Emergent Multi-Cellular Properties Regulating Pancreatic Islet Function

糖尿病是由胰岛素分泌不足和随后的葡萄糖稳态丧失引起的 由于分泌胰岛素的 β 细胞功能障碍或死亡。 β细胞内 胰岛不能自主发挥功能：β 细胞之间以及与其他细胞之间存在广泛的相互作用 控制胰岛素分泌调节的内分泌细胞。此前，我们和其他人 确立了间隙连接介导的电通信的关键作用 β 细胞之间协调电活动动态、Ca² 升高和胰岛素 释放。 β细胞在功能上是异质的，但不同群体的β细胞发挥作用的方式不同。 β细胞对整个胰岛功能的影响尚不清楚。因此， 我们研究计划的总体目标是了解胰岛功能是如何确定的 通过不同β细胞群之间的耦合。在上一个资助期间，我们 发现并表征了完整胰岛内不同的 β 细胞亚群， 影响整个胰岛电活动的动力学和葡萄糖敏感性。无论多么关键 我们的理解仍然存在差距。这包括功能亚群如何首先影响两者 胰岛素分泌的相和第二相动态；功能性的存在和作用 人类胰岛的亚群；以及糖尿病亚群的变化如何影响胰岛 功能。为了解决这些悬而未决的问题，我们设计了 3 个具体目标来测试我们的整体目标 假设：具有不同功能特征的 β 细胞群发挥作用 通过电对胰岛 Ca2 反应的多个方面进行不成比例的控制 耦合。 1) 描述β细胞亚群如何协调初始第一阶段 葡萄糖升高后胰岛的反应； 2) 描述存在的特征 人类胰岛的功能亚群和电通讯； 3）确定 健康条件下和 2 型功能亚群的间隙连接依赖性 糖尿病。通过了解胰岛内异质 β 细胞群如何相互作用，我们将 获得对胰岛电和胰岛素分泌反应如何调节的基本了解。 因此，可能不成比例地影响某些β细胞的治疗靶点 种群可能提供在致病条件下控制胰岛的新方法。

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.