Mechanisms of insulin secretion mediated by alpha cells

α细胞介导的胰岛素分泌机制

• 批准号: 10242122
• 负责人: Jonathan E Campbell
• 金额: $ 41.43万
• 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/10242122
• 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; 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.

细胞介导的胰岛素分泌机制