The overall hypotheses being tested in these studies of glucagon biosynthesis and metabolism is that the regulation of the expression of the glucagon gene is critically important during the switch from fasting (catabolic to the fed (anabolic) state. The glucagon gene is expressed in both the pancreas and the intestine. Remarkably, by mechanisms of alternative post-translational processing of proglucagon, the pancreas produces the bioactive peptide glucagon, the anti-insulin hormone important in the fasting state to maintain blood glucose levels. In intestine the bioactive hormone produced is glucagon-like peptide-I (GLP- I), a newly discovered incretin peptide that has potent insulinotropic actions. It is proposed that: 1) During fasting glucagon gene expression is tonically elevated due to the low insulin and relatively low glucose levels and high neuroadrenergic inputs likely mediated by cAMP-dependent signalling pathways. 2) Oral nutrients induce intestinal L-cells to release the insulinotropic hormone GLP-I that activates specific cAMP- coupled receptors on pancreatic B-cells and, synergetically with glucose, stimulates insulin release and production. 3) Insulin release from B- cells directly inhibits the secretion of glucagon from the pancreatic A- cells through the interactions of an insulin-sensitive DNA-binding protein with an enhanson located within the G3 enhancer element of the glucagon promoter. Thus the expression of the glucagon gene serves two purposes in the switch from a catabolic to an anabolic state. GLP-I helps turn on the release and production of the anabolic hormone insulin and helps turn off the release and production of the catabolic hormone glucagon. We propose to continue our long-term investigations of the mechanisms involved in the transcriptional expression of the glucagon gene. We specifically propose to: a) clone and examine the structural and functional properties of the G3 enhancer binding protein involved in the insulin response; b) investigate the CREB-associated proteins (CAPs) that modulate cAMP-responsive transcription mediated through the cAMP- response element. Further, we plan to investigate the regulation of expression of the GLP-I receptor gene and the mechanism of action of GLP- I on the stimulation of insulin secretion. Specifically, we plan to clone the GLP receptor and to: a) examine the expression of the gene at the RNA and protein levels in pancreas and extrapancreatic tissues. In particular, to determine whether the expression of the gene is down- regulated of dys-regulated in animal models with NIDDM. (b) to characterize the cis-acting enhancer elements and DNA-binding proteins that are involved in the tissue type specific expression of the receptor gene. c) determine the hierarchy of actions of GLP-related peptides in mediating the actions of GLP-I as it pertains to binding affinities and activation of the cAMP-dependent signal transduction pathway. The importance of hormones encoded in the glucagon gene in the maintenance of glucose homeostasis, and their potential relevance to the pathogenesis of non-insulin dependent diabetes mellitus, provides compelling interest in learning more about the controlling factors involved in the expression of the gene.

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Physiological Chemistry Study Section (PC)
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Massachusetts General Hospital
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