Interrelationship among insulin,glucagon and somatostatin secretory responses to exendin-4 in the perfused rat pancreas

We have investigated the effect of exendin-4 on insulin, glucagon and somatostatin output in the perfused rat pancreas. At 9 mM glucose, exendin-4 potentiated the insulin and somatostatin responses to arginine and reduced the glucagon response to this amino acid. Thus, this reduction might be thought to be paracrine-mediated through the concomitant increase in insulin and somatostatin concentrations. At 3.2 mM glucose, exendin-4 did not affect insulin secretion, reduced glucagon release and stimulated somatostatin output. Furthermore, exendin-4 reduced glucagon secretion as induced by a glucose decline (from 11 to 3.2 mM) without affecting insulin or somatostatin responses. In summary, exendin-4 stimulated insulin and somatostatin secretion and reduced glucagon release. The glucagonostatic effect of exendin-4 was observed under conditions in which insulin and somatostatin were not affected, thus indicating that exendin-4, per se, inhibits A-cell secretion. Indeed, an additional glucagonostatic effect of exendin-4, mediated by its stimulation of insulin and/or somatostatin secretion, cannot be ruled out.