DESCRIPTION (taken from the application) The long term goal of this research is to define the roles of MAP kinase cascades in the regulation and function of insulin-secreting cells. MAP kinase have provided a focal point for rapid advances in understanding of intracellular signal transduction. In the insulinoma cell line INS-1, a model system for glucose regulated insulin secretion, as well as in rat islets, the MAP kinases ERK1 and ERK2 are activated by glucose and agents that induce and potentiate insulin secretion. In the presence of glucose, ERKs are translocate to nuclei of INS-1 cells. Norther blot and reporter assays using a construct containing the rat insulin gene promoter suggest that ERK activity is required for glucose-dependent insulin transcription. An elevation of circulating free fatty acids often precedes the onset of non-insulin transcription. An elevation of circulating free fatty acids often precedes the onset of non-insulin-dependent diabetes and may be involved in the development of insulin resistances. Long term exposure of INS-1 cells to free fatty acids caused a marked increase in ERK activity, as much as 10-fold after 7 days. Thus, our goals are to define the mechanisms use by ERKs to regulate insulin transcription, to assess their importance relative to other mechanisms that regulate insulin transcription, and to define the relationship between RK activity and the actions of elevated fatty acids on beta cells. The stress-responsive MAP kinase pathways, containing p38 MAP kinases and c-Jun-N-terminal kinase/stress-activated protein kinases (JNK/SAPKs), have been implicated in the actions of cytokines and other agents that induce inflammatory responses. These pathways may be involved in the normal and impaired functions of islets. Given the effects of ERKs on transcription, our goals are to determine if activation of the stress-sensitive MAP kinase pathways by glucose, cytokines, and other stimuli alter the biosynthesis of insulin.