Grant: $218,750 - National Institutes of Health - Sep. 25, 2009
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Award Description: Understanding the interplay between pancreatic á- and â-cells that exerts local control on glucagon secretion is the focus of this application. Blood glucose levels are controlled primarily by two hormones, insulin, which governs tissue uptake and utilization of glucose and inhibits glucose production by the liver, and glucagon, which counteracts the inhibitory action of insulin on hepatic glucose production. Diabetes is a bi-hormonal disorder and impaired á-cell function, in the context of insulin deficiency or insulin resistance, contributes to the hyperglycemia that is the hallmark of the disease. In type 1 diabetes, the major clinical consequence of defective glucagon secretion is insulin-induced hypoglycemia and fear of hypoglycemia is the main limitation to achieving good glycemic control and thus preventing the secondary complications of hyperglycemia. Considerable clinical evidence shows that elevated glucagon, secondary to altered á-cell function, contributes to postprandial hyperglycemia in type 2 diabetes. Glucagon secretion can be suppressed by â-cell secretory products and paracrine control of á-cell function, the intra-islet insulin hypothesis, is well documented. Using a high-to-low glucose switch-off protocol we have shown that Zn2+, co-secreted with insulin, can suppress glucagon secretion during hypoglycemia and we have hypothesized that KATP channels that modulate Ca2+ signaling may be a target for Zn2+. Hyperglycemia can also suppress á-cell secretion potentially via a KATP channel dependent action on Ca2+ signaling. Glucagon secretion is potently stimulated by epinephrine and norepinephrine, but the relative importance of local control of á-cell function vs their response(s) to hypothalamic and other CNS inputs remains controversial. Our specific aims are to: Specific Aim #1. Evaluate the role of KATP channels in the suppression of glucagon secretion by Zn2+. Specific Aim #2. Determine the relative importance of â-cell secretory products, insulin, Zn2+, GABA and ATP, in the suppression of glucagon release. Specific Aim #3. Evaluate the relative importance of local vs CNS control of á-cell function using mice with targeted
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This award's data was last updated on Sep. 25, 2009. Help expand these official descriptions using the wiki below.