Age- And Gender-related Changes In Glucose Homeostasis In Glucocorticoid-treated Rats

The disruption to glucose homeostasis upon glucocorticoid (GC) treatment in adult male rats has not been fully characterized in older rats or in females. Thus, we evaluated the age- and gender-related changes in glucose homeostasis in GC-treated rats. We injected male and female rats at 3 months and 12 months of age with either dexamethasone (1.0 mg/kg body mass, intraperitoneally) or saline, daily for 5 days. All of the GC-treated rats had decreased body mass and food intake, and adrenal hypotrophy. Increased glycemia was observed in all of the GC-treated groups and only the 3-month-old female rats were not glucose intolerant. Dexamethasone treatment resulted in hyperinsulinemia and hypertriacylglyceridemia in all of the GC-treated rats. The glucose-stimulated insulin secretion (GSIS) was higher in all of the dexamethasone-treated animals, but it was less pronounced in the older animals. The β-cell mass was increased in the younger male rats treated with dexamethasone. We conclude that dexamethasone treatment induces glucose intolerance in both the 3- and 12-month-old male rats as well as hyperinsulinemia and augmented GSIS. Three-month-old female rats are protected from glucose intolerance caused by GC, whereas 12-month-old female rats developed the same complications that were present in 3- and 12-month-old male rats.9210867878Angelini, N., Rafacho, A., Boschero, A.C., Bosqueiro, J.R., Involvement of the cholinergic pathway in glucocorticoid-induced hyperinsulinemia in rats (2010) Diabetes Res. Clin. Pract, 87, pp. 184-191. , PMID:19962776Beard, J.C., Halter, J.B., Best, J.D., Pfeifer, M.A., Porte, D., Jr., Dexamethasone-induced insulin resistance enhances B cell responsiveness to glucose level in normal men (1984) Am. J. Physiol, 247, pp. E592-E596. , PMID: 6388353Binnert, C., Ruchat, S., Nicod, N., Tappy, L., Dexamethasone-induced insulin resistance shows no gender difference in healthy humans (2004) Diabetes Metab, 30, pp. 321-326. , PMID:15525874Caldefie-Chézet, F., Moinard, C., Minet-Quinard, R., Gachon, F., Cynober, L., Vasson, M., Dexamethasone treatment induces long-lasting hyperleptinemia and anorexia in old rats (2001) Metabolism, 50, pp. 1054-1058. , PMID:11555838Caperuto, L.C., Anhê, G.F., Amanso, A.M., Ribeiro, L.M., Medina, M.C., Souza, L.C., Distinct regulation of IRS proteins in adipose tissue from obese aged and dexamethasone-treated rats (2006) Endocrine, 29, pp. 391-398. , PMID:16943575Chimin, P., Farias Toda, S., Torres-Leal, F.L., Bolsoni-Lopes, A., Campaña, A.B., Andreotti, S., Chronic glucocorticoid treatment enhances lipogenic activity in visceral adipocytes of male Wistar rats (2014) Acta Physiol. (Oxf.), 211, pp. 409-420. , PMID:24410866Choi, S.B., Jang, J.S., Hong, S.M., Jun, D.W., Park, S., Exercise and dexamethasone oppositely modulate beta-cell function and survival via independent pathways in 90% pancreatectomized rats (2006) J. Endocrinol, 190, pp. 471-482. , PMID:16899580De Paula, F.M., Boschero, A.C., Carneiro, E.M., Bosqueiro, J.R., Rafacho, A., Insulin signaling proteins in pancreatic islets of insulin-resistant rats induced by glucocorticoid (2011) Biol. Res, 44, pp. 251-257. , PMID:22688912De Toro-Martín, J., Fernández-Millán, E., Lizárraga-Mollinedo, E., López-Oliva, E., Serradas, P., Escrivá, F., (2014) Predominant Role of GIP in the Development of a Metabolic Syndrome-like Phenotype in Female Wistar Rats Submitted to Forced Catch-up Growth. Endocrinology, , In press. PMID:25032669Fink, R.I., Kolterman, O.G., Olefsky, J.M., The physiological significance of the glucose intolerance of aging (1984) J. Gerontol, 39, pp. 273-278. , PMID:6371116Fransson, L., Dos Santos, C., Wolbert, P., Sjöholm, A., Rafacho, A., Ortsäter, H., Liraglutide counteracts obesity and glucose intolerance in a mouse model of