Emergent Multi-Cellular Properties Regulating Pancreatic Islet Function

糖尿病是由于分泌胰岛素的β细胞功能障碍或死亡而导致的胰岛素分泌不足和随后的葡萄糖稳态丧失所致。胰岛内的β细胞并不是自主发挥功能的：β细胞之间以及与控制胰岛素分泌调节的其他内分泌细胞之间发生了广泛的相互作用。以前，我们和其他人建立了缝隙连接介导的β细胞之间的电通讯的关键作用，该通讯协调电活动、[Ca~(2+)]升高和胰岛素释放的动态。β细胞在功能上是异质性的，但不同群体的β细胞如何影响整个胰岛的功能还知之甚少。因此，我们研究计划的总体目标是了解胰岛功能是如何由不同的β细胞群之间的耦合决定的。在之前的资助期间，我们发现并表征了完整胰岛内不同的β细胞亚群，这些细胞亚群可以影响整个胰岛电活动的动力学和葡萄糖敏感性。然而，我们在理解方面仍然存在严重差距。这包括功能亚群如何影响胰岛素分泌的第一阶段和第二阶段动态；功能亚群在人类胰岛中的存在和作用；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，我们设计了三个具体的目标来检验我们的总体假设：具有不同功能特征的β细胞群体通过电信号对胰岛[钙]反应的多个方面施加不成比例的控制。 耦合。1)描述β细胞亚群如何协调血糖升高后胰岛的初始第一时相反应；2)表征原位人类胰岛中功能亚群和电通讯的存在；3)确定与2型糖尿病相关的条件如何影响功能亚群和胰岛反应性。通过了解胰岛内异种β细胞群体如何相互作用，我们将从根本上了解胰岛电和胰岛素分泌反应是如何调节的。因此，可能不成比例地影响特定β细胞群体的治疗靶点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 how conditions associated with type2 diabetes impact functional sub-populations and islet responsiveness. 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.