Diabetes mellitus is a chronic disease that has been associated with memory loss, neurological disorders, and Alzheimer's disease. Some studies show the importance of physical exercise to prevent and minimize various neurological disorders. It is believed that the positive effects of exercise on brain functions are mediated by brain insulin and insulin-like growth factor-1 (IGF-1) signaling. In this study, we investigate the role of swimming exercise training on hippocampus proteins related to insulin/IGF-1 signaling pathway in Type 1 diabetic rats and its effects on spatial memory. Wistar rats were divided into four groups namely sedentary control, trained control, sedentary diabetic (SD), and trained diabetic (TD). Diabetes was induced by Alloxan (ALX) (32 mg/kg b.w.). The training program consisted in swimming 5 days/week, 1 h/day, per 6 weeks, supporting an overload corresponding to 90% of the anaerobic threshold. We employed ALX-induced diabetic rats to explore learning and memory abilities using Morris water maze test. At the end of the training period, the rats were sacrificed 48 h after their last exercise bout when blood samples were collected for serum glucose, insulin, and IGF-1 determinations. Hippocampus was extracted to determinate protein expression (IR, IGF-1R, and APP) and phosphorylation (AKT-1, AKT-2, Tau, and β-amyloide proteins) by Western Blot analysis. All dependent variables were analyzed by two-way analysis of variance with significance level of 5%. Diabetes resulted in hyperglycemia and hypoinsulinemia in both SD and TD groups (P<0.05); however, in the training-induced group, there was a reduction in blood glucose in TD. The average frequency in finding the platform decreased in SD rats; however, exercise training improved this parameter in TD rats. Aerobic exercise decreased Tau phosphorylation and APP expression, and increased some proteins related to insulin/IGF-1 pathway in hippocampus of diabetic rats. Thus, these molecular adaptations from exercise training might contribute to improved spatial learning and memory in diabetic organisms. © 2014 Wiley Periodicals, Inc.246703711Abrass, C.K., Diabetic proteinuria (1984) Am J Nephrol, 4, pp. 337-346Araujo, D.M., Lapchak, P.A., Collier, B., Chabot, J.G., Quirion, R., Insulin-like growth factor-1 (somatomedin-C) receptors in the rat brain: Distribution and interaction with the hippocampal cholinergic system (1989) Brain Res, 484, pp. 130-138Asano, T., Fujishiro, M., Kushiyama, A., Nakatsu, Y., Yoneda, M., Kamata, H., Sakoda, H., Role of phosphatidylinositol 3-kinase activation on insulin action and its alteration in diabetic conditions (2007) Biol Pharm Bull, 9, pp. 1610-1616Bhat, N.R., Thirumangalakudi, L., Increased Tau phosphorylation and impaired brain insulin/IGF signaling in mice fed a high fat/high cholesterol diet (2013) J Alzheimers Dis, 36, pp. 781-789Boyd, K., (1990), 16, pp. 97-98. , The Council of Europe's first Symposium on Bioethics: Strasbourg. Journal of medical ethicsBrandeis, R., Brandys, Y., Yehuda, S., The use of the Morris Water Maze in the study of memory and learning (1989) Int J Neurosci, 48, pp. 29-69Carro, E., Nuñez, A., Busiguina, S., Torres-Aleman, I., Circulating insulin-like growth factor I