Reports of the effects of amylin and amylin agonists on insulin secretion have varied widely. Some confusion can be attributed to the use of human amylin, which has been shown to readily fall out of solution resulting in low estimates of bioactivity. Some confusion can be resolved by assessing the probability that this had happened. The view taken here, supported by authors using reliable and well-characterized ligands (representing the preponderance of recent studies), is that exogenously administered amylin agonists inhibit insulin secretion, at least partly via activation of an amylin-like receptor linked to Gi-mediated inhibition of cAMP in islets. There may additionally be autonomic extrapancreatic effects of amylin on insulin secretion that derive from its action at the area postrema. Studies with amylin receptor antagonists, including human studies, indicate that endogenously secreted amylin may physiologically inhibit beta-cell secretion (insulin and amylin) via feedback inhibition that is characteristic of many other hormones. Part of this inhibition may be local (paracrine), as indicated by the amylin sensitivity of isolated preparations and the fact that the concentration of secreted products in the islet interstitium can be over 100-fold higher than in the circulation (Bendayan, 1993).