CHOLECYSTOKININ AND SOMATOSTATIN MODULATE THE GLUCOSE-INDUCED INSULIN-SECRETION BY DIFFERENT MECHANISMS IN PANCREATIC-ISLETS - A STUDY ON PHOSPHOLIPASE-C ACTIVITY AND CALCIUM REQUIREMENT

To study the interaction between the phospholipase C activation and th e insulin secretion, isolated pancreatic islets were stimulated with g lucose and the sulfated cholecystokinin octapeptide (CCK). To discrimi nate between intracellular mechanisms, experiments with agents inhibit ing adenylyl cyclase and calcium-channels like somatostatin and verapa mil, were performed. The phospholipase C activity, i.e. the accumulati on of inositol phosphates, was increased by CCK (100 nmol l-1) at 3.3 mmol l-1 glucose. This effect of CCK did not require extracellular Ca2 +, was not inhibited by somatostatin (100 nmol l-1), and no concomitan t increase in the insulin secretion was observed. Both the phospholipa se C activity and the insulin secretion increased in response to 12 mm ol l-1 glucose. Somatostatin was able in some extent to inhibit these effects of glucose. At 12 mmol l-1 glucose, the phospholipase C activi ty and the insulin secretion were potentiated by CCK. CCK also counter acted the effect of somatostatin on the phospholipase C activity and t he insulin secretion. Verapamil (2.5 umol l-1) more or less completely inhibited both the glucose-induced phospholipase C activity and the i nsulin secretion. Moreover, whereas the CCK-induced increase in the ph ospholipase C activity was unaffected, verapamil blocked the CCK-induc ed increase in the insulin secretion. We conclude that CCK directly ac tivates phospholipase C, whereas glucose and somatostatin modulates ph ospholipase C via a Ca2+-dependent mechanism. CCK potentiates the insu lin secretion by increased phospholipase C activity, but with a requir ement of glucose at an apparent threshold level of Ca2+-influx.