The broad objective of this project is to contribute towards the elucidation of the biochemistry and physiology of the hormone-secreting alpha and beta cells of the islets of Langerhans, with particular emphasis on the mechanism of control of insulin and glucagon secretion. We have been using the toadfish in our studies since in this species, in contrast to mammals, the islet of Langerhans is segregated into a discrete mass separate from the pancreatic acinar tissue. We are studying the uptake and metabolism of different substrates by the islet and the effect of various agents on hormone release from islet cells in vitro and from isolated secretion granules, particularly with a view towards clarifying the role of the pyridine nucleotides and sulfhydryl (SH) groups in hormone release. We have also been studying the mechanism of the diabetogenic action of alloxan in the belief that understanding the basis of the selectivity of alloxan for the beta cells may provide significant information on the unique properties of these cells which enable them to carry out their specific functions. Our evidence indicates that alloxan increases the permeability of islet tissue by reacting with essential SH groups at or near the sugar transport site in the beta cell membrane, and that its selectivity for the beta cells arises, at least partly, from differences in the SH groups in different cell membranes. Therefore, we are attempting to define the exact nature of these groups and their differences in different cells, and to isolate and characterize the cell membrane unit with which alloxan reacts. BIBLIOGRAPHIC REFERENCES: Watkins, D. and Cooperstein, S.J. Effect of Alloxan on Islet Tissue Permeability: Protection and Reversal by Dithiols. J. Pharmacol. Exptl. Therapeutics 199: 575-582 (1976). Watkins, D. and Daly, S. Effect of Sulfhydryl-Binding Reagents on Glucagon Release from Isolated Secretion Granules. Diabetes 25: 389 (1976) (Abstract).