My research program is divided into clinical investigation and basic research components. Clinical investigation approaches include studies aimed at identifying in vivo mechanisms underlying the pathogenesis of non-insulin dependent diabetes mellitus, obesity, and other disorders of insulin resistance. Studies are in progress to identify the relative role of each organ system (muscle, liver and fat) to the pathophysiology of NIDDM. In addition, a number of protocols are underway exploring new modes of therapy for established NIDDM as well as means of primary prevention for this disease. A major focus for the basic research program is to understand the molecular and cellular mechanisms of insulin and IGF-I action. An important emphasis is placed on understanding the structure/function relationship of the cognate receptors for these ligands. Approaches used include the use of site directed mutagenesis to modify the insulin and/or IGF-I receptor cDNAs followed by transfection of these modified cDNAs into host mammalian cells for biologic studies. Several functional domains of these receptor proteins have been identified which mediate the divergent and convergent signaling pathway of these two hormone receptor systems. For example, a domain of the insulin receptor has been identified which mediates the metabolic signaling properties of this receptor, whereas the other biologic effects of this receptor are intrinsic to other domains. The downstream signaling pathways of thee receptors are also under intensive investigation. These include studies of the mechanisms whereby insulin and IGF-I stimulate transcription of a series of early response genes and what are the signaling molecules which lie between the receptor and the DNA response elements which mediate these signaling pathways.