mediates effects of exercise on the brain (2000) J Neurosci, 20, pp. 2926-2933Carro, E., Trejo, J.L., Busiguina, S., Torres-Aleman, I., Circulating insulin-like growth factor I mediates the protective effects of physical exercise against brain insults of different etiology and anatomy (2001) Neurosci, 21, pp. 5678-5684Carro, E., Trejo, J.L., Gomez-Isla, T., LeRoith, D., Torres-Aleman, I., Serum insulin-like growth factor I regulates brain amyloid-beta levels (2002) Nat Med, 8, pp. 1390-1397Cassilhas, R.C., Antunes, H.K., Tufik, S., de Mello, M.T., Mood, anxiety, and serum IGF-1 in elderly men given 24 weeks of high resistance exercise (2010) Percept Mot Skills, 110, pp. 265-276Clodfelder-Miller, B.J., Zmijewska, A.A., Johnson, G.V., Jope, R.S., Tau is hyperphosphorylated at multiple sites in mouse brain in vivo after streptozotocin-induced insulin deficiency (2006) Diabetes, 55, pp. 3320-3325Craft, S., Asthana, S., Cook, D.G., Baker, L.D., Cherrier, M., Purganan, K., Insulin dose-response effects on memory and plasma amyloid precursor protein in Alzheimer's disease: Interactions with apolipoprotein E genotype (2003) Psychoneuroendocrinology, 28, pp. 809-822Da Luz, G., Frederico, M.J., da Silva, S., Vitto, M.F., Cesconetto, P.A., de Pinho, R.A., Pauli, J.R., De Souza, C.T., Endurance exercise training ameliorates insulin resistance and reticulum stress in adipose and hepatic tissue in obese rats (2011) Eur J Appl Physiol, 111, pp. 2015-2023De La Monte, S.M., Metabolic derangements mediate cognitive impairment and Alzheimer's disease: Role of peripheral insulin-resistance diseases (2012) Panminerva Med, 3, pp. 171-178De La Monte, S.M., Wands, J.R., Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: Relevance to Alzheimer's disease (2005) J Alzheimers Dis, 7, pp. 45-61De Senna, P.N., Ilha, J., Baptista, P.P., do Nascimento, P.S., Leite, M.C., Paim, M.F., Gonçalves, C.A., Xavier, L.L., Effects of physical exercise on spatial memory and astroglial alterations in the hippocampus of diabetic rats (2011) Metab Brain Dis, 4, pp. 269-279Ding, Q., Vaynman, S., Akhavan, M., Ying, Z., Gomez-Pinilla, F., Insulin-like growth factor I interfaces with brain-derived neurotrophic factor-mediated synaptic plasticity to modulate aspects of exercise-induced cognitive function (2006) Neuroscience, 3, pp. 823-833Foster, P.P., Rosenblatt, K.P., Kuljiš, R.O., Exercise-induced cognitive plasticity, implications for mild cognitive impairment and Alzheimer's disease (2011) Front Neurol, 2, pp. 1-15Gaspar, J.M., Baptista, F.I., Galvão, J., Castilho, A.F., Cunha, R.A., Ambrósio, A.F., Diabetes differentially affects the content of exocytotic proteins in hippocampal and retinal nerve terminals (2010) Neuroscience, 4, pp. 1589-1600Gomes, R.J., Caetano, F.H., De Mello, M.A.M., Luciano, E., Effects of chronic exercise on growth factors in diabetic rats (2005) J Exerc Physiol, 8, pp. 16-23Gomes, R.J., Mello, M.A.R., Caetano, F.H., Sibuya, C.Y., Anaruma, C.A., Rogatto, G.P., Pauli, J.R., Luciano, E., Effects of swimming training on bone mass and the GH/IGF-1 axis in diabetic rats (2006) Growth Horm IGF Res, 16, pp. 326-331Gomes, R.J., de Oliveira, C.A., Ribeiro, C., Mota, C.S., Moura, L.P., Tognoli, L.M., Leme, J.A., de Mello, M.A., Effects