glucocorticoid-induced metabolic syndrome (2014) Diabetol. Metab. Syndr, 6, p. 3. , PMID:24423471Frias, J.P., McAraeg, G.B., Ofrecio, J., Yu, J.G., Olefsky, J.M., Kruszynska, Y.T., Decreased susceptibility to fatty acid-induced peripheral tissue insulin resistance in women (2001) Diabetes, 50, pp. 1344-1350. , PMID:11375335Gama, R., Medina-Layachi, N., Ranganath, L., Hampton, S., Marks, V., Hyperproinsulinaemia in elderly subjects: Evidence for age-related pancreatic beta-cell dysfunction (2000) Ann. Clin. Biochem, 37, pp. 367-371. , PMID:10817253Gathercole, L.L., Lavery, G.G., Morgan, S.A., Cooper, M.S., Sinclair, A.J., Tomlinson, J.W., 11β-hydroxysteroid dehydrogenase 1: Translational and therapeutic aspects (2013) Endocr. Rev, 34, pp. 525-555. , PMID:23612224Giozzet, V.A., Rafacho, A., Boschero, A.C., Carneiro, E.M., Bosqueiro, J.R., Dexamethasone treatment in vivo counteracts the functional pancreatic islet alterations caused by malnourishment in rats (2008) Metabolism, 57, pp. 617-624. , PMID:18442623Hevener, A., Reichart, D., Janez, A., Olefsky, J., Female rats do not exhibit free fatty acid-induced insulin resistance (2002) Diabetes, 51, pp. 1907-1912. , PMID:12031980Holness, M.J., Smith, N.D., Greenwood, G.K., Sugden, M.C., Interactive influences of peroxisome proliferator-activated receptor alpha activation and glucocorticoids on pancreatic beta cell compensation in insulin resistance induced by dietary saturated fat in the rat (2005) Diabetologia, 48, pp. 2062-2068. , PMID:16132960Kahn, S.E., Hull, R.L., Utzschneider, K.M., Mechanisms linking obesity to insulin resistance and type 2 diabetes (2006) Nature, 444, pp. 840-846. , PMID:17167471Karlsson, S., Ostlund, B., Myrsén-Axcrona, U., Sundler, F., Ahrén, B., Beta cell adaptation to dexamethasone-induced insulin resistance in rats involves increased glucose responsiveness but not glucose effectiveness (2001) Pancreas, 22, pp. 148-156. , PMID:11249069Lin, K.H., Liou, T.L., Hsiao, L.C., Hwu, C.M., Clinical and biochemical indicators of homeostasis model assessment-estimated insulin resistance in postmenopausal women (2011) J. Chin. Med. Assoc, 74, pp. 442-447. , PMID:22036135Maedler, K., Schumann, D.M., Schulthess, F., Oberholzer, J., Bosco, D., Berney, T., Aging correlates with decreased beta-cell proliferative capacity and enhanced sensitivity to apoptosis: A potential role for Fas and pancreatic duodenal homeobox-1 (2006) Diabetes, 55, pp. 2455-2462. , PMID:16936193(2011) Guide for the Care and Use of Laboratory Animals, , www.nap.edu/catalog.php?record_id=12910, 8th Ed. National Academy Press, Washington, D.CNicod, N., Giusti, V., Besse, C., Tappy, L., Metabolic adaptations to dexamethasone-induced insulin resistance in healthy volunteers (2003) Obes. Res, 11, pp. 625-631. , PMID:12740452Novelli, M., De Tata, V., Bombara, M., Lorenzini, A., Masini, M., Pollera, M., Insufficient adaptive capability of pancreatic endocrine function in dexamethasone-treated ageing rats (1999) J. Endocrinol, 162, pp. 425-432. , PMID:10467234Ogawa, A., Johnson, J.H., Ohneda, M., McAllister, C.T., Inman, L., Alam, T., Roles of insulin resistance and beta-cell dysfunction in dexamethasoneinduced diabetes (1992) J. Clin. Invest, 90, pp. 497-504. , PMID: 1644920Ohneda, M., Johnson, J.H., Inman, L.R., Unger, R.H., GLUT-2 function in glucose-unresponsive beta cells of dexamethasone-induced diabetes in rats (1993) J. Clin. Invest, 92, pp. 1950-1956. , PMID:8408647Pacini, G., Valerio, A., Beccaro, F., Nosadini, R., Cobelli, C., Crepaldi, G., Insulin sensitivity and beta-cell responsivity are not decreased in elderly subjects with normal OGTT (1988) J. Am. Geriatr. Soc, 36, pp. 317-323. , PMID:3280644Palmer, J.P., Ensinck, J.W., Acute-phase insulin secretion and glucose tolerance in young and aged normal men and diabetic patients (1975) J. Clin. Endocrinol. Metab, 41, pp. 