AMYLIN (ISLET AMYLOID POLYPEPTIDE) INHIBITION OF INSULIN RELEASE IN THE PERFUSED RAT PANCREAS - IMPLICATION OF THE ADENYLATE-CYCLASE CAMP SYSTEM

Amylin inhibits glucose-induced insulin secretion in the rat pancreas. To study the mechanism by which amylin acts on the B-cell, we have in vestigated, in the perfused rat pancreas, the effect of synthetic rat amylin (75 pM) on insulin release elicited by secretagogues acting on the B-cell via the adenylate cyclase/cAMP system, i.e., glucagon (10 n M), gastric inhibitory polypeptide (GIP, 1 nM), forskolin (1 muM) and isobutylmethylxanthine (IBMX, 75 muM). In addition, we examined the ef fect of amylin on GIP-induced insulin release in pancreata from rats p retreated with pertussis toxin, an agent which inactivates certain Gi proteins coupled to adenylate cyclase. Amylin inhibited the insulin re sponse to glucagon (approx. 70%), GIP (approx. 90%), IBMX (approx. 75% ) as well as the early phase of forskolin-induced insulin output (appr ox. 74%). However, amylin failed to modify GIP-induced insulin release in pancreata obtained from pertussis toxin pretreated rats. These res ults would indicate that the inhibitory effect of amylin on insulin se cretion could be, at least in part, attributed to its interfering with the adenylate cyclase/cAMP system. Furthermore, prevention of the inh ibitory effect of amylin on GIP-induced insulin output by pertussis to xin pretreatment, supports the concept that amylin can inhibit insulin release via a pertussis toxin-sensitive Gi protein coupled to the ade nylate cyclase system.