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.

项目概要/摘要 了解对胰高血糖素分泌进行局部控制的胰腺 ¿- 和 ¿-细胞之间的相互作用 是本应用的重点。血糖水平主要由两种激素控制，即胰岛素， 控制组织对葡萄糖的吸收和利用，并抑制肝脏和胰高血糖素产生葡萄糖， 它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 高血糖是该疾病的标志。在 1 型糖尿病中，主要的临床后果是 胰高血糖素分泌缺陷是胰岛素引起的低血糖，而对低血糖的恐惧是主要限制因素 实现良好的血糖控制，从而预防高血糖的继发并发症。 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有助于 2 型糖尿病餐后高血糖。胰高血糖素分泌可被 ¿ 细胞分泌抑制 产品和旁分泌控制细胞功能，即胰岛内胰岛素假说，已得到充分记录。使用 高至低葡萄糖关闭方案 我们已经证明，与胰岛素共同分泌的 Zn2+ 可以抑制 低血糖期间胰高血糖素分泌，我们假设调节 Ca2+ 的 KATP 通道 信号传导可能是 Zn2+ 的目标。高血糖还可能通过 KATP 抑制 ¿-细胞分泌 Ca2+ 信号传导的通道依赖性作用。已知氨基酸可通过以下两种方式刺激胰高血糖素分泌： 代谢和生电效应，但葡萄糖和氨基酸生理水平之间的相互作用是 尚未得到很好的理解，并且 细胞中氨基酸转运蛋白的身份还处于初级阶段。胰高血糖素的分泌量是 受到肾上腺素和去甲肾上腺素的强烈刺激，但 ¿ 细胞的局部控制相对重要 功能与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： 具体目标#1。 具体目标#2。 具体目标#3。 具体目标#4。 评估 KATP 通道在 Zn2+ 抑制胰高血糖素分泌中的作用。 确定 ¿-细胞分泌产物、胰岛素、Zn2+、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 Sur1KO 胰岛并识别相关的 ¿-细胞转运蛋白和/或途径。 使用小鼠评估局部与中枢神经系统控制 ¿ 细胞功能的相对重要性 靶向删除 ¿-细胞 KATP 通道。