The role of EphA-ephrin-A signaling in glucose-inhibition of glucagon secretion

EphA-ephrin-A 信号在葡萄糖抑制胰高血糖素分泌中的作用

基本信息

批准号：
8913159
负责人：
Troy Hutchens
金额：
$ 4.81万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-04 至 2016-09-03
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8913159
关键词：
Address Agonist Alpha Cell Antibodies Beta Cell Blood Glucose Caring Cell Communication Cell physiology Cells Data Development Diabetes Mellitus Dose Environment Eph Family Receptors EphA4 Receptor Ephrins Exocytosis Fluorescence Microscopy Functional disorder Glucagon Glucose Goals Health Hormones Human Hyperglycemia Immunofluorescence Immunologic Insulin Insulin Antagonists Islet Cell Islets of Langerhans Mediating Metabolic Modeling Molecular Molecular Biology Monitor Mus Paracrine Communication Pathology Patients Pattern Phenotype Physiological Physiology Play Population Protocols documentation Publishing Receptor Signaling Regulation Reporting Research Role Signal Pathway Signal Transduction Somatostatin Sorting - Cell Movement Therapeutic Whole Organism base blood glucose regulation cell growth regulation design diabetes management diabetic patient inhibitor/antagonist insulin secretion insulin signaling islet mouse model novel novel therapeutics pancreatic juice paracrine research study response restoration success therapeutic target treatment strategy type I and type II diabetes

Address Agonist Alpha Cell Antibodies Beta Cell Blood Glucose Caring Cell Communication Cell physiology Cells Data Development Diabetes Mellitus Dose Environment Eph Family Receptors EphA4 Receptor Ephrins Exocytosis Fluorescence Microscopy Functional disorder Glucagon Glucose Goals Health Hormones Human Hyperglycemia Immunofluorescence Immunologic Insulin Insulin Antagonists Islet Cell Islets of Langerhans Mediating Metabolic Modeling Molecular Molecular Biology Monitor Mus Paracrine Communication Pathology Patients Pattern Phenotype Physiological Physiology Play Population Protocols documentation Publishing Receptor Signaling Regulation Reporting Research Role Signal Pathway Signal Transduction Somatostatin Sorting - Cell Movement Therapeutic Whole Organism base blood glucose regulation cell growth regulation design diabetes management diabetic patient inhibitor/antagonist insulin secretion insulin signaling islet mouse model novel novel therapeutics pancreatic juice paracrine research study response restoration success therapeutic target treatment strategy type I and type II diabetes

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项目摘要

DESCRIPTION (provided by applicant): The islets of Langerhans play a central role in blood glucose homeostasis through glucose regulated dose-dependent hormone secretion. The therapeutic success of insulin has led most diabetes research to be focused on β-cells. Recently however, glucagon (secreted by α-cells) has been shown to significantly contribute to the pathophysiology of diabetes. In both type 1 and type 2 diabetes, glucagon secretion is inappropriately elevated and dysregulated, further exacerbating hyperglycemia. Thus, understanding the mechanisms underlying α-cell function and glucagon secretion represents an important avenue in the development of new therapeutic strategies for diabetes management. In combination with current treatments, therapeutics based on novel α-cell targets will benefit patients with type 1 and type 2 diabetes by addressing multiple causes of hyperglycemia. Despite the important physiologic role of glucagon, the mechanisms regulating its secretion remain poorly understood. The Piston lab has recently published data suggesting that GIGS is not intrinsic to α-cells, and that the inhibition of glucagon secretion is independent of Ca2+ influx. Our data show that similar to diabetic patients, pure populations of sorted α-cells displa an increase in glucagon secretion at low glucose and a loss of glucose-inhibition of glucagon secretion (GIGS). Additionally, intracellular [Ca2+] is elevated in α-cells in response to increase in glucose that inhibit glucagon secretion. The necessity of the intraislet environment for appropriate glucagon secretion cannot be explained solely through paracrine signaling, as sorted α-cells are no longer sensitive to proposed paracrine inhibitors (insulin and somatostatin). Here, we propose a new juxtacrine signaling dependent model of GIGS that regulates glucagon secretion downstream of Ca2+ influx. Juxtacrine signaling through the EphA-ephrin-A signaling pathways has been shown to play an important role in both the basal and glucose dependent hormone secretion from islet β-cells. Since the α-cell is closely related to the β-cell, we speculate that a similar mechanism plays a role in basal glucagon secretion and GIGS. Interestingly, both human and mouse α-cells only express a single Eph receptor, EphA4. In preliminary studies pharmacologically inhibiting EphA4 receptor signaling, glucagon secretion was elevated at basal glucose and secretion was inappropriately stimulated response to glucose. These two findings mirror the glucagon secretion patterns observed in both sorted α-cells and diabetic patients, indicating the importance of EphA4 receptor signaling in mediating glucagon secretion at basal and elevated glucose. We hypothesize that EphA4 receptor signaling in α-cells is required for the appropriate suppression of glucagon secretion at basal glucose and for GIGS. Additionally, we hypothesize EphA4 receptor signaling is permissive for additional paracrine inhibitory signals (insulin and/or somatostatin).

