{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T15:26:41Z","timestamp":1779377201907,"version":"3.53.1"},"reference-count":138,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,16]],"date-time":"2022-07-16T00:00:00Z","timestamp":1657929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Molecular Mechanisms of Growth Hormone and Melatonin","award":["SAF 2007 66878-C02-01"],"award-info":[{"award-number":["SAF 2007 66878-C02-01"]}]},{"name":"Molecular Mechanisms of Growth Hormone and Melatonin","award":["RETICEF-RD12\/0043\/0032"],"award-info":[{"award-number":["RETICEF-RD12\/0043\/0032"]}]},{"name":"Principal Investigator","award":["SAF 2007 66878-C02-01"],"award-info":[{"award-number":["SAF 2007 66878-C02-01"]}]},{"name":"Principal Investigator","award":["RETICEF-RD12\/0043\/0032"],"award-info":[{"award-number":["RETICEF-RD12\/0043\/0032"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In order to investigate the possible beneficial effects of GH administration on the aging process, 24-month-old rats of both sexes and 10-month-old SAMP8 mice were used. Male rats showed increased fat content and decreased lean body mass together with enhanced vasoconstriction and reduced vasodilation of their aortic rings compared to young adult animals. Chronic GH treatment for 10 weeks increased lean body mass and reduced fat weight together with inducing an enhancement of the vasodilatory response by increasing eNOS and a reduction of the constrictory responses. Old SAMP8 male mice also showed insulin resistance together with a decrease in insulin production by the endocrine pancreas and a reduced expression of differentiation parameters. GH treatment decreased plasma levels and increased pancreatic production of insulin and restored differentiation parameters in these animals. Ovariectomy plus low calcium diet in rabbits induced osteoporosis Titanium implants inserted into these rabbit tibiae showed after one month lesser bone to implant (BIC) surface and bone mineral density (BMD). Local application of GH in the surgical opening was able to increase BIC in the osteoporotic group. The hippocampus of old rats showed a reduction in the number of neurons and also in neurogenesis compared to young ones, together with an increase of caspases and a reduction of Bcl-2. GH treatment was able to enhance significantly only the total number of neurons. In conclusion, GH treatment was able to show beneficial effects in old animals on all the different organs and metabolic functions studied.<\/jats:p>","DOI":"10.3390\/ijms23147848","type":"journal-article","created":{"date-parts":[[2022,7,17]],"date-time":"2022-07-17T22:57:06Z","timestamp":1658098626000},"page":"7848","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Effects of GH on the Aging Process in Several Organs: Mechanisms of Action"],"prefix":"10.3390","volume":"23","author":[{"given":"Jes\u00fas \u00c1. F.","family":"Tresguerres","sequence":"first","affiliation":[{"name":"Department of Physiology, School of Medicine, Complutense University of Madrid, Avda. Complutense, s\/n, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5855-6325","authenticated-orcid":false,"given":"Isabel","family":"Fern\u00e1ndez-Tresguerres","sequence":"additional","affiliation":[{"name":"Department of Clinical Dental Specialties, School of Dentistry, Complutense University of Madrid, Avda. Complutense, s\/n, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9709-0089","authenticated-orcid":false,"given":"Jos\u00e9","family":"Vi\u00f1a","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, University of Valencia, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1556-192X","authenticated-orcid":false,"given":"Lisa","family":"Rancan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Medicine, Complutense University of Madrid, Avda. Complutense, s\/n, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4646-4199","authenticated-orcid":false,"given":"Sergio D.","family":"Paredes","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, Complutense University of Madrid, Avda. Complutense, s\/n, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0344-9877","authenticated-orcid":false,"given":"Beatriz","family":"Linillos-Pradillo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Medicine, Complutense University of Madrid, Avda. Complutense, s\/n, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Vara","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Medicine, Complutense University of Madrid, Avda. Complutense, s\/n, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,16]]},"reference":[{"key":"ref_1","unstructured":"Tresguerres, J.A.F. (2020). Hormona de crecimiento. Fisiolog\u00eda Humana, McGraw Hill."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1159\/000180971","article-title":"Somatostatin as a physiological regulator of pulsatile growth hormone secretion","volume":"29","author":"Tannenbaum","year":"1988","journal-title":"Horm. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1210\/edrv-8-2-115","article-title":"Effect of growth hormone on carbohydrate and lipid metabolism","volume":"8","author":"Davidson","year":"1987","journal-title":"Endocr Rev."