This research program is an attack on certain basic questions of the physiology and pathology of pancreatic islets through direct analysis of pure islet tissues: What are the metabolic events taking place in endocrine cells during increased secretory activity? And what goes wrong in alpha and beta cells at the biochemical level during development of experimental or genetic diabetes? An attempt to tackle these problems is made by the combined use of several approaches: 1) evaluation of the islets hormone releasing function in various nutritional, pharmacological and pathological states by analysis of insulin and glucagon release in vivo, with the isolated perfused pancreas and with isolated perifused or batch incubated islets in vitro; 2) characterization of the electrical response of beta cells in isolated islets or in monolayer tissue cultures; 3) investigation of the factors that control the metabolism of the major calorigenic fuels. The methodology to tackle these major problems has been developed or adapted in our laboratory. Of particular chemical analytical importance are highly refined enzymatic fluorometric, GLC masspectrometric or radiometric chemical and immunochemical micromethods for measuring enzyme activities and metabolites or cofactor levels as indicators of biochemical mechanisms. Equally significant methodologically are the methods allowing continuous monitoring of hormone releasing function of islet cells. It is believed that this broad approach will continue to provide insight into a) the complex interrelationships between intermediary metabolism of pancreatic islets and hormone release and b) the derrangement of these relationships in disease.