Hypoglycemia and alpha cell regulation

低血糖和α细胞调节

• 批准号: 7922789
• 负责人: Joseph Bryan
• 金额: $ 21.88万
• 依托单位: PACIFIC NORTHWEST RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7922789
• 关键词: Address; Affect; Alpha Cell; Amino Acid Transporter; Amino Acids; Biological Assay; Blindness; Blood Glucose; Cell membrane; Cell physiology; Cell secretion; Cells; Clinical; Complications of Diabetes Mellitus; Data; Dependence; Detection; Diabetes Mellitus; Disease; Electrophysiology (science); Epinephrine; Equilibrium; Erectile dysfunction; Exocytosis; Failure; Fibrinogen; Fright; GCG gene; GNAI2 gene; Glucagon; Glucose; Hepatic; Hormonal; Hormones; Human; Hyperglycemia; Hypoglycemia; Hypothalamic structure; In Vitro; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Ion Channel; Islet Cell; Joints; Kidney Diseases; Laboratories; Liver; Measurement; Mediating; Mediator of activation protein; Membrane; Membrane Potentials; Metabolic; Metabolic Pathway; Metabolism; Modeling; Mus; Nerve; Neurosecretory Systems; Non-Insulin-Dependent Diabetes Mellitus; Norepinephrine; Pancreas; Paracrine Communication; Pathway interactions; Physiological; Physiology; Plasma; Play; Potassium Channel; Process; Proteins; Protocols documentation; Public Health; Purinoceptor; Rattus; Regulation; Relative (related person); Reporting; Rodent; Role; Secondary to; Secretory Cell; Signal Transduction; Simulate; Streptozocin; Stroke; Testing; Therapeutic; Tissues; Wild Type Mouse; Work; abstracting; blood glucose regulation; falls; gamma-Aminobutyric Acid; ghrelin; glucose metabolism; glucose production; glycemic control; heart disease risk; in vivo; insight; islet; mouse model; paracrine; prevent; receptor; research study; response; uptake; voltage

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.

项目摘要/摘要 了解胰腺 - 和®之间的相互作用，以执行胰高血糖素分泌的局部控制 是此应用程序的重点。血糖水平主要由两种激素控制，胰岛素，它们 控制葡萄糖的组织摄取和利用，并抑制肝脏和胰高血糖素的葡萄糖产生 这抵消了胰岛素对肝葡萄糖产生的抑制作用。糖尿病是双激素 在胰岛素缺乏或胰岛素抵抗的背景下，疾病和受损的功能有助于 高血糖是该疾病的标志。在1型糖尿病中，是 胰高血糖素的分泌有缺陷是胰岛素诱导的低血糖，对低血糖的恐惧是对 达到良好的血糖控制，从而阻止了高血糖的继发并发症。 大量的临床证据表明，升高的胰高血糖素（继发于改变 - 细胞功能）有助于 在2型糖尿病中餐后高血糖。胰高血糖素的分泌可以被细胞分泌抑制 有充分的文献记录了对€细胞功能的产物和旁分泌控制，即胰岛素内胰岛素假说。使用 高低葡萄糖开关协议我们已经表明，与胰岛素共归化的Zn2+可以抑制 低血糖期间的胰高血糖素分泌，我们假设调节Ca2+的KATP通道 信号传导可能是Zn2+的目标。高血糖还可以通过KATP抑制 - 细胞分泌 对CA2+信号传导的信道依赖性动作。已知氨基酸通过两者都刺激胰高血糖素的分泌 代谢和电源作用，但是氨基酸的葡萄糖和生理水平之间的相互作用是 不太了解，并且氨基酸转运蛋白在� -cells中的身份是基本的。胰高血糖素的分泌是 可能受到肾上腺素和去甲肾上腺素的刺激，但局部控制的相对重要性 - 功能与他们对下丘脑和其他中枢神经系统输入的反应仍然存在争议。我们的具体目标 是： 特定目标＃1。 特定目标＃2。 特定目标＃3。 特定目标＃4。 评估KATP通道在Zn2+抑制胰高血糖素分泌中的作用。 确定 - 细胞分泌产品，胰岛素，Zn2+，GABA和GABA和 ATP，在抑制胰高血糖素释放中。 确定氨基酸刺激胰高血糖素从野生型释放的机制 和sur1ko胰岛并识别涉及的细胞转运蛋白和/或途径。 评估使用小鼠对本地与中枢神经系统控制的相对重要性 带有目标缺失� -CELL KATP通道。