},{"key":"ref_4","unstructured":"Tresguerres, J.A.F. (2000). Prote\u00ednas transportadoras. Receptores. Acciones biol\u00f3gicas de IGF-I. Tratado de Endocrinolog\u00eda B\u00e1sica y Cl\u00ednica, S\u00edntesis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1111\/j.1365-2265.1993.tb00974.x","article-title":"Increased body fat mass and decreased extracellular fluid volume in adults with growth hormone deficiency","volume":"38","author":"Bosaeus","year":"1993","journal-title":"Clin. Endocrinol."},{"key":"ref_6","first-page":"460","article-title":"Beyond the somatopause: Growth hormone deficiency in adults over the age of 60 years","volume":"81","author":"Toogood","year":"1996","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/S0950-351X(98)80023-2","article-title":"Ageing and growth hormone status","volume":"12","author":"Toogood","year":"1998","journal-title":"Baillieres Clin. Endocrinol. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s10522-004-7380-0","article-title":"Effect of insulin and growth hormone on rat heart and liver oxidative stress in control and caloric restricted animals","volume":"6","author":"Sanz","year":"2005","journal-title":"Biogerontology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1089\/10945450152850669","article-title":"Natural and synthetic growth hormone secretagogues: Endocrine and nonendocrine activities suggesting their potential usefulness as anti-aging drug interventions","volume":"4","author":"Ghigo","year":"2001","journal-title":"J. Anti-Aging Med."},{"key":"ref_10","unstructured":"Hoffman, A.R., Pyka, G., Lieberman, S.A., Ceda, G.P., Marcus, R., M\u00fcller, E.E., Cocchi, D., and Locatelli, V. (1993). Growth Hormone and Somatomedins during Lifespan, Springer Science & Business Media."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1056\/NEJM199007053230101","article-title":"Effects of human growth hormone in men over 60 years old","volume":"323","author":"Rudman","year":"1990","journal-title":"N. Engl. J. Med."},{"key":"ref_12","first-page":"470","article-title":"Effects of recombinant human growth hormone on metabolic indices, body composition, and bone turnover in healthy elderly women","volume":"79","author":"Holloway","year":"1994","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_13","first-page":"193","article-title":"Effects of six-month administration of recombinant human growth hormone to healthy elderly subjects","volume":"9","author":"Cuttica","year":"1997","journal-title":"Aging"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1093\/gerona\/glr083","article-title":"Effect of a combined treatment with growth hormone and melatonin in the cardiological aging on male SAMP8 mice","volume":"66","author":"Forman","year":"2011","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_15","first-page":"1287","article-title":"Mitochondria as sources and targets of damage in cellular aging","volume":"50","author":"Gambini","year":"2012","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1093\/ajcn\/87.1.142","article-title":"Oral administration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance","volume":"87","author":"Domenech","year":"2008","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.freeradbiomed.2007.02.001","article-title":"Moderate exercise is an antioxidant: Upregulation of antioxidant genes by training","volume":"44","author":"Domenech","year":"2008","journal-title":"Free Radic. Biol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1111\/j.1600-079X.2006.00385.x","article-title":"Effect of exogenous administration of melatonin and growth hormone on pro-antioxidant functions of the liver in aging male rats","volume":"42","author":"Kireev","year":"2007","journal-title":"J. Pineal. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s10522-009-9242-2","article-title":"Hormonal regulation of pro-inflammatory and lipid peroxidation processes in liver of old ovariectomized female rats","volume":"11","author":"Kireev","year":"2010","journal-title":"Biogerontology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1007\/s10522-009-9245-z","article-title":"Cardiological aging in SAM model: Effect of chronic treatment with growth hormone","volume":"11","author":"Forman","year":"2010","journal-title":"Biogerontology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1089\/rej.2011.1166","article-title":"Effect of growth hormone treatment on pancreatic inflammation, oxidative stress, and apoptosis related to aging in SAMP8 mice","volume":"14","author":"Cuesta","year":"2011","journal-title":"Rejuvenation Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/S0531-5565(03)00156-6","article-title":"Body composition and vascular effects of growth hormone administration in old female rats","volume":"38","author":"Castillo","year":"2003","journal-title":"Exp. Gerontol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1385\/ENDO:26:1:011","article-title":"Effect of growth hormone and estrogen administration on hepatocyte alterations in old ovariectomized female wistar rats","volume":"26","author":"Castillo","year":"2005","journal-title":"Endocrine"},{"key":"ref_24","first-page":"315","article-title":"Effect of long-term GHRH and somatostatin administration on GH release and body weight in prepubertal female rats","volume":"55","author":"Ariznavarreta","year":"1999","journal-title":"J. Physiol. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1046\/j.1365-2265.2002.01559.x","article-title":"Growth hormone deficiency and vascular risk","volume":"57","author":"McCallum","year":"2002","journal-title":"Clin. Endocrinol."},{"key":"ref_26","first-page":"8S","article-title":"The insulin resistance-dyslipidemic syndrome of visceral obesity: Effect on patients\u2019 risk","volume":"6","year":"1998","journal-title":"Obes. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1007\/s13539-012-0089-z","article-title":"From muscle wasting to sarcopenia and myopenia: Update 2012","volume":"3","author":"Morley","year":"2012","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"708","DOI":"10.7326\/0003-4819-124-8-199604150-00002","article-title":"Growth hormone replacement in healthy older men improves body composition but not functional ability","volume":"124","author":"Papadakis","year":"1996","journal-title":"Ann. Intern. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1093\/gerona\/glt187","article-title":"Growth hormone replacement therapy prevents sarcopenia by a dual mechanism: Improvement of protein balance and of antioxidant defenses","volume":"69","author":"Brioche","year":"2014","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1519\/00139143-200932020-00008","article-title":"Sarcopenia\u2014Mechanisms and treatments","volume":"32","author":"Jones","year":"2009","journal-title":"J. Geriatr. Phys. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"135","DOI":"10.2310\/6650.2005.00309","article-title":"Insulin-like growth factor I-mediated skeletal muscle hypertrophy is characterized by increased mTOR-p70S6K signaling without increased akt phosphorylation","volume":"53","author":"Song","year":"2005","journal-title":"J. Investig. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1152\/japplphysiol.00221.2002","article-title":"Invited review: Role of insulin in translational control of protein synthesis in skeletal muscle by amino acids or exercise","volume":"93","author":"Kimball","year":"2002","journal-title":"J. Appl. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1152\/jappl.1997.83.4.1270","article-title":"Myogenic regulatory factors during regeneration of skeletal muscle in young, adult, and old rats","volume":"83","author":"Marsh","year":"1997","journal-title":"J. Appl. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2149","DOI":"10.1152\/japplphysiol.00513.2005","article-title":"Resting and load-induced levels of myogenic gene transcripts differ between older adults with demonstrable sarcopenia and young men and women","volume":"99","author":"Kim","year":"2005","journal-title":"J. Appl. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1113\/jphysiol.2002.032136","article-title":"Expression of IGF-I splice variants in young and old human skeletal muscle after high resistance exercise","volume":"547","author":"Hameed","year":"2003","journal-title":"J. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1016\/j.exger.2004.08.010","article-title":"Growth factors and muscle ageing","volume":"39","author":"Goldspink","year":"2004","journal-title":"Exp. Gerontol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"12457","DOI":"10.1073\/pnas.94.23.12457","article-title":"Double muscling in cattle due to mutations in the myostatin gene","volume":"94","author":"McPherron","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1002\/jcp.22127","article-title":"Regulatory factors and cell populations involved in skeletal muscle regeneration","volume":"224","author":"Grefte","year":"2010","journal-title":"J. Cell Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1096\/fj.11-198663","article-title":"Myostatin is associated with age-related human muscle stem cell dysfunction","volume":"26","author":"McKay","year":"2012","journal-title":"FASEB J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1002\/hep.510240536","article-title":"Aging of the liver: Age-associated mitochondrial damage in intact hepatocytes","volume":"24","author":"Sastre","year":"1996","journal-title":"Hepatology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/S0092-8674(00)81410-5","article-title":"A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis","volume":"92","author":"Puigserver","year":"1998","journal-title":"Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1016\/j.addr.2009.06.006","article-title":"Mitochondrial biogenesis in exercise and in ageing","volume":"61","author":"Borras","year":"2009","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.cell.2006.09.024","article-title":"Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators","volume":"127","author":"Drori","year":"2006","journal-title":"Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1007\/s11357-011-9264-y","article-title":"Age associated low mitochondrial biogenesis may be explained by lack of response of PGC-1\u03b1 to exercise training","volume":"34","author":"Nascimento","year":"2012","journal-title":"Age"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/0140-6736(90)91812-O","article-title":"Premature mortality due to cardiovascular disease in hypopituitarism","volume":"336","author":"Bengtsson","year":"1990","journal-title":"Lancet"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1046\/j.1365-2265.1999.00671.x","article-title":"Endothelial dysfunction in hypopituitary adults with growth hormone deficiency","volume":"50","author":"Evans","year":"1999","journal-title":"Clin. Endocrinol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"11","DOI":"10.33549\/physiolres.930000.49.11","article-title":"Age-related endothelial dysfunction with respect to nitric oxide, endothelium-derived hyperpolarizing factor and cyclooxygenase products","volume":"49","author":"Matz","year":"2000","journal-title":"Physiol. Res."},{"key":"ref_48","first-page":"1","article-title":"Alteraciones endoteliales en el envejecimiento","volume":"19","author":"Cediel","year":"1999","journal-title":"Nefrologia"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1111\/j.1532-5415.2000.tb03911.x","article-title":"Aging is associated with endothelial dysfunction in the human forearm vasculature","volume":"48","author":"Andrawis","year":"2000","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1089\/biores.2015.0032","article-title":"Melatonin counteracts at a transcriptional level the inflammatory and apoptotic response secondary to ischemic brain injury induced by middle cerebral artery blockade in aging rats","volume":"4","author":"Paredes","year":"2015","journal-title":"Biores. Open Access"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1007\/s10522-005-4805-3","article-title":"Effect of recombinant human growth hormone administration on body composition and vascular function and structure in old male wistar rats","volume":"6","author":"Castillo","year":"2005","journal-title":"Biogerontology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1111\/j.1600-079X.2004.00199.x","article-title":"Effect of melatonin administration on parameters related to oxidative damage in hepatocytes isolated from old wistar rats","volume":"38","author":"Castillo","year":"2005","journal-title":"J. Pineal Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3515","DOI":"10.1210\/endo.138.8.5330","article-title":"Decreases in cerebral microvasculature with age are associated with the decline in growth hormone and insulin-like growth factor 1","volume":"138","author":"Sonntag","year":"1997","journal-title":"Endocrinology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"B364","DOI":"10.1093\/gerona\/56.8.B364","article-title":"Growth hormone increases regional coronary blood flow and capillary density in aged rats","volume":"56","author":"Khan","year":"2001","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/S0197-4580(99)00008-1","article-title":"Senescence-accelerated mouse (SAM): A biogerontological resource in aging research","volume":"20","author":"Takeda","year":"1999","journal-title":"Neurobiol. Aging"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S0047-6374(98)00009-8","article-title":"Difference between senescence-accelerated prone and resistant mice in response to insulin in the heart","volume":"102","author":"Kurokawa","year":"1998","journal-title":"Mech. Ageing Dev."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1111\/j.1600-079X.2007.00433.x","article-title":"Chronic administration of melatonin reduces cerebral injury biomarkers in SAMP8","volume":"42","author":"Sureda","year":"2007","journal-title":"J. Pineal Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1016\/j.exger.2005.05.007","article-title":"The senescence-accelerated prone mouse (SAMP8): A model of age-related cognitive decline with relevance to alterations of the gene expression and protein abnormalities in Alzheimer\u2019s disease","volume":"40","author":"Butterfield","year":"2005","journal-title":"Exp. Gerontol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1007\/s10522-007-9108-4","article-title":"The senescence accelerated mouse (SAM-P8) as a model for the study of vascular functional alterations during aging","volume":"8","author":"Llorens","year":"2007","journal-title":"Biogerontology"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"B52","DOI":"10.1093\/geronj\/47.2.B52","article-title":"Early onset of age-related impairment of aversive and appetitive learning in the SAMP-P\/8 mouse","volume":"47","author":"Flood","year":"1992","journal-title":"J. Gerontol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/0197-4580(93)90092-P","article-title":"Age-related changes in the pharmacological improvement of retention in senescence accelerated mouse (SAM)","volume":"14","author":"Flood","year":"1993","journal-title":"Neurobiol. Aging"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1172\/JCI112389","article-title":"Chronic hyperglycemia is associated with impaired glucose influence on insulin secretion. A study in normal rats using chronic in vivo glucose infusions","volume":"77","author":"Leahy","year":"1986","journal-title":"J. Clin. Invest."