of exercise training on hippocampus concentrations of insulin and IGF-1 in diabetic rats (2009) Hippocampus, 10, pp. 981-987Hawley, J.A., Lessard, S.J., Exercise training-induced improvements in insulin action (2008) Acta Physiol, 192, pp. 127-135Jessen, N., Goodyear, L.J., Contraction signaling to glucose transport in skeletal muscle (2005) J Appl Physiol, 99, pp. 330-337Kar, S., Seto, D., Doré, S., Hanisch, U., Quirion, R., Insulin-like growth factors-I and -II differentially regulate endogenous acetylcholine release from the rat hippocampal formation (1997) Proc Natl Acad Sci USA, 25, pp. 14054-14059King, M.R., Anderson, N.J., Guernsey, S., Jolivalt, C.G., Glycogen Synthase Kinase-3 Inhibition Prevents Learning Deficits in Diabetic Mice (2013) Journal of Neurosci Research, 91, pp. 506-514Leme, J.A., Silveira, R.F., Gomes, R.J., Moura, R.F., Sibuya, C.A., Mello, M.A., Luciano, E., Long-term physical training increases liver IGF-I in diabetic rats (2009) Growth Horm IGF Res, 3, pp. 262-266Li, Z., Zhang, W., Grunberger, G., Sima, A.A.F., Hippocampal neuronal apoptosis in type 1 diabetes (2002) Brain Res, 946, pp. 212-231Luciano, E., Mello, M.A.R., Atividade física e metabolismo de proteínas em músculo de ratos diabéticos experimentais (1998) Rev Paul Educ Fi{dotless}s, 12, pp. 202-209Luciano, E., Carneiro, E.M., Carvalho, C.R.O., Carvalheira, J.B.C., Peres, S.B., Reis, M.A.B., Saad, M.J.A., Velloso, L.A., Endurance training improves responsiveness to insulin and modulates insulin signal transduction through the phosphatidylinositol 3-kinase/Akt-1 pathway (2002) Eur J Endocrinol, 147, pp. 149-157Manning, B.D., Cantley, L.C., AKT/PKB signaling: Navigating downstream (2007) Cell, 7, pp. 1261-1274McCarter, J.F., Liebscher, S., Bachhuber, T., Abou-Ajram, C., Hübener, M., Hyman, B.T., Haass, C., Meyer-Luehmann, M., Clustering of plaques contributes to plaque growth in a mouse model of Alzheimer's disease (2013) Acta Neuropathol, 2, pp. 179-188McCarthy, A.M., Lindgren, S., Mengeking, M.A., Tsalikian, E., Engvall, J.C., Effects of diabetes on learning in children (2002) Pediatrics, 109, pp. E91-E110Morris, R., Developments of a water-maze procedure for studying spatial learning in the rat (1984) J Neurosci Methods, 1, pp. 47-60Munshi, M., Grande, L., Hayes, M., Ayres, D., Suhl, E., Capelson, R., Lin, S., Weinger, K., Cognitive dysfunction is associated with poor diabetes control in older adults (2006) Diab Care, 8, pp. 1794-1799Nemoto, T., Satoh, S., Maruta, T., Kanai, T., Yoshikawa, N., Miyazaki, S., Yanagita, T., Wada, A., Homologous posttranscriptional regulation of insulin-like growth factor-I receptor level via glycogen synthase kinase-3beta and mammalian target of rapamycin in adrenal chromaffin cells: Effect on tau phosphorylation (2010) Neuropharmacology, 7, pp. 1097-1108Nisticò, R., Cavallucci, V., Piccinin, S., Macrì, S., Pignatelli, M., Mehdawy, B., Blandini, F., D'Amelio, M., Insulin receptor β-subunit haploinsufficiency impairs hippocampal late-phase LTP and recognition memory (2012) Neuromol Med, 4, pp. 262-269Nogueira, D.M., Strufaldi, B., Hirata, M.H., Abdalla, D.S.P., Hirata, R.D.C., (1990), pp. 153-168. , Sangue-Parte 1. In: Nogueira DM, Strufaldi B, Hirata MH, Abdalla DSP, Hirata