Glucose activates both KATP channel-dependent and KATP channel-independent signaling pathways in human islets

Insulin secretion by isolated islets of Langerhans from 19 human donors (9 women and 10 men) was studied in vitro to test the hypothesis that human islets contain both the K-ATP channel-dependent and the K-ATP channel-independent signaling pathways. The results demonstrated the presence of both of these major pathways of glucose signaling. Thus, insulin secretion was stimulated by high glucose concentrations, by the sulfonylurea tolbutamide, and by a depolarizing concentration of potassium chloride. Diazoxide, which activates the K-ATP channel, completely blocked the stimulation of release by glucose. Stimulation of insulin release by tolbutamide, which inhibits the K-ATP channel and depolarizes the beta-cell, and inhibition of glucose-stimulated release by diazoxide, which activates the channel and repolarizes the beta-cell, confirm the involvement of the K-ATP channel-dependent pathway in glucose signaling. The participation of the K-ATP channel-independent pathway in the stimulation of insulin release by glucose was demonstrated for the first time in human islets. This was done in two ways. The first method, in the presence of diazoxide, blocked the action of glucose on the K-ATP channel in combination with a depolarizing concentration of KCI to raise [Ca2+](i). Under these conditions, glucose stimulated insulin release. A second method to demonstrate the involvement of the K-ATP channel-independent pathway was to close the K-ATP channels with tolbutamide. Again, with no possibility of further action on the K-ATP channel, glucose stimulated insulin release. In a final series of experiments, glucose-stimulated insulin release was profoundly inhibited by somatostatin, clonidine, and prostaglandin E-2, but not by galanin.