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.2337\/diab.45.8.1003","article-title":"Hexosamines and insulin resistance","volume":"45","author":"McClain","year":"1996","journal-title":"Diabetes"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"281","DOI":"10.7326\/0003-4819-131-4-199908170-00008","article-title":"Pharmacologic therapy for type 2 diabetes mellitus","volume":"131","author":"DeFronzo","year":"1999","journal-title":"Ann. Intern. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2528","DOI":"10.1172\/JCI2401","article-title":"Differential expression of the insulin gene transcriptional repressor CCAAT\/enhancer-binding protein beta and transactivator islet duodenum homeobox-1 in rat pancreatic beta cells during the development of diabetes mellitus","volume":"101","author":"Seufert","year":"1998","journal-title":"J. Clin. Invest."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"258","DOI":"10.2337\/diab.46.2.258","article-title":"Reduced insulin, GLUT2, and IDX-1 in beta-cells after partial pancreatectomy","volume":"46","author":"Zangen","year":"1997","journal-title":"Diabetes"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3905","DOI":"10.1242\/jcs.02513","article-title":"ER stress and SREBP-1 activation are implicated in beta-cell glucolipotoxicity","volume":"118","author":"Wang","year":"2005","journal-title":"J. Cell Sci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"30261","DOI":"10.1074\/jbc.272.48.30261","article-title":"Fatty acids decrease IDX-1 expression in rat pancreatic islets and reduce GLUT2, glucokinase, insulin, and somatostatin levels","volume":"272","author":"Gremlich","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1007\/s00125-006-0536-5","article-title":"Changes in gene expression in beta cells after islet isolation and transplantation using laser-capture microdissection","volume":"50","author":"Ahn","year":"2007","journal-title":"Diabetologia"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1007\/s00109-005-0640-x","article-title":"Oxidative stress, ER stress, and the JNK pathway in type 2 diabetes","volume":"83","author":"Kaneto","year":"2005","journal-title":"J. Mol. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/S0140-6736(75)92375-2","article-title":"The essential role of glucagon in the pathogenesis of diabetes mellitus","volume":"1","author":"Unger","year":"1975","journal-title":"Lancet"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2300","DOI":"10.1210\/jc.2002-020735","article-title":"Selective beta-cell loss and alpha-cell expansion in patients with type 2 diabetes mellitus in Korea","volume":"88","author":"Yoon","year":"2003","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"624","DOI":"10.2337\/diabetes.53.3.624","article-title":"Structural and functional abnormalities in the islets isolated from type 2 diabetic subjects","volume":"53","author":"Deng","year":"2004","journal-title":"Diabetes"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1007\/s00125-005-1692-8","article-title":"Suppression of pdx-1 perturbs proinsulin processing, insulin secretion and GLP-1 signalling in INS-1 cells","volume":"48","author":"Wang","year":"2005","journal-title":"Diabetologia"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.cmet.2005.07.001","article-title":"Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice","volume":"2","author":"Moynihan","year":"2005","journal-title":"Cell Metab."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1007\/s11892-009-0034-5","article-title":"The role of FOXO in the regulation of metabolism","volume":"9","author":"Gross","year":"2009","journal-title":"Curr. Diab. Rep."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.ghir.2010.12.007","article-title":"Growth hormone can improve insulin resistance and differentiation in pancreas of senescence accelerated prone male mice (SAMP8)","volume":"21","author":"Cuesta","year":"2011","journal-title":"Growth Horm. IGF Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1002\/dmrr.2631","article-title":"The beneficial effect of growth hormone treatment on islet mass in streptozotocin-treated mice","volume":"31","author":"Scheinman","year":"2015","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_79","first-page":"492","article-title":"Osseointegration of oral implants in older and younger adults","volume":"13","author":"Bryant","year":"1998","journal-title":"Int. J. Oral Maxillofac. Implants."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1159\/000048929","article-title":"Age-related bone loss: Old bone, new facts","volume":"48","author":"Chan","year":"2002","journal-title":"Gerontology"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1016\/S0142-9612(01)00213-7","article-title":"Osteointegration of hydroxyapatite-coated and uncoated titanium screws in long-term ovariectomized sheep","volume":"23","author":"Rocca","year":"2002","journal-title":"Biomaterials"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1097\/01.ID.0000099750.26582.4B","article-title":"Estrogen deficiency affects bone healing around titanium implants: A histometric study in rats","volume":"12","author":"Duarte","year":"2003","journal-title":"Implant Dent."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1359\/jbmr.2003.18.3.393","article-title":"Growth hormone increases bone mineral content in postmenopausal osteoporosis: A randomized placebo-controlled trial","volume":"18","author":"Nilsson","year":"2003","journal-title":"J. Bone Miner. Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.2174\/092986711795029708","article-title":"Resveratrol, a phytochemical inducer of multiple cell death pathways: Apoptosis, autophagy and mitotic catastrophe","volume":"18","author":"Delmas","year":"2011","journal-title":"Curr. Med. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"3251","DOI":"10.1210\/jc.2015-1757","article-title":"Effect of growth hormone treatment on fractures and quality of life in postmenopausal osteoporosis: A 10-year follow-up study","volume":"100","author":"Krantz","year":"2015","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1097\/00003086-199102000-00004","article-title":"Bone growth factors","volume":"263","author":"Mohan","year":"1991","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_87","first-page":"387","article-title":"Potent effect of recombinant growth hormone on bone mineral density and body composition in adults with panhypopituitarism","volume":"126","author":"Degerblad","year":"1992","journal-title":"Acta Endocrinol."},{"key":"ref_88","first-page":"1344","article-title":"Increased bone density after recombinant human growth hormone (GH) therapy in adults with isolated GH deficiency","volume":"76","author":"Tsatsoulis","year":"1993","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/8756-3282(90)90075-A","article-title":"Increased mechanical strength of healing rat tibial fractures treated with biosynthetic human growth hormone","volume":"11","author":"Bak","year":"1990","journal-title":"Bone"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1002\/jbmr.5650050610","article-title":"A short course of recombinant human growth hormone treatment stimulates osteoblasts and activates bone remodeling in normal human volunteers","volume":"5","author":"Brixen","year":"1990","journal-title":"J. Bone Miner. Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S1096-6374(98)80022-1","article-title":"The use of growth hormone in adults: A review of the last 10 years, the present and a perspective for the future","volume":"8","author":"Bengtsson","year":"1998","journal-title":"Growth Horm. IGF Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1034\/j.1600-0501.2002.130609.x","article-title":"Local administration of growth hormone enhances periimplant bone reaction in an osteoporotic rabbit model","volume":"13","author":"Tresguerres","year":"2002","journal-title":"Clin. Oral Implants Res."},{"key":"ref_93","first-page":"725","article-title":"Validation of an osteoporotic animal model for dental implant analyses: An in vivo densitometric study in rabbits","volume":"26","author":"Tresguerres","year":"2011","journal-title":"Int. J. Oral. Maxillofac. Implants"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1007\/BF00298723","article-title":"Growth hormone stimulates proliferation and differentiation of normal human osteoblast-like cells in vitro","volume":"52","author":"Kassem","year":"1993","journal-title":"Calcif. Tissue Int."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1034\/j.1600-0501.2002.130604.x","article-title":"Histomorphometric and fluorescence microscopic analysis of bone remodelling after installation of implants using an osteotome technique","volume":"13","author":"Nkenke","year":"2002","journal-title":"Clin. Oral Implants Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1530\/eje.0.1330180","article-title":"Reduced bone mineral density in adults with growth hormone (GH) deficiency: Increased bone turnover during 12 months of GH substitution therapy","volume":"133","author":"Degerblad","year":"1995","journal-title":"Eur. J. Endocrinol."},{"key":"ref_97","first-page":"131","article-title":"Growth hormone stimulates proliferation of normal human bone marrow stromal osteoblast precursor cells in vitro","volume":"4","author":"Kassem","year":"1994","journal-title":"Growth Regul."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1210\/endo.137.1.8536635","article-title":"Stimulatory effect of growth hormone on bone resorption and osteoclast differentiation","volume":"137","author":"Nishiyama","year":"1996","journal-title":"Endocrinology"},{"key":"ref_99","first-page":"807","article-title":"Effects of local administration of growth hormone in peri-implant bone: An experimental study with implants in rabbit tibiae","volume":"18","author":"Tresguerres","year":"2003","journal-title":"Int. J. Oral Maxillofac. Implants"},{"key":"ref_100","first-page":"193","article-title":"Histologic, morphometric and densitometric study of peri-implant bone in rabbits with local administration of GH","volume":"20","author":"Tresguerres","year":"2005","journal-title":"Int. J. Oral Maxillofac. Implants"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"751","DOI":"10.11607\/jomi.5320","article-title":"Local application of GH to enhance osseointegration in osteoporotic bones. A morphometric and densitometric study","volume":"32","author":"Tresguerres","year":"2017","journal-title":"Int. J. Oral Maxilofac. Implants"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1089\/rej.2020.2369","article-title":"Growth Hormone As Antiaging Factor in Old Bones","volume":"24","author":"Tresguerres","year":"2021","journal-title":"Rejuvenation Res."