498-503. , PMID:1159058Rafacho, A., Roma, L.P., Taboga, S.R., Boschero, A.C., Bosqueiro, J.R., Dexamethasone-induced insulin resistance is associated with increased connexin 36 mRNA and protein expression in pancreatic rat islets (2007) Can. J. Physiol. Pharmacol, 85, pp. 536-545. , PMID:17632589Rafacho, A., Giozzet, V.A., Boschero, A.C., Bosqueiro, J.R., Functional alterations in endocrine pancreas of rats with different degrees of dexamethasone-induced insulin resistance (2008) Pancreas, 36, pp. 284-293. , PMID:18362843Rafacho, A., Ribeiro, D.L., Boschero, A.C., Taboga, S.R., Bosqueiro, J.R., Increased pancreatic islet mass is accompanied by activation of the insulin receptor substrate-2/serine-threonine kinase pathway and augmented cyclin D2 protein levels in insulin-resistant rats (2008) Int. J. Exp. Pathol, 89, pp. 264-275. , PMID:18429991Rafacho, A., Quallio, S., Ribeiro, D.L., Taboga, S.R., Paula, F.M., Boschero, A.C., The adaptive compensations in endocrine pancreas from glucocorticoid-treated rats are reversible after the interruption of treatment (2010) Acta Physiol, 200, pp. 223-235. , PMID:20456283Rafacho, A., Abrantes, J.L., Ribeiro, P.F.M., Pinto, M.E., Boschero, A.C., Morphofunctional alterations in endocrine pancreas of short- and longterm dexamethasone-treated rats (2011) Horm. Metab. Res, 43, pp. 275-281. , PMID:21225543Rafacho, A., Boschero, A.C., Ortsäter, H., Functional and molecular aspects of glucocorticoids in the endocrine pancreas and glucose homeostasis (2012) State of the Art of Therapeutic Endocrinology, , Edited by Dr. Sameh Magdeldin. InTechReaven, E., Curry, D., Moore, J., Reaven, G., Effect of age and environmental factors on insulin release from the perfused pancreas of the rat (1983) J. Clin. Invest, 71, pp. 345-350. , PMID:6337185Schäcke, H., Döcke, W.D., Asadullah, K., Mechanisms involved in the side effects of glucocorticoids (2002) Pharmacol. Ther, 96, pp. 23-43. , PMID:12441176Sengupta, P., A scientific review of age determination for a laboratory rat: How old is it in comparison with human age? (2011) Biomed. Int, 2, pp. 81-89Shimizu, M., Kawazu, S., Tomono, S., Ohno, T., Kato, N., Ishi, C., Age-related alteration of pancreatic beta-cell function. Increased proinsulin and proinsulin-to-insulin molar ratio in elderly, but not in obese, subjects without glucose intolerance (1996) Diabetes Care, 19, pp. 8-11. , PMID:8720525Song, Y., Manson, J.E., Tinker, L., Howard, B.V., Kuller, L.H., Nathan, L., Insulin sensitivity and insulin secretion determined by homeostasis model assessment and risk of diabetes in multiethnic cohort of women: The Women's Health Initiative Observational Study (2007) Diabetes Care, 30, pp. 1747-1752. , PMID:17468352Soriano, S., Ropero, A.B., Alonso-Magdalena, P., Ripoll, C., Quesada, I., Gassner, B., Rapid regulation of K(ATP) channel activity by 17{beta}-estradiol in pancreatic {beta}-cells involves the estrogen receptor {beta} and the atrial natriuretic peptide receptor (2009) Mol. Endocrinol, 23, pp. 1973-1982. , PMID:19855088Stojanovska, L., Rosella, G., Proietto, L., Evolution of dexamethasoneinduced insulin resistance in rats (1990) Am. J. Physiol, 258, pp. E748-E756. , PMID: 2185660Thunhorst, R.L., Beltz, T.G., Johnson, A.K., Glucocorticoids increase salt appetite by promoting water and sodium excretion (2007) Am. J. Physiol. Regul. Integr. Comp. Physiol, 293, pp. R1444-R1451. , PMID:17596327Tomas, F.M., The anti-catabolic efficacy of insulin-like growth factor-I is enhanced by its early administration to rats receiving dexamethasone (1998) J. Endocrinol, 157, pp. 89-97. , PMID:9614362Vital, P., Larrieta, E., Hiriart, M., Sexual dimorphism in insulin sensitivity and susceptibility to develop diabetes in rats (2006) J. Endocrinol, 190, pp. 425-432. , PMID:16899575Weir, G.C., Bonner-Weir, S., Five stages of evolving beta-cell dysfunction during progression to diabetes (2004) Diabetes, 