Mechanisms of insulin secretion mediated by alpha cells

α细胞介导的胰岛素分泌机制

• 批准号: 10462666
• 负责人: Jonathan E Campbell
• 金额: $ 41.04万
• 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/10462666
• 关键词: Address; Agonist; Alpha Cell; Animals; Area; B-Cell Antigen Receptor; 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; Regulation; Reporting; Role; Signal Pathway; Signal Transduction; Structure of alpha Cell of islet; System; Testing; Tissues; Transcript; Work; antagonist; 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 potential; 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 胰岛含有多种内分泌细胞，这些细胞产生与控制密切相关的激素。 分泌胰岛素的细胞是最丰富且研究最多的细胞类型。  细胞功能障碍导致胰岛素产生不足，最终导致高血糖。 2 型糖尿病 (T2D) 的病理生理表型中，α 细胞是第二丰富的细胞类型。 胰岛，但对 α 细胞功能或这些细胞在葡萄糖稳态中的作用知之甚少。 细胞分泌胰高血糖素，它被规范地描述为一种高血糖剂和一种重要的抗血糖药物。 预防低血糖的调节激素被描述为不适当的胰高血糖素。 然而，胰高血糖素受体的分泌被认为是 T2D 中高血糖的驱动力。 (GCGR) 在  细胞上表达，胰高血糖素是一种有效的胰岛素促分泌素。 最近提出α-细胞合成并分泌胰高血糖素样肽1（GLP-1），通过替代 GLP-1 受体 (GLP-1R) 的加工也在  细胞上表达，并且 GLP-1R 激动剂目前可用于治疗 T2D，以增加胰岛素的产生，这引起了人们的兴趣。 -与-细胞旁分泌相互作用可能控制胰岛素的产生并最终控制葡萄糖稳态。 此外，这种观点认为 T2D 中胰高血糖素分泌增加可能是一种  细胞试图增加  细胞胰岛素产量的补偿机制。 因此，我们发现 T2D 中 α 细胞活性的增加本身并不致病，而是中断 -与-细胞之间的通讯会导致胰岛素产生减少和高血糖。 该项目的总体目标是了解  细胞如何调节  细胞功能，确定其重要性 正常葡萄糖耐量的关系，并确定关键节点的致病性。 通过首先了解  细胞背景下  到  细胞通信的重要性来实现这一目标 功能和总体葡萄糖耐量，然后确定该轴在该过程中是否发生变化 我们还将定义 α 细胞胰高血糖素与 GLP-1 的相对重要性。 生产来描述为什么 α 细胞会产生两种胰岛素促分泌剂。同样，我们将确定 GCGR 与 GLP-1R 在  细胞中的重要性，以确定这些系统是否是冗余系统或者是否具有 这项工作将利用新颖的方法涵盖细胞系和原代组织。 小鼠模型，并通过在人类受试者中进行关键实验来确定转化潜力 为了全面了解 α- 到 β-细胞通讯在正常和糖尿病患者中的重要性 该项目的完成将增强我们对 α 细胞功能的理解，以便识别。 如何最好地靶向这种细胞类型来治疗 T2D。