Impaired suppression of growth hormone release by somatostatin in cultured adenohypophyseal cells of spontaneously diabetic BB/W rats.
The effects of the diabetic state on the somatotroph's responsiveness to the secretagogues GRF and (Bu)2-cAMP and to the inhibitor somatostatin (SRIF) were evaluated in enzymatically dissociated rat adenohypophyseal cells in primary monolayer culture. Primary cultures were prepared from pituitary tissue of spontaneously diabetic BB/W rats 23-51 days after the onset of hyperglycemia and glycosuria and of age-matched diabetes-resistant control rats. Dose-related stimulation of GH release by GRF and (Bu)2cAMP did not differ significantly in the two preparations. There was no evidence of abnormal sensitivity to TRH in cultured somatotrophs of diabetic rats. Dose-related suppression of (Bu)2cAMP (0.5 mM)-stimulated GH release by 0.01-10 nM SRIF, on the other hand, was significantly affected by diabetes, as indicated by a parallel shift of the dose-response curve to the right and an increase in the IC50 value from 76 +/- 2 to 204 +/- 5 pM (mean +/- SEM; n = 3; P less than 0.001). Maximal suppression by 10 nM SRIF was identical in the two preparations. The degree to which the cultured cells' responsiveness to SRIF was reduced was unrelated to the duration and severity of the diabetic state. Hypothalamic SRIF content did not differ significantly between diabetic and diabetes-resistant rats (186 +/- 12 vs. 178 +/- 10 ng/mg protein). Nevertheless, the SRIF concentration may be elevated in hypophysealportal blood of diabetic rats; we, therefore, examined the effect of prolonged exposure of the cell cultures to SRIF or SMS 201-995 on the subsequent suppression of (Bu)2cAMP-stimulated GH release by SRIF. Addition of either SRIF (10 nM) or SMS 201-995 (5.5 nM) to the culture medium for 4 days significantly increased the IC50 values for SRIF to values similar to those obtained in cultured cells of diabetic rats. We conclude that the somatotrophs of diabetic rats are relatively resistant to SRIF. Since prolonged exposure to SRIF in vitro produced similar resistance, the desensitization in diabetic rats may be due to elevated concentrations of SRIF in hypophyseal-portal blood. This impaired responsiveness to SRIF may contribute to aberrant GH secretion in diabetes.
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D013006:Growth Hormone / Q000378:metabolism*; D013007:Growth Hormone-Releasing Hormone / Q000494:pharmacology; D007031:Hypothalamus / Q000378:metabolism; D008297:Male; D015282:Octreotide / Q000494:pharmacology; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011913:Rats, Inbred BB; D011919:Rats, Inbred Strains; D013004:Somatostatin / Q000494:pharmacology*
D013004:Somatostatin; D003994:Bucladesine; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone; D015282:Octreotide