53, pp. S16-S21. , PMID:15561905Willi, S.M., Kennedy, A., Wallace, P., Ganaway, E., Rogers, N.L., Garvey, W.T., Troglitazone antagonizes metabolic effects of glucocorticoids in humans: Effects on glucose tolerance, insulin sensitivity, suppression of free fatty acids, and leptin (2002) Diabetes, 51, pp. 2895-2902. , PMID:12351424Xue, B., Kim, Y.B., Lee, A., Toschi, E., Bonner-Weir, S., Kahn, C.R., Protein-tyrosine phosphatase 1B deficiency reduces insulin resistance and the diabetic phenotype in mice with polygenic insulin resistance (2007) J. Biol. Chem, 282, pp. 23829-23840. , PMID:1754516

Disruption Of Glucose Tolerance Caused By Glucocorticoid Excess In Rats Is Partially Prevented, But Not Attenuated, By Arjunolic Acid

Arjunolic acid (AA) obtained from plants of the Combretaceae family has shown anti-diabetic effects. Here, we analyzed whether the diabetogenic effects of dexamethasone (DEX) treatment on glucose homeostasis may be prevented or attenuated by the concomitant administration of AA. Adult Wistar rats were assigned to the following groups: vehicle-treated (Ctl), DEX-treated (1 mg/kg body weight intraperitoneally for 5 days) (Dex), AA-treated (30 mg/kg body weight by oral gavage twice per day) (Aa), AA treatment previous to and concomitant to DEX treatment (AaDex), and AA treatment after initiation of DEX treatment (DexAa). AA administration significantly ameliorated (AaDex) (P>0.05), but did not attenuate (DexAa), the glucose intolerance induced by DEX treatment. AA did not prevent or attenuate the elevation in hepatic glycogen and triacylglycerol content caused by DEX treatment. All DEX-treated rats exhibited hepatic steatosis that seemed to be more pronounced when associated with AA treatment given for a prolonged period (AaDex). Markers of liver function and oxidative stress were not significantly altered among the groups. Therefore, AA administered for a prolonged period partially prevents the glucose intolerance induced by DEX treatment, but it fails to produce this beneficial effect when given after initiation of GC treatment. Since AA may promote further hepatic steatosis when co-administered with GCs, care is required when considering this phytochemical as a hypoglycemiant and/or insulin-sensitizing agent.5210972982Ortsäter, H., Sjöholm, A., Rafacho, A., Regulation of glucocorticoid receptor signaling and the diabetogenic effects of glucocorticoid excess (2012) State of the art of therapeutic endocrinology, p. 1. , InTech, RijekaRhen, T., Cidlowski, J.A., Antiinflammatory action of glucocorticoids: New mechanisms for old drugs (2005) N Engl J Med, 353, p. 1711Schäcke, H., Döcke, W.D., Asadullah, K., Mechanims involved in the side effects of glucocorticoids (2002) Pharmacol Ther, 96, p. 23Wajngot, A., Giacca, A., Grill, V., Vranic, M., Efendic, S., The diabetogenic effects of glucocorticoids are more pronounced in low- than in high-insulin responders (1992) Proc Natl Acad Sci USA, 89, p. 6035Schneiter, P., Tappy, L., Kinetics of dexamethasone-induced alterations of glucose metabolism in healthy humans (1998) Am J Physiol, 275, p. E806Nicod, N., Giusti, V., Besse, C., Tappy, L., Metabolic adaptations to dexamethasone-induced insulin resistance in healthy volunteers (2003) Obes Res, 11, p. 625Rafacho, A., Quallio, S., Ribeiro, D.L., Taboga, S.R., Paula, F.M., Boschero, A.C., Bosqueiro, J.R., The adaptive compensations in endocrine pancreas from glucocorticoid-treated rats are reversible after the interruption of treatment (2010) Acta Physiol, 200, p. 223Rafacho, A., Abrantes, J.L., Ribeiro, D.L., Paula, F.M., Pinto, M.E., Boschero, A.C., Bosqueiro, J.R., Morphofunctional alterations in endocrine pancreas of short- and long-term dexamethasone-treated rats (2011) Horm Metab Res, 43, p. 275Rafacho, A., Boschero, A.C., Ortsäter, H., Functional and molecular aspects of glucocorticoid in the endocrine