GH responses to GHRH and GHRP-6 in Streptozotocin (STZ)-diabetic rats.
GH responses to GHRH, the physiologic hypothalamic stimulus, and GHRP-6, a synthetic hexapeptide that binds the Ghrelin receptor, were studied in rats treated with streptozotocin (STZ), an experimental model of diabetes. Sprague-Dawley male rats received a single injection either of STZ (70 mg/Kg in 0.01 M SSC, i.p.) or of the vehicle (0.01 M SSC). GH responses were challenged with two different doses of GHRH (1 and 10 microg/kg) or GHRP-6 (3 and 30 microg/kg) and with a combination of both at low (1 + 3 microg/kg) or high (10 + 30 microg/kg) doses, respectively. We observed a dose-dependent effect for GH responses to GHRH both in STZ-treated rats and in controls. However, we could not find significant differences between STZ-rats and controls. GH responses to GHRP-6 occurred in a dose-dependent manner in STZ-rats, but not in controls. GH responses to GHRP-6 in both groups were clearly lower than those elicited by GHRH. GH responses to 30 microg/Kg of GHRP-6 were significantly greater in STZ-rats than in controls (AUC: 3549.9 +/- 1001.4 vs. 2046.4 +/- 711.7; p<0.05). The combined administration of GHRH plus GHRP-6 was the most potent stimuli for GH in both groups. The administration of doses in the lower range (1 + 3 microg/Kg, GHRH + GHRP-6 respectively) induced a great peak of GH in STZ-rats and in control rats, revealing a synergistic effect of GHRH and GHRP-6 in both groups. When the higher doses were administered (10 + 30 microg/kg), GH levels in time 5, and AUC were significantly higher in control rats. In addition, a negative correlation between WT (weight tendency) values and GH responses, represented as AUC, could be established in STZ-rats (r2=-0.566, p=0.004 for GHRH; r2=-0.412, p=0.028 for GHRP-6). Thus, the more negative the values of WT were, the more severe the metabolic alteration and, therefore, the higher the GH response to GHRH and GHRHP-6. In conclusion, our results do not support the existence of a functional hypothalamic hypertone of SS in diabetic rats, as GH responses were not usually reduced in STZ-rats, except when both secretagogues were administered together at the higher doses. Besides, GH responses to GHRH and GHRP-6 were inversely correlated with the severity of the metabolic alteration in STZ-rats, meaning that worse glycaemic control promoted higher GH secretion. These results resemble those found in humans, where GH responses to secretagogues are increased in type-1 diabetes and depend on hyperglycaemia, and are representative of not well-controlled insulin-dependent diabetic status.
Laboratoire Homéosthasie, Allostasie, Pathologie, Université Victor Ségalen, Bordeaux 2, Rué Léo Saignat, 146, 33.076- Bordeaux, France.
Yolanda
Y
Diz Chaves
Carlos
C
Spuch Calvar
Diégo
D
Pérez Tilve
Federico
F
Mallo Ferrer
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005951:Glucose Tolerance Test; D013006:Growth Hormone / Q000097:blood; D013007:Growth Hormone-Releasing Hormone / Q000008:administration & dosage / Q000627:therapeutic use*; D007275:Injections, Intravenous; D008297:Male; D009842:Oligopeptides / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
D009842:Oligopeptides; C041048:growth hormone releasing hexapeptide; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone