Hypothalamic Mediation of Reduced GH Secretion in Diabetic Rats: Evidence for Reduced Cholinergic Inhibition of Somatostatin Release

The Goto-Kaklzakl (GK) rat is a new model of dlabetes mellltus and In thls study we have characterized the dlabetlc and growth hormone (GH) secretory status of male GK rats at 6 and 16 weeks of age. We have also lnvestlgated the role of endogenous somatostatln (SS) and chollnerglc nian~pulation on the GH responses to GH-releas~ng hormone (GHRH) GK rats were non-obese wlth slgnlflcant fastlng hyperglycaeni~a. hyperlnsullnaem~a and absent lnsulln responses to IV glucose. The GH response to GHRH was reduced at 16 weeks compared with normal, age-matched Wlstar rats but no d~fferences were observed at 6 weeks. Pretreatment of older rats (16 weeks) wlth antl-somatostatin antlbodles (SS-Ab) slgnlflcantly Increased GH responses to GHRH In both normal and GK groups Chollnerglc augmenta-tlon wlth pyrldostlgmlne (PD) reversed the blunted GH responses to GHRH ~n older GK rats but had no effect In the normal or young (6 weeks) GK rats. These results lndlcate that SS release medlates the blunted GH response to GHRH In GK rats and that reduced hypothalamlc chollnerglc slgnalllng to the somatostatlnerglc neurone may mediate the Increase In SS release. Thls vlew IS supported by the results from rn v~tro studles In whlch cholinerglc muscarlnlc blockade wlth plrenzeplne (PIR) caused dose-related stlmulatlon of SS release from normal rat hypothalaml but was wlthout effect on GK rat hypothalanii. The cause of thls alteration In hypothalamlc functlon IS, at present, unknown G r o n th hormone ( G H ) regulatory mechanisms are p ro found l~ altered in d~abetes mellitus in both animals and humans bu