RDC, editors. Metodos de Bioquimica Clinica. Pancast, São Paulo, BrazilPatel, S., Doble, B., Woodgett, J.R., Glycogen synthase kinase-3 in insulin and Wnt signalling: A double-edged sword? (2004) Biochem Soc Trans, 32, pp. 803-808Planel, E., Tatebayashi, Y., Miyasaka, T., Liu, L., Wang, L., Herman, M., Yu, W.H., Takashima, A., Insulin dysfunction induces in vivo tau hyperphosphorylation through distinct mechanisms (2007) J Neurosci, 50, pp. 13635-13648Qu, Z., Jiao, Z., Sun, X., Zhao, Y., Ren, J., Xu, G., Effects of streptozotocin-induced diabetes on tau phosphorylation in the rat brain (2011) Brain Res, 1383, pp. 300-306Reisi, P., Alaei, H., Babri, S., Sharifi, M.R., Mohaddes, G., Effects of treadmill running on spatial learning and memory in streptozotocin-induced diabetic rats (2009) Neurosci Lett, 2, pp. 79-83Schwarz, A.J., Brasel, J.A., Hintz, R.L., Mohan, S., Cooper, D.M., Acute effect of brief low- and high-intensity exercise on circulating insulin-like growth factor (IGF) I, II, and IGF-binding protein-3 and its proteolysis in young healthy men (1996) J Clin Endocrinol Metab, 81, pp. 3492-3497Steen, E., Terry, B.M., Rivera, E.J., Cannon, J.L., Neely, T.R., Tavares, R., Xu, X.J., de la Monte, S.M., Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease-Is this type 3 diabetes? (2005) J Alzheimers Dis, 7, pp. 63-80Taniguchi, C.M., Emanuelli, B., Kahn, C.R., Critical nodes in signalling pathways: Insights into insulin action (2006) Nat Rev Mol Cell Biol, 7, pp. 85-96Tegtbur, U., Busse, M.W., Braumann, K.M., Estimation of an individual equilibrium between lactate production and catabolism during exercise (1993) Med Sci Sports Exerc, 25, pp. 620- 627Trejo, J.L., Carro, E., Torres-Aleman, I., Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus (2001) J. Neurosci., 21, pp. 1628-1634Tully, T., Bourtchouladze, R., Scott, R., Tallman, J., Targeting the CREB pathway for memory enhancers (2003) Nat Rev Drug Discov, 4, pp. 267-277Vale, R.G., de Oliveira, R.D., Pernambuco, C.S., de Meneses, Y.P., Novaes Jda, S., de Andrade Ade, F., Effects of muscle strength and aerobic training on basal serum levels of IGF-1 and cortisol in elderly women (2009) Arch Gerontol Geriatr, 3, pp. 343-347Voltarelli, F.A., Gobatto, C.A., de Mello, M.A., Determination of anaerobic threshold in rats using the lactate minimum test (2002) Braz J Med Biol Res, 11, pp. 1389-1394Xu, W.L., von Strauss, E., Qiu, C.X., Winblad, B., Fratiglioni, L., Uncontrolled diabetes increases the risk of Alzheimer's disease: A population-based cohort study (2009) Diabetologia, 52, pp. 1031-1039You, J.S., Kim, C.J., Kim, M.Y., Byun, Y.G., Ha, S.Y., Han, B.S., Yoon, B.C., Long-term treadmill exercise-induced neuroplasticity and associated memory recovery of streptozotocin-induced diabetic rats: An experimenter blind, randomized controlled study (2009) NeuroRehabilitation, 3, pp. 291-297Zhang, W.J., Tan, Y.F., Yue, J.T., Vranic, M., Wojtowicz, J.M., Impairment of hippocampal neurogenesis in streptozotocin-treated diabetic rats (2008) Acta Neurol Scand, 117, pp. 205-210Zhang, X., Xu, L., He, D., Ling, S., Endoplasmic reticulum stress-mediated hippocampal neuron apoptosis involved in diabetic cognitive impairment (2013) Biomed Res Int, 2013, p. 924327