THE MECHANISM OF ACTION OF A NEWLY DEVELOPED BLOOD GLUCOSE-LOWERING HORMONE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Introduction: The research program under the direction of Dr. Holz at New York University School of Medicine is one in which he has sought to identify and characterize novel therapeutic strategies that might be of use for the treatment of type 2 (adult-onset) diabetes mellitus. To this end, he has focused on ascertaining the blood glucose-lowering properties of an insulinotropic hormone that is currently under clinical investigation. This hormone is glucagon-like peptide-1-(7-36)-amide (GLP-1), a peptide secreted by enteroendocrine L-cells of the distal intestine, and which when administered to type 2 diabetic subjects, lowers blood glucose concentration. GLP-1: GLP-1 exhibits a number of important biological actions at the endocrine pancreas. Earlier on it was recognized that GLP-1 stimulates pancreatic beta-cell insulin gene transcription, translational biosynthesis of proinsulin, and glucose-dependent insulin secretion. What has recently become appreciated is that GLP-1 also exerts growth factor-like effects on beta-cells. For example, GLP-1 stimulates the proliferation of rodent beta-cells, thereby increasing their number substantially. This growth factor-like action has attracted attention because it suggests that GLP-1 might stimulate an increase of beta-cell mass not only in type 2 diabetic subjects, but perhaps in type 1 (juvenile-onset) diabetic subjects as well. The purpose of the research relating to this Sub Proposal concerns the action of GLP-1 to stimulate pancreatic insulin secretion. We intend to develop a method for following the modulation of beta-cell glucose metabolism by GLP. The Central Hypothesis presented here is that GLP-1 upregulates beta-cell glucose metabolism, thereby facilitating membrane depolarization and Ca2+ influx that initiates beta-cell insulin secretion. This action of GLP-1 might relate to its reported ability to stimulate mitochondrial ATP production, as reported by Rutter and co-workers (Biochem. J. 2003).