The mechanisms of insulin release in normal and diabetic pancreas are investigated. The main regulator of insulin release, glucose, seems to act through two independent mechanisms on the B cell: 1-Cyclic AMP dependent, acute initiation of insulin release. The acute effect of glucose, and of other insulin releasers, is in our hands obligatorily accompanied by stimulation of islet cyclic AMP levels. In islets from diabetic animals this effect of glucose is lost, although limited data indicate that other cyclic AMP stimulators may still be active in such islets. Work is planned to investigate systematically under which conditions the cyclic AMP response to glucose is lost while it is maintained to methylanthins, cholera toxin, barium, sulfonylureas, etc. This may lead to the recognition of the coupler of the glucose effect on adenylate cyclase, and hence of the basic deficiency in (maturity-onset) diabetes. 2-Time-dependent potentiation. This effect of glucose builds up a memory in the islet that, on later stimulation, enhances the efficiency of cyclic AMP to release insulin. Work is planned to investigate whether protein synthesis, or accumulation of high energy products in the B cell, or changes in the redox state are responsible for the memory. It seems to be intact in diabetes; this will be investigated systematically. Also the effect of dietary manipulations and obesity on this memory will be studied. Finally, the population studies are performed in order to characterize subjects with low insulin response and follow them (glucose tolerance) over prolonged periods.