Glucose is the primary regulator of insulin secretion. In type II diabetes, this regulatory system is disrupted resulting in insufficient insulin secretion. The long-term goals of this project are to reveal the mechanisms used by pancreatic beta cells to sense ambient glucose levels and to identify defects which may produce diabetes. The immediate aims of this project are to evaluate the unique, low affinity glucose phosphorylation and glucose transport systems of pancreatic islet cells. The low affinity phosphorylation of glucose catalyzed by the enzyme glucokinase was suggested more than ten years ago to regulate glucose metabolism and glucose stimulated insulin secretion in pancreatic beta cells. To test this hypothesis the glucose phosphorylating enzymes will be increased in beta cells to determine whether the response of the beta cell has been sensitized to glucose. Transgenic mice will be used for these studies because they provide an excellent model of normal islet cell function and they allow modifications to be made in gene expression of specific cell types. Glucose transport has also been implicated in pancreatic beta cell glucose sensing because several rodent models of diabetes demonstrates defective beta cell glucose transport. This finding has led to the suggestion that regulation of beta cell activity by glucose may be a function of the low affinity, beta cell glucose transporter acting in conjunction with beta cell glucokinase. To evaluate this hypothesis glucose transport activity will be enhanced in beta cells of transgenic mice and the predicted potentiating effect on insulin secretion will be determined.
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