Hypoglycemia and alpha cell regulation

项目摘要/摘要 了解胰腺细胞和局部控制胰升糖素分泌的细胞之间的相互作用 是本应用程序的重点。血糖水平主要由两种荷尔蒙控制，胰岛素，它 控制组织对葡萄糖的摄取和利用，抑制肝脏葡萄糖的产生，以及高血糖素， 它抵消了胰岛素对肝脏葡萄糖产生的抑制作用。糖尿病是一种双激素的疾病。 在胰岛素缺乏或胰岛素抵抗的情况下，细胞功能紊乱和受损会导致 高血糖是这种疾病的标志。1型糖尿病的主要临床后果是 胰升糖素分泌缺陷是胰岛素引起的低血糖，对低血糖的恐惧是限制 达到良好的血糖控制，从而预防高血糖的继发性并发症。 大量的临床证据表明，细胞功能改变导致的胰升糖素升高 到2型糖尿病的餐后高血糖。细胞分泌可抑制胰高血糖素的分泌 产品和旁分泌控制细胞功能，即胰岛内胰岛素假说，已有很好的文献记载。使用 我们已经证明，与胰岛素共分泌的锌离子可以抑制 低血糖时高血糖素的分泌，我们假设调节钙离子的KATP通道 信号转导可能是锌离子的靶标。高血糖也可能通过KATP抑制细胞分泌。 钙离子信号的通道依赖性作用。已知氨基酸通过两种途径刺激胰高血糖素的分泌 代谢和产生电的影响，但葡萄糖和氨基酸生理水平之间的相互作用是 目前尚不清楚，细胞内氨基酸转运体的特性尚不清楚。高血糖素的分泌是 被肾上腺素和去甲肾上腺素有效刺激，但局部控制细胞的相对重要性 功能与它们对下丘脑和其他中枢神经系统输入的反应(S)仍然存在争议。我们的具体目标 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通道在锌抑制胰高血糖素分泌中的作用。 确定细胞分泌产物、胰岛素、锌离子、GABA和 ATP，在抑制胰高血糖素的释放。 氨基酸刺激野生型胰升糖素释放的机制探讨 和Sur1KO胰岛，并确定所涉及的细胞转运体和/或通路。 用小鼠评价局部和中枢神经系统控制细胞功能的相对重要性 有针对性地删除细胞内的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.