pancreas and glucose homeostasis (2012) State of the art of therapeutic endocrinology, p. 121. , InTech, RijekaVan Raalte, D.H., Nofrate, V., Bunck, M.C., Van Iersel, T., Elassaiss Schaap, J., Nässander, U.K., Heine, R.J., Diamant, M., Acute and 2-week exposure to prednisolone impair different aspects of beta-cell function in healthy men (2010) Eur J Endocrinol, 162, p. 729Willi, S.M., Kennedy, A., Wallace, P., Ganaway, E., Rogers, N.L., Garvey, W.T., Troglitazone antagonizes metabolic effects of glucocorticoids in humans: Effects on glucose tolerance, insulin sensitivity, suppression of free fatty acids, and leptin (2002) Diabetes, 51, p. 2895Thomas, C.R., Turner, S.L., Jefferson, W.H., Bailey, C.J., Prevention of dexamethasone-induced insulin resistance by metformin (1998) Biochem Pharmacol, 56, p. 1145Ragavan, B., Krishnakumari, S., Effect of terminalia arjuna stem bark extract on the activities of marker enzymes in alloxan induced diabetic rats (2005) AncSci Life, 25, p. 8Ragavan, B., Krishnakumari, S., Antidiabetic effect of T. arjuna bark extract in alloxan induced diabetic rats (2006) Indian J Clin Biochem, 21, p. 123Manna, P., Sinha, M., Sil, P.C., Protective role of arjunolic acid in response to streptozotocin-induced type-I diabetes via the mitochondrial dependent and independent pathways (2009) Toxicology, 257, p. 53Biswas, M., Kar, B., Bhattacharya, S., Kumar, R.B., Ghosh, A.K., Haldar, P.K., Antihyperglycemic activity and antioxidant role of Terminalia arjuna leaf in streptozotocin-induced diabetic rats (2011) Pharm Biol, 49, p. 335Manna, P., Das, J., Ghosh, J., Sil, P.C., Contribution of type 1 diabetes to rat liver dysfunction and cellular damage via activation of NOS, PARP, IkappaBalpha/NF- kappaB, MAPKs, and mitochondria-dependent pathways: Prophylatic role of arjunolic acid (2010) Free RadicBiol Med, 48, p. 1465Facundo, V., Rios, K.A., Medeiros, C.M., Militão, J.S.L.T., Miranda, A.L., Epifanio, R.A., Carvalho, M.P., Rezende, C.M., Arjunolic acid ethanolic extract of Combretum leprosum root and its use as a potential multi-functional phytomedicine and drug for neurodegenerative disorders: Anti-inflammatory and anticholinesterasic activities (2005) J Braz Chem Soc, 16, p. 1309Rafacho, A., Marroquí, L., Taboga, S.R., Abrantes, J.L., Silveira, L.R., Boschero, A.C., Carneiro, E.M., Quesada, I., Glucocorticoids in vivo induce both insulin hypersecretion and enhanced glucose sensitivity of stimulus- secretion coupling in isolated rat islets (2010) Endocrinology, 151, p. 85Paula, F.M., Boschero, A.C., Carneiro, E.M., Bosqueiro, J.R., Rafacho, A., Insulin signaling proteins in pancreatic islets of insulin-resistant rats induced by glucocorticoid (2011) Biol Res, 44, p. 251Matthews, D.R., Hosker, J.P., Rudenski, A.S., Naylor, B.A., Treacher, D.F., Turner, R.C., Homeostatic model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man (1985) Diabetologia, 28, p. 412Guerrero-Romero, F., Simental-Mendia, L.E., Gonzalez-Ortiz, M., Martínez-Abundis, E., Ramos-Zavala, M.G., Hernández-Gonzales, S.O., Jacques-Camarena, O., Rodríguez-Morán, M., The product of triglycerides and glucose, a simple measure of insulin sensitivity. Comparison with the euglycemic- hyperinsulinemic clamp (2010) J Clin Endocrinol Metab, 95, p. 3347Lo, S., Russell, J.C., Taylor, A.W., Determination of glycogen in small tissue samples (1970) J Appl Physiol, 28, p. 234Giozzet, V.A., Rafacho, A., Boschero, A.C., Carneiro, E.M., Bosqueiro, J.R., Dexamethasone treatment in vivo counteracts the functional pancreatic islet alterations caused by malnourishment in rats (2008) Metabolism, 57, p. 617Tietze, F., Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: Applications to mammalian blood and other tissues (1969) Anal Biochem, 27, p. 502Draper, H.H., Hadley, M., Malondialdehyde determination as index of lipid peroxidation (1990) Methods Enzymol, 186, p. 