},{"key":"ref_103","first-page":"1068","article-title":"The effects of growth hormone on the initial bone formation around implants","volume":"24","author":"Cutando","year":"2009","journal-title":"Int. J. Oral Maxillofac. Implants"},{"key":"ref_104","first-page":"41","article-title":"Preliminary study of the effects of growth hormone substitution therapy on bone mineral density and serum osteocalcin levels in adults with growth hormone deficiency","volume":"128","author":"Soop","year":"1993","journal-title":"Acta Endocrinol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1159\/000063443","article-title":"Bone densitometry: Assessing the effects of growth hormone treatment in adults","volume":"54","author":"Ortolani","year":"2000","journal-title":"Horm. Res."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1006\/frne.2000.0200","article-title":"Growth hormone in the brain: Characteristics of specific brain targets for the hormone and their functional significance","volume":"21","author":"Nyberg","year":"2000","journal-title":"Front. Neuroendocrinol."},{"key":"ref_107","first-page":"55","article-title":"Quality of life of adults with growth hormone deficiency: A controlled study","volume":"356","author":"Westphal","year":"1989","journal-title":"Acta Paediatr. Scand. Suppl."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1159\/000181584","article-title":"Psychological well-being before and after growth hormone treatment in adults with growth hormone deficiency","volume":"33","author":"McGauley","year":"1990","journal-title":"Horm. Res."},{"key":"ref_109","first-page":"309","article-title":"Treatment of adults with growth hormone (GH) deficiency with recombinant human GH","volume":"76","author":"Bengtsson","year":"1993","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1111\/j.1365-2265.1994.tb02452.x","article-title":"Decreased psychological well-being in adult patients with growth hormone deficiency","volume":"40","author":"Wilhelmsen","year":"1994","journal-title":"Clin. Endocrinol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"3585","DOI":"10.1210\/jcem.80.12.8530603","article-title":"Quality of life in adults with growth hormone (GH) deficiency: Response to treatment with recombinant human GH in a placebo-controlled 21-month trial","volume":"80","author":"Burman","year":"1995","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1159\/000012276","article-title":"Quality of life and cognitive function in patients with pituitary insufficiency","volume":"67","author":"Burman","year":"1998","journal-title":"Psychother. Psychosom."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/S0306-4530(97)00092-9","article-title":"Cognitive changes during growth hormone replacement in adult men","volume":"23","author":"Deijen","year":"1998","journal-title":"Psychoneuroendocrinology"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"2596","DOI":"10.1210\/jcem.84.8.5916","article-title":"The effects of 10 years of recombinant human growth hormone (GH) in adult GH-deficient patients","volume":"84","author":"Gibney","year":"1999","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1203\/00006450-199903000-00005","article-title":"Possible protective role of growth hormone in hypoxia-ischemia in neonatal rats","volume":"45","author":"Gustafson","year":"1999","journal-title":"Pediatr. Res."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1515\/jpem-2000-s623","article-title":"A role for the somatotropic axis in neural development, injury and disease","volume":"13","author":"Scheepens","year":"2000","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/S0306-4522(01)00109-9","article-title":"Growth hormone as a neuronal rescue factor during recovery from CNS injury","volume":"104","author":"Scheepens","year":"2001","journal-title":"Neuroscience"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1126\/science.278.5337.419","article-title":"The endocrinology of aging","volume":"278","author":"Lamberts","year":"1997","journal-title":"Science."},{"key":"ref_119","first-page":"35","article-title":"Neurons, glia, and plasticity in normal brain aging","volume":"10","author":"Finch","year":"2002","journal-title":"Adv. Gerontol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/S0531-5565(02)00160-2","article-title":"The neurobiology of memory changes in normal aging","volume":"38","author":"Erickson","year":"2003","journal-title":"Exp. Gerontol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/S0531-5565(02)00159-6","article-title":"Effects of aging on the hippocampal formation in a naturally occurring animal model of mild cognitive impairment","volume":"38","author":"Gallagher","year":"2003","journal-title":"Exp. Gerontol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S0301-0082(02)00126-0","article-title":"Impact of aging on hippocampal function: Plasticity, network dynamics, and cognition","volume":"69","author":"Rosenzweig","year":"2003","journal-title":"Prog. Neurobiol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"2027","DOI":"10.1523\/JNEUROSCI.16-06-02027.1996","article-title":"Neurogenesis in the dentate gyrus of the adult rat: Age-related decrease of neuronal progenitor proliferation","volume":"16","author":"Kuhn","year":"1996","journal-title":"J. Neurosci."