crossref","unstructured":"Yip PK, He YY, Hsu CY, Garg N, Marangos P, Hogan EL: Effect of plasma glucose on infarct size in focal cerebral ischemia-reperfusion. Neurology\u200841:899\u2013905,1991","DOI":"10.1212\/WNL.41.6.899"},{"key":"2022031209365118500_R17","doi-asserted-by":"crossref","unstructured":"Voll CL, Auer RN: The effect of postischemic blood glucose levels on ischemic brain damage in the rat. Ann Neurol\u200824:638\u2013646,1988","DOI":"10.1002\/ana.410240508"},{"key":"2022031209365118500_R18","doi-asserted-by":"crossref","unstructured":"Garg R, Chaudhuri A, Munschauer F, Dandona P: Hyperglycemia, insulin, and acute ischemic stroke: a mechanistic justification for a trial of insulin infusion therapy. Stroke\u200837:267\u2013273,2006","DOI":"10.1161\/01.STR.0000195175.29487.30"},{"key":"2022031209365118500_R19","doi-asserted-by":"crossref","unstructured":"Duarte AI, Santos MS, Oliveira CR, Rego AC: Insulin neuroprotection against oxidative stress in cortical neurons: involvement of uric acid and glutathione antioxidant defenses. Free Radic Biol Med\u200839:876\u2013889,2005","DOI":"10.1016\/j.freeradbiomed.2005.05.002"},{"key":"2022031209365118500_R20","doi-asserted-by":"crossref","unstructured":"Almeida S, Domingues A, Rodrigues L, Oliveira CR, Rego AC: FK506 prevents mitochondrial-dependent apoptotic cell death induced by 3-nitropropionic acid in rat primary cortical cultures. Neurobiol Dis\u200817:435\u2013444,2004","DOI":"10.1016\/j.nbd.2004.07.002"},{"key":"2022031209365118500_R21","doi-asserted-by":"crossref","unstructured":"Rego AC, Santos MS, Oliveira CR: Adenosine triphosphate degradation products after oxidative stress and metabolic dysfunction in cultured retinal cells. J Neurochem\u200869:1228\u20131235,1997","DOI":"10.1046\/j.1471-4159.1997.69031228.x"},{"key":"2022031209365118500_R22","doi-asserted-by":"crossref","unstructured":"Sedmak JJ, Grossberg FE: A rapid, sensitive and versatile assay for protein using coomassie brilliant blue G250. Anal Biochem\u200879:544\u2013552,1977","DOI":"10.1016\/0003-2697(77)90428-6"},{"key":"2022031209365118500_R23","unstructured":"Heinz F, Wei\u03b2er H: Creatine phosphate. In Methods of Enzymatic Analysis. 3rd ed. Bergmeyer HU, Bergmeyer J, Gra\u03b2l M, Eds. VCH,1985, p.507\u2013514"},{"key":"2022031209365118500_R24","doi-asserted-by":"crossref","unstructured":"Erecinska M, Nelson D: Effects of 3-nitropropionic acid on synaptosomal energy and transmitter metabolism: relevance to neurodegenerative brain diseases. J Neurochem\u200863:1033\u20131041,1994","DOI":"10.1046\/j.1471-4159.1994.63031033.x"},{"key":"2022031209365118500_R25","doi-asserted-by":"crossref","unstructured":"Gupta RC, Dettbarn WD: Prevention of kainic acid seizures-induced changes in levels of nitric oxide and high-energy phosphates by 7-nitroindazole in rat brain regions. Brain Res\u2008981:184\u2013192,2003","DOI":"10.1016\/S0006-8993(03)03034-8"},{"key":"2022031209365118500_R26","doi-asserted-by":"crossref","unstructured":"Schulte G, Fredholm BB: Signalling from adenosine receptors to mitogen-activated protein kinases. Cell Signal\u200815:813\u2013827,2003","DOI":"10.1016\/S0898-6568(03)00058-5"},{"key":"2022031209365118500_R27","doi-asserted-by":"crossref","unstructured":"Cunha RA: Adenosine as a neuromodulator and as a homeostatic regulator in the nervous system: different roles, different sources and different receptors. Neurochem Int\u200838:107\u2013125,2001","DOI":"10.1016\/S0197-0186(00)00034-6"},{"key":"2022031209365118500_R28","doi-asserted-by":"crossref","unstructured":"Agostinho P, Caseiro P, Rego AC, Duarte EP, Cunha RA, Oliveira CR: Adenosine modulation of D-[3H]aspartate release in cultured retina cells exposed to oxidative stress. Neurochem