Hypoglycemia and alpha cell regulation

项目总结/摘要 了解对胰高血糖素分泌施加局部控制的胰腺<$-和<$-细胞之间的相互作用 是这个应用程序的重点。血糖水平主要由两种激素控制，胰岛素， 控制葡萄糖的组织摄取和利用并抑制肝脏产生葡萄糖，胰高血糖素， 其抵消胰岛素对肝葡萄糖产生的抑制作用。糖尿病是一种双激素 在胰岛素缺乏或胰岛素抵抗的情况下，胰岛素分泌紊乱和细胞功能受损， 高血糖是这种疾病的标志。在1型糖尿病中， 胰高血糖素分泌缺陷是胰岛素诱导的低血糖症，对低血糖症的恐惧是 实现良好的血糖控制，从而防止高血糖症的继发并发症。 大量临床证据表明，继发于细胞功能改变的胰高血糖素升高， 2型糖尿病患者的餐后高血糖。胰高血糖素分泌可被胰高血糖素分泌抑制。 产物和旁分泌控制胰岛细胞功能，胰岛内胰岛素假说，是有据可查的。使用 我们已经表明，与胰岛素共分泌Zn 2+可以抑制 低血糖时胰高血糖素分泌，我们假设调节Ca 2+的KATP通道 信号传导可以是Zn 2+的靶。高血压还可能通过KATP抑制β-细胞分泌 对Ca 2+信号传导的通道依赖性作用。已知氨基酸通过两种途径刺激胰高血糖素分泌 代谢和产电效应，但葡萄糖和氨基酸的生理水平之间的相互作用是 还没有很好地理解，并且在细胞中氨基酸转运蛋白的身份是基本的。胰高血糖素分泌是 强有力地刺激肾上腺素和去甲肾上腺素，但相对重要的是局部控制的<$-细胞 功能与其对下丘脑和其他CNS输入的反应仍然存在争议。我们的具体目标 是： 具体目标#1。 具体目标#2。 具体目标#3 具体目标#4 评价KATP通道在Zn 2+抑制胰高血糖素分泌中的作用。 确定细胞分泌产物、胰岛素、Zn 2+、GABA和 ATP，抑制胰高血糖素释放。 确定氨基酸刺激野生型胰高血糖素释放的机制 和Sur 1 KO胰岛，并确定涉及的细胞转运蛋白和/或途径。 使用小鼠评价局部与中枢神经系统对细胞功能控制的相对重要性 有针对性地删除细胞KATP通道。

Project Summary/Abstract Understanding the interplay between pancreatic ¿- and ¿-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 ¿-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 ¿-cell function, contributes to postprandial hyperglycemia in type 2 diabetes. Glucagon secretion can be suppressed by ¿-cell secretory products and paracrine control of ¿-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 ¿-cell secretion potentially via a KATP channel dependent action on Ca2+ signaling. Amino acids are known to stimulate glucagon secretion via both metabolic and electrogenic effects, but the interplay between glucose and physiologic levels of amino acids is not well understood and the identity of amino acid transporters in ¿-cells is rudimentary. Glucagon secretion is potently stimulated by epinephrine and norepinephrine, but the relative importance of local control of ¿-cell function vs their response(s) to hypothalamic and other CNS inputs remains controversial. Our specific aims are to: Specific Aim #1. Specific Aim #2. Specific Aim #3. Specific Aim #4. Evaluate the role of KATP channels in the suppression of glucagon secretion by Zn2+. Determine the relative importance of ¿-cell secretory products, insulin, Zn2+, GABA and ATP, in the suppression of glucagon release. Determine the mechanism of amino acid stimulation of glucagon release from wild-type and Sur1KO islets and identify the ¿-cell transporters and/or pathways involved. Evaluate the relative importance of local vs CNS control of ¿-cell function using mice with targeted deletion of ¿-cell KATP channels.