描述（由适用提供）：通过葡萄糖调节的剂量依赖性的horsene分泌，Langerhans的胰岛在血糖稳态中起着核心作用。胰岛素的理论成功使大多数糖尿病研究集中在β细胞上。然而，最近，胰高血糖素（由α细胞分泌）已显示出显着有助于糖尿病的病理生理学。在1型和2型糖尿病中，胰高血糖素分泌不当升高和失调，进一步加剧了高血糖。这是理解α细胞功能和牙木分泌的基础机制，代表了开发新的糖尿病治疗策略的重要途径。结合当前的治疗，基于新型α细胞靶标的治疗将通过解决多种原因的高血糖原因来使1型和2型糖尿病患者受益。尽管胰高血糖素具有重要的生理作用，但恢复其分泌的机制仍然很少理解。活塞实验室最近发布了数据，表明GIG不是α细胞固有的，并且抑制胰高血糖素分泌与CA2+影响无关。我们的数据表明，与糖尿病患者类似，分类的α细胞的纯种群显示出低血糖时胰高血糖素分泌的增加和胰高血糖素分泌的葡萄糖抑制作用丧失（GIGS）。另外，α细胞的细胞内[Ca2+]升高，响应抑制胰高血糖素分泌的葡萄糖增加。对于适当的胰高血糖素分泌的环境必要的环境不能仅通过旁分泌信号传导来解释，因为分类的α细胞不再对提出的旁分泌抑制剂（胰岛素和生长抑素）敏感。在这里，我们提出了一个新的近折信号传导模型，该模型调节Ca2+影响下游的胰高血糖素分泌。已经证明，通过Epha-磷-A信号通路的近距离信号传导在胰岛β细胞的基底和葡萄糖依赖性的牛section中都起着重要作用。由于α细胞与β细胞密切相关，因此我们推测类似的机制在基底胰高血糖素分泌和GIG中起作用。有趣的是，人和小鼠α细胞仅表达单个EPH受体EPHA4。在初步研究的药理学抑制EPHA4受体信号传导中，基本葡萄糖的分泌升高，分泌不当刺激对葡萄糖的反应。这两个发现反映了在排序的α细胞和糖尿病患者中观察到的谷物分泌模式，表明EPHA4受体信号传导在基础和葡萄糖升高的胰高血糖素分泌中的重要性。我们假设α细胞中的Epha4受体信号转导在基础葡萄糖和GIG上适当抑制胰高血糖素的分泌需要。此外，我们假设EPHA4受体信号传导允许使用其他旁分泌抑制信号（胰岛素和/或生长抑素）。