Int\u200836:255\u2013265,2000","DOI":"10.1016\/S0197-0186(99)00113-8"},{"key":"2022031209365118500_R29","doi-asserted-by":"crossref","unstructured":"Cunha RA, Sebastia\u0303o AM, Ribeiro JA: Ecto-5\u2032-nucleotidase is associated with cholinergic nerve terminals in the hippocampus but not in the cerebral cortex of the rat. J Neurochem\u200859:657\u2013666,1992","DOI":"10.1111\/j.1471-4159.1992.tb09420.x"},{"key":"2022031209365118500_R30","doi-asserted-by":"crossref","unstructured":"Mark RJ, Pang Z, Geddes JW, Uchida K, Mattson MP: Amyloid beta-peptide impairs glucose transport in hippocampal and cortical neurons: involvement of membrane lipid peroxidation. J Neurosci\u200817:1046\u20131054,1997","DOI":"10.1523\/JNEUROSCI.17-03-01046.1997"},{"key":"2022031209365118500_R31","doi-asserted-by":"crossref","unstructured":"Lovell MA, Xie C, Markesbery WR: Acrolein, a product of lipid peroxidation, inhibits glucose and glutamate uptake in primary neuronal cultures. Free Rad Biol Med\u200829:714\u2013720,2000","DOI":"10.1016\/S0891-5849(00)00346-4"},{"key":"2022031209365118500_R32","doi-asserted-by":"crossref","unstructured":"Maddux BA, See W, Lawrence JC Jr, Goldfine AL, Goldfine ID, Evans JL: Protection against oxidative stress-induced insulin resistance in rat L6 muscle cells by micromolar concentrations of \u03b1-lipoic acid. Diabetes\u200850:404\u2013410,2001","DOI":"10.2337\/diabetes.50.2.404"},{"key":"2022031209365118500_R33","doi-asserted-by":"crossref","unstructured":"Matthews RT, Yang L, Jenkins BG, Ferrante RJ, Rosen BR, Kaddurah-Daouk R, Beal MF: Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington\u2019s disease. J Neurosci\u200818:156\u2013163,1998","DOI":"10.1523\/JNEUROSCI.18-01-00156.1998"},{"key":"2022031209365118500_R34","doi-asserted-by":"crossref","unstructured":"Mishra OP, Delivoria-Papadopoulos M, Cahillane G, Wagerle LC: Lipid peroxidation as the mechanism of modification of brain 5\u2032-nucleotidase activity in vitro. Neurochem Res\u200815:237\u2013242,1990","DOI":"10.1007\/BF00968666"},{"key":"2022031209365118500_R35","doi-asserted-by":"crossref","unstructured":"Almeida CG, Mendonc\u0327a A, Cunha RA, Ribeiro JA: Adenosine promotes neuronal recovery from reactive oxygen species induced lesion in rat hippocampal slices. Neurosci Lett\u2008339:127\u2013130,2003","DOI":"10.1016\/S0304-3940(02)01478-7"},{"key":"2022031209365118500_R36","doi-asserted-by":"crossref","unstructured":"Oliveira JC, Constantino MD, Sebastia\u0303o AM, Ribeiro JA: Ascorbate\/Fe3+-induced peroxidation and inhibition of the binding of A1 adenosine receptor ligands in rat brain membranes. J Neurochem Int\u200826:263\u2013268,1995","DOI":"10.1016\/0197-0186(94)00124-D"},{"key":"2022031209365118500_R37","doi-asserted-by":"crossref","unstructured":"Alfaro TM, Vigia E, Oliveira CR, Cunha RA: Effect of free radicals on adenosine A2A and dopamine D2 receptors in the striatum of young adult and aged rats. Neurochem Int\u200845:733\u2013738,2004","DOI":"10.1016\/j.neuint.2004.02.003"},{"key":"2022031209365118500_R38","doi-asserted-by":"crossref","unstructured":"Seaquist ER, Damberg GS, Tkac I, Gruetter R: The effect of insulin on in vivo cerebral glucose concentrations and rates of glucose transport\/metabolism in humans. Diabetes\u200850:2203\u20132209,2001","DOI":"10.2337\/diabetes.50.10.2203"},{"key":"2022031209365118500_R39","doi-asserted-by":"crossref","unstructured":"Prasannan KG: Effect of insulin on glucose metabolism in cerebral cortex slices under aerobic and anaerobic conditions. J Neurochem\u200819:1825\u20131828,1972","DOI":"10.1111\/j.1471-4159.1972.tb06231.x"},{"key":"2022031209365118500_R40","doi-asserted-by":"crossref","unstructured":"Bingham EM, Hopkins D, Smith D, Pernet A, Hallett W, Reed L, Marsden PK, Amiel SA: The role of insulin in human brain