HYPOTHALAMIC MEDIATION OF REDUCED GH SECRETION IN DIABETIC RATS - EVIDENCE FOR REDUCED CHOLINERGIC INHIBITION OF SOMATOSTATIN RELEASE

The Goto-Kakizaki (GK) rat is a new model of diabetes mellitus and in this study we have characterized the diabetic and growth hormone (GH) secretory status of male GK rats at 6 and 16 weeks of age. We have als o investigated the role of endogenous somatostatin (SS) and cholinergi c manipulation on the GH responses to GH-releasing hormone (GHRH). GK rats were non-obese with significant fasting hyperglycaemia, hyperinsu linaemia and absent insulin responses to IV glucose, The GH response t o GHRH was reduced at 16 weeks compared with normal, age-matched Wista r rats but no differences were observed at 6 weeks, Pretreatment of ol der rats (16 weeks) with anti-somatostatin antibodies (SS-Ab) signific antly increased GH responses to GHRH in both normal and GK groups, Cho linergic augmentation with pyridostigmine (PD) reversed the blunted GH responses to GHRH in older GK rats but had no effect in the normal or young (6 weeks) GK rats, These results indicate that SS release media tes the blunted GH response to GHRH in GK rats and that reduced hypoth alamic cholinergic signalling to the somatostatinergic neurone may med iate the increase in SS release, This view is supported by the results from in vitro studies in which cholinergic muscarinic blockade with p irenzepine (PIR) caused dose-related stimulation of SS release from no rmal rat hypothalami but was without effect on GK rat hypothalami. The cause of this alteration in hypothalamic function is, at present, unk nown.