421Reznick, A.Z., Packer, L., Oxidative damage to proteins: Spectrophotometric method for carbonyl assay (1994) Methods Enzymol, 233, p. 357Weir, G.C., Bonner-Weir, S., Five stages evolving beta-cell dysfunction during progression to diabetes Diabetes, 53 (2004) suppl, 3, p. S16Burén, J., Lai, Y.C., Lungdren, M., Eriksson, J.W., Jensen, J., Insulin action and insulin signaling in fat and muscle from dexamethasone-treated rats (2008) Arch Biochem Biophys, 474, p. 91Mokuda, O., Sakamoto, Y., Ikeda, T., Mashiba, H., Sensitivity and responsiveness of glucose output to insulin in isolated perfused liver from dexamethasone-treated rats (1991) Horm Metab Res, 23, p. 53Longano, C.A., Fletcher, H.P., Insulin release after acute hydrocortisone treatment in mice (1983) Metabolism, 32, p. 603Manna, P., Sil, P.C., Impaired redox signaling and mitochondrial uncoupling contributes vascular inflammation and cardiac dysfunction in type 1 diabetes (2012) Protective role of arjunolic acid, Biochimie, 94, p. 786Muoio, D.M., Newgard, C.B., Obesity-related derangements in metabolic regulation (2006) Annu Rev Biochem, 75, p. 36

Multiparameter monitoring of Fogo Island, Cape Verde, for volcanic risk mitigation

Fogo Island in the Cape Verde Archipelago (North Atlantic) is a stratovolcano of nearly conical shape that rises 2829 m above sea level and 6000 m above the surrounding seafloor. With a population of 40 000, the island has known intense historical volcanic activity since AD 1500, with an average interval between eruptions of the order of 20 years. Twentieth-century rates were more subdued, with only two flank eruptions in 1951 and 1995. Following the 1995 eruption, increased awareness of the volcanic hazard affecting the population of the island led to the deployment of the permanent VIGIL Network. Seismographic stations (both broadband and short-period), tiltmeters and a CO2 sensor where installed in Fogo, together with a telemetry infrastructure to allow remote real-time monitoring. A broadband seismographic station was installed in neighbour Brava Island. The operation of the network was complemented by the introduction of routine geodetic and microgravity surveying and the operation of an automatic meteorological station. In this paper, we describe the methodology adopted to monitor the volcanic activity, combining real-time data analysis (volcanotectonic and volcanic earthquakes, volcanic tremor and tilt) with repeated surveying at intervals of several months (GPS, microgravity). Examples of data from the first years of operation are presented. In particular, the data pertaining to a period of anomalous activity in September–October 2000 are discussed, in the context of the risk mitigation strategy currently being developed

The experimental facility for the Search for Hidden Particles at the CERN SPS

The Search for Hidden Particles (SHiP) Collaboration has shown that the CERN SPS accelerator with its 400 GeV/c proton beam offers a unique opportunity to explore the Hidden Sector [1-3]. The proposed experiment is an intensity frontier experiment which is capable of searching for hidden particles through both visible decays and through scattering signatures from recoil of electrons or nuclei. The high-intensity experimental facility developed by the SHiP Collaboration is based on a number of key features and developments which provide the possibility of probing a large part of the parameter space for a wide range of models with light long-lived super-weakly interacting particles with masses up to (10) GeV/c2 in an environment of extremely clean background conditions. This paper describes the proposal for the experimental facility together with the most important feasibility studies. The paper focuses on the challenging new ideas behind the beam extraction and beam delivery, the proton beam dump, and the suppression of beam-induced background