Emergent Multi-Cellular Properties Regulating Pancreatic Islet Function

调节胰岛功能的新兴多细胞特性

• 批准号: 10713356
• 负责人: Richard KP Benninger
• 金额: --
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-05 至 2023-05-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10713356
• 关键词: Ablation; Activities of Daily Living; Acute; Address; Affect; Beta Cell; Blood Glucose; Cells; Cessation of life; Characteristics; Communication; Computer Models; Coupling; Cyclic AMP; Dependence; Diabetes Mellitus; Drug Targeting; Endocrine; Environment; Experimental Models; Failure; Functional disorder; Funding; Gap Junctions; Glucagon; Glucose; Goals; Heterogeneity; Human; Image; Imaging Device; Immunofluorescence Immunologic; In Situ; Insulin; Islets of Langerhans; Knowledge; Lasers; Mediating; Metabolic; Modeling; Mus; Pancreas; Pathogenicity; Permeability; Phase; Phenotype; Population; Population Heterogeneity; Preparation; Preventive treatment; Property; Regulation; Reporter; Research; Role; Slice; System; Testing; blood glucose regulation; design; diabetogenic; experimental study; insulin regulation; insulin secretion; islet; mouse model; pancreatic islet function; pharmacologic; programs; recruit; response; small molecule; therapeutic target; tool; Ablation; Activities of Daily Living; Acute; Address; Affect; Beta Cell; Blood Glucose; Cells; Cessation of life; Characteristics; Communication; Computer Models; Coupling; Cyclic AMP; Dependence; Diabetes Mellitus; Drug Targeting; Endocrine; Environment; Experimental Models; Failure; Functional disorder; Funding; Gap Junctions; Glucagon; Glucose; Goals; Heterogeneity; Human; Image; Imaging Device; Immunofluorescence Immunologic; In Situ; Insulin; Islets of Langerhans; Knowledge; Lasers; Mediating; Metabolic; Modeling; Mus; Pancreas; Pathogenicity; Permeability; Phase; Phenotype; Population; Population Heterogeneity; Preparation; Preventive treatment; Property; Regulation; Reporter; Research; Role; Slice; System; Testing; blood glucose regulation; design; diabetogenic; experimental study; insulin regulation; insulin secretion; islet; mouse model; pancreatic islet function; pharmacologic; programs; recruit; response; small molecule; therapeutic target; tool

Diabetes is caused by insufficient secretion of insulin and subsequent loss of glucose homeostasis as a result of dysfunction or death of insulin-secreting β-cells. β-cells within the islet do not function autonomously: extensive interactions occur between β-cells and with other endocrine cells that control the regulation of insulin secretion. Previously, we and others established a critical role for gap-junction mediated electrical communication between β-cells that coordinates the dynamics of electrical activity, Ca² elevations and insulin release. β-cells are functionally heterogenous, yet the way in which different populations of β-cells influence the function of the whole islet is poorly understood. As such, the overall goal of our research program is to understand how islet function is determined by coupling between the diverse populations of β-cells. In the previous funding period, we discovered and characterized distinct sub-populations of β-cells within the intact islet, that can influence the dynamics and glucose sensitivity of whole islet electrical activity. However critical gaps in our understanding remain. This includes how functional sub-populations impact both first phase and second phase dynamics of insulin secretion; the presence and role of functional sub-populations in human islets; and how changes in sub-populations in diabetes impact islet function. To address these open questions, we have designed 3 specific aims to test our overall hypothesis: that populations of β-cells with distinct functional characteristics exert disproportionate control over multiple aspects of the islet Ca² response, via electrical coupling. 1) Characterize how β-cell sub-populations coordinate the initial first-phase response of the islet following glucose elevation; 2) Characterize the presence of functional sub-populations and electrical communication in human islets insitu; 3) Determine the gap junction dependence for functional sub-populations under healthy conditions and in type2 diabetes. By understanding how heterogenous β-cell populations within the islet interact, we will gain fundamental understanding how islet electrical and insulin secretion response is regulated. Thus, therapeutic targets which may disproportionately influence a certain β-cell population may provide new ways to control the islet under pathogenic conditions.

糖尿病是由胰岛素分泌不足和随后葡萄糖稳态丧失引起的 由于胰岛素分泌β细胞的功能障碍或死亡。 β细胞内 胰岛不能自主运行：β细胞之间发生了广泛的相互作用，并且与其他 控制调节胰岛素分泌的内分泌细胞。以前，我们和其他人 确立了间隙 - 连接介导的电通通信的关键作用 在协调电活动动力学的β细胞之间，CA²升高和胰岛素 发布。 β细胞在功能上是异质的，但是不同种群的方式 β细胞影响整个胰岛的功能知之甚少。因此， 我们研究计划的总体目标是了解如何确定胰岛功能 通过在β细胞的潜水员种群之间耦合。在上一个资金期间，我们 在完整胰岛内发现并表征了β细胞的不同亚种群，可以 影响整个胰岛电活动的动力学和葡萄糖敏感性。但是关键 我们理解的差距仍然存在。这包括功能子人群的影响如何首先 胰岛素分泌的相位和第二相动力学；功能的存在和作用 人类胰岛中的亚种群；以及糖尿病中亚人群的变化如何影响胰岛 功能。为了解决这些开放的问题，我们设计了3个特定目标来测试我们的整体 假设：具有不同功能特征的β细胞种群 通过电气对胰岛CA²响应的多个方面的控制不成比例 耦合。 1）表征β细胞子组合如何协调初始第一阶段 胰岛升高后胰岛的反应； 2）表征存在 人类胰岛中的功能亚群和电通信； 3）确定 在健康条件下和类型2中，功能子群的间隙连接依赖性 糖尿病。通过了解胰岛中的异质β细胞种群如何相互作用，我们将 获得基本了解胰岛电和胰岛素分泌反应的调节。 那是可能影响某个β细胞的治疗靶标 人口可以提供新的方法来控制病原条件下的胰岛。