The long range goal of this project is to contribute to our understanding of the role of the hormone glucagon in diabetes mellitus and in intracellular signaling in general. Our immediate goals are to design and synthesize peptide analogs that will be potent antagonists of the hormone, using as our principal tool, solid phase peptide synthesis. Such inhibitors are expected to aid in the studies of the mechanism of action of glucagon at the receptor level, and might provide a potentially therapeutic agent for the in vivo regulation of blood glucose in the management of diabetes. We are extending the scope of our research to include structure-function studies of the glucagon receptor itself using a synthetic glucagon receptor gene. Functional characterization of the receptor will yield invaluable information on hormone/receptor/ G-protein/effector interactions. A combination of synthetic chemical, biochemical, and molecular biological approaches is most likely to advance our understanding of pep tide hormone-mediated signal transduction and the control of diseases like diabetes mellitus.