glucose: an 18fluoro-deoxyglucose positron emission tomography study. Diabetes\u200851:3384\u20133390,2002","DOI":"10.2337\/diabetes.51.12.3384"},{"key":"2022031209365118500_R41","doi-asserted-by":"crossref","unstructured":"Watson GS, Craft S: Modulation of memory by insulin and glucose: neuropsychological observations in Alzheimer\u2019s disease. Eur J Pharmacol\u2008490:97\u2013113,2004","DOI":"10.1016\/j.ejphar.2004.02.048"},{"key":"2022031209365118500_R42","doi-asserted-by":"crossref","unstructured":"Mattson MP, Maudsley S, Martin B: A neural signaling triumvirate that influences ageing and age-related disease: insulin\/IGF-1, BDNF and serotonin. Ageing Res Rev\u20083:445\u2013464,2004","DOI":"10.1016\/j.arr.2004.08.001"},{"key":"2022031209365118500_R43","doi-asserted-by":"crossref","unstructured":"Hamabe W, Fujita R, Ueda H: Neuronal necrosis inhibition by insulin through protein kinase C activation. J Pharmacol Exp Ther\u2008307:205\u2013212,2003","DOI":"10.1124\/jpet.103.053033"},{"key":"2022031209365118500_R44","doi-asserted-by":"crossref","unstructured":"Whitesell RR, Ward M, McCall AL, Granner DK, May JM: Coupled glucose transport and metabolism in cultured neuronal cells: determination of the rate-limiting step. J Cereb Blood Flow Metab\u200815:814\u2013826,1995","DOI":"10.1038\/jcbfm.1995.102"},{"key":"2022031209365118500_R45","doi-asserted-by":"crossref","unstructured":"Huang TJ, Verkhratsky A, Fernyhough P: Insulin enhances mitochondrial inner membrane potential and increases ATP levels through phosphoinositide 3-K in adult sensory neurons. Mol Cell Neurosci\u200828:42\u201354,2005","DOI":"10.1016\/j.mcn.2004.08.009"},{"key":"2022031209365118500_R46","doi-asserted-by":"crossref","unstructured":"Henneberg N, Hoyer S: Short-term or long-term intracerebroventricular (ivc) infusion of insulin exhibits a discrete anabolic effect on cerebral energy metabolism in the rat. Neurosci Lett\u2008175:153\u2013156,1994","DOI":"10.1016\/0304-3940(94)91102-9"},{"key":"2022031209365118500_R47","doi-asserted-by":"crossref","unstructured":"van der Heide LP, Kamal A, Artola A, Gispen WH, Ramakers GMJ: Insulin modulates hippocampal activity-dependent synaptic plasticity in a N-methyl-D-aspartate receptor and phosphatidyl-inositol-3-K-dependent manner. J Neurochem\u200894:1158\u20131166,2005","DOI":"10.1111\/j.1471-4159.2005.03269.x"},{"key":"2022031209365118500_R48","doi-asserted-by":"crossref","unstructured":"Voll CL, Auer RN: Insulin attenuates ischemic brain damage independent of its hypoglycemic effect. J Cereb Blood Flow Metab\u200811:1006\u20131014,1991","DOI":"10.1038\/jcbfm.1991.168"},{"key":"2022031209365118500_R49","doi-asserted-by":"crossref","unstructured":"Hamilton MG, Tranmer BI, Auer RN: Insulin reduction of cerebral infarction due to transient focal ischemia. J Neurosurg\u200882:262\u2013268,1995","DOI":"10.3171\/jns.1995.82.2.0262"},{"key":"2022031209365118500_R50","doi-asserted-by":"crossref","unstructured":"Johan Groeneveld AB, Beishuizen A, Visser FC: Insulin: a wonder drug in the critically ill?Crit Care\u20086:102\u2013105,2002","DOI":"10.1186\/cc1463"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/55\/10\/2863\/339772\/zdb01006002863.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/55\/10\/2863\/339772\/zdb01006002863.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:06:43Z","timestamp":1667405203000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/55\/10\/2863\/14214\/Insulin-Restores-Metabolic-Function-in-Cultured"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,10,1]]},"references-count":50,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2006,10,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db06-0030","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,10,1]]}}}