The somatostatin subtype-2 receptor antagonist, BIM-23627, improves the catabolic effects induced by long-term glucocorticoid treatment in the rat.
BIM-23627 is a synthetic peptide with "in vitro" and "in vivo" properties consistent with a pure sst2 antagonist. The aim of the present study was to evaluate the effects of long-term administration of BIM-23627 and the combined effects of BIM-23627 and dexamethasone (DEX) on the somatotropic axis, including growth, epididymal fat accumulation, glucose homeostasis and insulin activity, in young male rats. Beginning on day 23 of age, 16 animals were treated daily with saline or DEX (40 microg/kg/daily). Each group was subdivided into two paired groups and treated with either vehicle or BIM-23627 (0.5 mg/kg, t.i.d.). The treatment period lasted 31 days. The animals were killed by decapitation; trunk blood and pituitaries were collected for the determination of hormone concentrations and GH mRNA expression, respectively. Based on plasma GH and IGF-I concentrations and GH mRNA expression in the pituitary, BIM-23627 was able to counteract the inhibitory effects of DEX on the somatotropic axis; however, only a partial reversal of somatic growth inhibition was observed. DEX-treated rats remained euglycemic, but their insulin levels were significantly increased, indicating an incipient insulin resistance. Although BIM-23627 itself tended to increase insulin concentration in saline-treated rats, its administration to DEX-treated rats reduced insulin levels (saline: 25+/-3; DEX: 55+/-16*; DEX+BIM-23627: 34+/-5; BIM-23627: 38+/-7 microIU/ml; *P<0.05 vs. saline), apparently improving the degree of insulin sensitivity. DEX administration significantly reduced circulating ghrelin, whereas the sst2 antagonist had no significant effect. An inverse correlation was found between ghrelin concentrations and plasma insulin levels. Both rats receiving DEX and rats receiving BIM-23627 had decreased plasma concentration of total testosterone (P<0.05); however, the effects of DEX and BIM-23627 were not additive. In conclusion, BIM-23627 may represent a new pharmacological agent to reduce the suppression of the GH-IGF-I axis in long-term GC treated patients and enhance insulin sensitivity. Further studies are required in order to fully optimize the SSTR-2 antagonist-induced reversal of DEX-induced somatic growth inhibition.
Tulipano
Giovanni
G
Department of Biomedical Sciences and Biotechnology, University of Brescia, Italy.
Rossi
Elena
E
Culler
Michael D
MD
Taylor
John E
JE
Bonadonna
Stefania
S
Locatelli
Vittorio
V
Cocchi
Daniela
D
Giustina
Andrea
A
D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005247:Feeding Behavior; D054439:Ghrelin; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D013006:Growth Hormone / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D036361:Peptide Hormones / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D010902:Pituitary Gland / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
C452813:BIM 23627; D054439:Ghrelin; D005938:Glucocorticoids; D007328:Insulin; D036361:Peptide Hormones; D010455:Peptides; D012333:RNA, Messenger; D017481:Receptors, Somatostatin; C106140:somatostatin receptor sst2A; D012313:RNA; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone; C094573:somatostatin receptor 5; D013006:Growth Hormone; D005947:Glucose