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/0165-3806(93)90008-X","article-title":"Localization and ontogeny of growth hormone receptor gene expression in the central nervous system","volume":"74","author":"Lobie","year":"1993","journal-title":"Dev. Brain Res."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"4384","DOI":"10.1210\/endo.137.10.8828499","article-title":"Growth hormone induces somatostatin and insulin-like growth factor I gene expression in the cerebral hemispheres of aging rats","volume":"137","author":"Velasco","year":"1996","journal-title":"Endocrinology"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1002\/jnr.490390202","article-title":"The insulin-like growth factor I system in the rat cerebellum: Developmental regulation and role in neuronal survival and differentiation","volume":"39","author":"Pons","year":"1994","journal-title":"J. Neurosci. Res."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1628","DOI":"10.1523\/JNEUROSCI.21-05-01628.2001","article-title":"Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus","volume":"21","author":"Trejo","year":"2001","journal-title":"J. Neurosci."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.neurobiolaging.2004.06.007","article-title":"Growth hormone prevents neuronal loss in the aged rat hippocampus","volume":"26","author":"Azcoitia","year":"2005","journal-title":"Neurobiol. Aging"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1515\/HMBCI.2011.115","article-title":"Effect of growth hormone and melatonin on the brain: From molecular mechanisms to structural changes","volume":"7","author":"Kireev","year":"2011","journal-title":"Horm. Mol. Biol. Clin. Investig."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1007\/s10522-013-9443-6","article-title":"Growth hormone and melatonin prevent age-related alteration in apoptosis processes in the dentate gyrus of male rats","volume":"14","author":"Kireev","year":"2013","journal-title":"Biogerontology"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1006\/exnr.1999.7107","article-title":"Vulnerability of the dentate gyrus to aging and intracerebroventricular administration of kainic acid","volume":"158","author":"Shetty","year":"1999","journal-title":"Exp. Neurol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/s00726-001-0134-2","article-title":"Repeated topical application of growth hormone attenuates blood-spinal cord barrier permeability and edema formation following spinal cord injury: An experimental study in the rat using evans blue, ([125])I-sodium and lanthanum tracers","volume":"23","author":"Nyberg","year":"2002","journal-title":"Amino Acids"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"4113","DOI":"10.1210\/en.2002-220261","article-title":"Growth hormone (GH) and GH-releasing peptide-6 increase brain insulin-like growth factor-I expression and activate intracellular signaling pathways involved in neuroprotection","volume":"143","author":"Frago","year":"2002","journal-title":"Endocrinology"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1002\/(SICI)1097-4547(19991215)58:6<815::AID-JNR8>3.0.CO;2-R","article-title":"Neuroprotective effects of estradiol in the adult rat hippocampus: Interaction with insulin-like growth factor-I signalling","volume":"58","author":"Azcoitia","year":"1999","journal-title":"J. Neurosci. Res."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"5678","DOI":"10.1523\/JNEUROSCI.21-15-05678.2001","article-title":"Circulating insulin-like growth factor I mediates the protective effects of physical exercise against brain insults of different etiology and anatomy","volume":"21","author":"Carro","year":"2001","journal-title":"J. Neurosci."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/S0092-8674(00)80405-5","article-title":"Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery","volume":"91","author":"Datta","year":"1997","journal-title":"Cell"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"30470","DOI":"10.3390\/ijms161226244","article-title":"Brain recovery after a plane crash: Treatment with growth hormone (GH) and neurorehabilitation: A case report","volume":"16","author":"Devesa","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_138","doi-asserted-by":"crossref","unstructured":"Devesa, J., Lema, H., Zas, E., Mun\u00edn, B., Taboada, P., and Devesa, P. (2016). Learning and memory recoveries in a young girl treated with growth hormone and neurorehabilitation. J. Clin. Med., 5.","DOI":"10.3390\/jcm5020014"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/14\/7848\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:52:00Z","timestamp":1760140320000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/14\/7848"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,16]]},"references-count":138,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["ijms23147848"],"URL":"https:\/\/doi.org\/10.3390\/ijms23147848","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,16]]}}}