Mechanisms of insulin secretion mediated by alpha cells

α细胞介导的胰岛素分泌机制

• 批准号: 10019379
• 负责人: Jonathan E Campbell
• 金额: $ 33.11万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10019379
• 关键词: Address; Agonist; Alpha Cell; Animals; Area; B-Lymphocytes; Belief; Beta Cell; Cell Communication; Cell Line; Cell physiology; Cell secretion; Cells; Cellular Stress; Clinical; Complement; Cyclic AMP; Data; Development; Diabetes Mellitus; Dimensions; Disease; Endocrine; Environment; Enzymes; Event; Fasting; Financial compensation; Functional disorder; GLP-I receptor; Genes; Glucagon; Glucagon Receptor; Glucose; Glucose Intolerance; Goals; Health; Hepatic; High Fat Diet; Hormones; Human; Hyperglycemia; Hypoglycemia; Impairment; Insulin; Interruption; Intervention; Islets of Langerhans; Ligands; Link; Maintenance; Mediating; Metabolic stress; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Paracrine Communication; Pathogenesis; Pathogenicity; Patients; Pattern; Peptide Receptor; Peptide Signal Sequences; Peptides; Pharmacology; Phenotype; Physiological; Plasma; Population; Prevention; Production; Proprotein Convertase 1; Proprotein Convertase 2; Receptors, Antigen, B-Cell; Regulation; Reporting; Role; Signal Pathway; Signal Transduction; Structure of alpha Cell of islet; System; Testing; Tissues; Transcript; Work; base; blood glucose regulation; cell type; diabetic; diabetic patient; driving force; drug development; effective therapy; experimental study; glucagon-like peptide; glucagon-like peptide 1; glucose production; glucose tolerance; human subject; hyperglucagonemia; impaired glucose tolerance; in vivo; insulin secretagogues; insulin secretion; islet; mouse model; novel; paracrine; proglucagon; real-time images; receptor; response; therapeutic target; transcriptome sequencing; translational study

Mechanisms of insulin secretion mediated by alpha cells Pancreatic islets contain multiple endocrine cells that produce hormones intimately involved in the control of glucose homeostasis. -cells, which secrete insulin, are both the most abundant cell type and the most studied cell type. -cell dysfunction leads to insufficient insulin production and ultimately hyperglycemia, the major pathophysiological phenotype of type 2 diabetes (T2D). -cells are the second most abundant cell type within islets, yet substantially less is known about -cell function or the role of these cells in glucose homeostasis. - cells secrete glucagon, which is canonically described as a hyperglycemic agent and an important counter- regulatory hormone in the prevention of hypoglycemia. -cell dysfunction is described as inappropriate glucagon secretion and is considered to be a driving force for hyperglycemia in T2D. However, glucagon receptors (GCGRs) are expressed on -cells and glucagon is a potent insulin secretagogue. Furthermore, it has been recently proposed that -cells synthesize and secrete glucagon-like peptide 1 (GLP-1), through alternative processing of the proglucagon gene transcript. GLP-1 receptors (GLP-1R) are also expressed on -cells, and GLP-1R agonists are currently available for use in T2D to increase insulin production. This raises the intriguing possibility that - to -cell paracrine interactions control insulin production and ultimately glucose homeostasis. Moreover, this perspective allows for the possibility that the increased glucagon secretion seen in T2D is a compensatory mechanism by which the -cells are attempting to increase -cell insulin production. Based on this, we hypothesize that increased -cell activity in T2D is not pathogenic per se, but rather, it is the interruption of - to -cell communication that results in decreased insulin production and hyperglycemia. Therefore, the overall goal of this project is to understand how -cells regulate -cell function, determine the importance of this relationship for normal glucose tolerance, and identify how severing the key node is pathogenic. We will accomplish this by first understanding the importance of - to -cell communication in the context of -cell function and overall glucose tolerance, and then determining if alterations in this axis occur during the development of -cell dysfunction. We will also define the relative importance of -cell glucagon versus GLP-1 production to delineate why -cells would produce two insulin secretagogues. Similarly, we will identify the importance of GCGR versus GLP-1R in -cells to determine if these are redundant systems or if they have unique roles in control of -cell function. This work will encompass cell lines and primary tissues, utilize novel mouse models, and determine the translational potential by conducting key experiments in human subjects in order to comprehensively understand the importance of - to -cell communication in normal and diabetic environments. Completion of this project will enhance our understanding of -cell function in order to identify how best to therapeutically target this cell type for the treatment of T2D.

α细胞介导的胰岛素分泌机制 胰岛含有多个内分泌细胞，它们产生的激素密切参与控制 葡萄糖动态平衡。分泌胰岛素的细胞是最丰富的细胞类型，也是研究最多的细胞类型 单元类型。细胞功能障碍导致胰岛素分泌不足，最终导致高血糖，主要 2型糖尿病的病理生理表型(T2D)。细胞是世界上第二丰富的细胞类型 然而，对细胞的功能或这些细胞在血糖稳态中的作用知之甚少。- 细胞分泌胰高血糖素，它被经典地描述为一种升糖剂和一种重要的抗糖尿病药物。 调节激素在预防低血糖中的作用。细胞功能障碍被描述为不适当的胰高血糖素 分泌，被认为是T2D高血糖的驱动力。然而，胰升糖素受体 (GCGRs)表达在细胞上，而胰高血糖素是一种有效的胰岛素促分泌剂。此外，它一直是 新近提出，-细胞通过多种途径合成和分泌胰高血糖素样肽-1。 原胰高血糖素基因转录本的加工。-细胞上也表达GLP-1受体。 GLP-1R激动剂目前可用于T2D以增加胰岛素的产生。这引发了一个耐人寻味的问题 -to--细胞旁分泌相互作用可能控制胰岛素的产生，最终控制葡萄糖的稳态。 此外，这种观点允许在T2D中看到的胰升糖素分泌增加是一种 细胞试图增加细胞胰岛素产生的代偿机制。基于 这一点，我们假设，在T2D中细胞活性增加本身并不是致病的，而是中断 导致胰岛素分泌减少和高血糖的-to细胞通讯障碍。因此， 这个项目的总体目标是了解细胞如何调节细胞功能，确定这一点的重要性 正常糖耐量的关系，并确定切断关键节点是如何致病的。我们会 要做到这一点，首先要了解-to-CELL通信在-CELL环境中的重要性 功能和整体糖耐量，然后确定这一轴是否在 -细胞功能障碍的发展。我们还将确定-细胞胰高血糖素与GLP-1的相对重要性 来描述为什么细胞会产生两种胰岛素促分泌剂。同样，我们将标识 比较GCGR和GLP-1R在细胞中的重要性，以确定这些系统是否为冗余系统 在控制细胞功能方面发挥独特的作用。这项工作将涵盖细胞系和初级组织，利用新的 小鼠模型，并通过在人类受试者身上进行关键实验来确定翻译潜力 为了全面了解正常人和糖尿病患者-to-细胞通讯的重要性 环境。该项目的完成将加深我们对-CELL功能的理解，以便识别 如何最好地以这种细胞类型作为治疗T2D的靶点。