title: Insulin and growth hormone-releasing peptide-6 (GHRP-6) have differential beneficial effects on cell turnover in the pituitary, hypothalamus and cerebellum of streptozotocin (STZ)-induced diabetic rats.
abstract: Poorly controlled type1 diabetes is associated with hormonal imbalances and increased cell death in different tissues, including the pituitary, hypothalamus and cerebellum. In the pituitary, lactotrophs are the cell population with the greatest increase in cell death, whereas in the hypothalamus and cerebellum astrocytes are most highly affected. Insulin treatment can delay, but does not prevent, diabetic complications. As ghrelin and growth hormone (GH) secretagogues are reported to prevent apoptosis in different tissues, and to modulate glucose homeostasis, a combined hormonal treatment may be beneficial. Hence, we analyzed the effect of insulin and GH-releasing peptide 6 (GHRP-6) on diabetes-induced apoptosis in the pituitary, hypothalamus and cerebellum of diabetic rats. Adult male Wistar rats were made diabetic by streptozotocin injection (65 mg/kg ip) and divided into four groups from diabetes onset: those receiving a daily sc injection of saline (1 ml/kg/day), GHRP-6 (150 μg/kg/day), insulin (1-8U/day) or insulin plus GHRP-6 for 8 weeks. Control non-diabetic rats received saline (1 ml/kg/day). Diabetes increased cell death in the pituitary, hypothalamus and cerebellum (P<0.05). In the pituitary, insulin treatment prevented diabetes-induced apoptosis (P<0.01), as well as the decline in prolactin and GH mRNA levels (P<0.05). In the hypothalamus, neither insulin nor GHRP-6 decreased diabetes-induced cell death. However, the combined treatment of insulin+GHRP-6 prevented the diabetes induced-decrease in glial fibrillary acidic protein (GFAP) levels (P<0.05). In the cerebellum, although insulin treatment increased GFAP levels (P<0.01), only the combined treatment of insulin+ GHRP-6 decreased diabetes-induced apoptosis (P<0.05). In conclusion, insulin and GHRP-6 exert tissue specific effects in STZ-diabetic rats and act synergistically on some processes. Indeed, insulin treatment does not seem to be effective on preventing some of the diabetes-induced alterations in the central nervous system.
authors.affiliation: Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Granado
authors.forename: Cristina
authors.initials: C
authors.lastname: García-Cáceres
authors.forename: María
authors.initials: M
authors.lastname: Tuda
authors.forename: Laura M
authors.initials: LM
authors.lastname: Frago
authors.forename: Julie A
authors.initials: JA
authors.lastname: Chowen
authors.forename: Jesús
authors.initials: J
authors.lastname: Argente
mesh_terms: D000818:Animals; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D050884:HSP72 Heat-Shock Proteins / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism / Q000473:pathology*; D007328:Insulin / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology*; D010902:Pituitary Gland / Q000378:metabolism / Q000473:pathology*; D010907:Pituitary Hormones / Q000235:genetics / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D054440:Receptors, Ghrelin / Q000235:genetics / Q000378:metabolism; D013311:Streptozocin; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; D050884:HSP72 Heat-Shock Proteins; D007328:Insulin; D009842:Oligopeptides; D010907:Pituitary Hormones; D018809:Proliferating Cell Nuclear Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D054440:Receptors, Ghrelin; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; C548904:insulin-like growth factor-1, rat; C041048:growth hormone releasing hexapeptide; D013311:Streptozocin; D007334:Insulin-Like Growth Factor I; D011972:Receptor, Insulin; D020169:Caspases