The long-term objective of this project is understand what happens to pancreatic islet cells in diabetes, with particular emphasis upon beta cells. All forms of human and experimental diabetes are characterized by a severe impairment of glucose-induced insulin secretion. Attention has previously focused upon the hypothesis that this is secondary to the deleterious influence of chronic hyperglycemia. The work has now shifted to the molecular basis of this defect.
The first aim of this proposal is to use a new model system to clarify the pathways of glucose metabolism responsible for glucose-induced insulin secretion. Studies will be done on transplanted islets exposed to chronic hyperglycemia by partial pancreatectomy. The beta cell glucose transporter GLUT2 will be examined by immunofluorescence, Western blotting, and determination of mRNA. These results will be correlated with insulin secretion patterns, measurements of glucose transport, and assessment of glucose metabolism via both utilization and oxidation pathways.
The second aim i s to examine beta cell birth and death in diabetes and transplantation. Studies have shown that beta cells have a considerably faster replication rate than has generally been appreciated. By measuring beta cell birth rate (BrdU incorporation), beta cell mass (quantitative morphometry), and beta cell size (electron microscopy), the rate of death can be quantified in transplanted islet tissue and diabetic states. Efforts will also be made to identify and characterize senescent beta cells. Finally, the birth of new beta cells from ducts has been found to be an important pathway, even in adult rats. Studies are designed to define the potential of this pathway in diabetic states. Diabetes and islet transplantation failure result from a deficiency in the maintenance of appropriate beta cell mass; therefore it is essential that more is learned about the birth and death of beta cells.
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