The delta cell as a key regulator of pancreatic islet biology

摘要 尽管胰岛分泌生长抑素(SST)，但对胰岛三角洲细胞的研究很少。 强大的抑制肽，对不同组织的动态平衡是必不可少的。在胰岛中，SST抑制 分泌胰岛素和胰升糖素，但对激活三角洲细胞和SST的机制知之甚少 分泌物。三角洲细胞在胰岛生物学和葡萄糖中的其他作用还没有被研究过，甚至没有被提出。 新陈代谢。神经系统、内分泌器官和局部邻近细胞，包括免疫细胞，可以 潜在地作为“开关”或“刹车”与三角洲细胞相互作用，以调节整个胰岛的功能。很明显 这种强大的抑制成分在胰岛中的相关性被忽视了。的位置。 三角洲细胞作为调节胰岛激素分泌的关键因素，需要解决才能理解 胰岛激素分泌是如何被调节的。这个提议的一般假设是，增量细胞是一个 旁分泌、免疫和神经信号汇聚并整合的信号中枢，设定SST水平 最终调节整个胰岛活动的分泌。这一假设将通过两个相关的但 而不是相互依存的目标。在目标1中，我们将研究GABA作为一个关键的旁分泌信号在三角洲细胞功能中的作用。 我们以前的结果表明，三角洲细胞的功能受到GABA的严格调节，GABA是一种由 β细胞通过葡萄糖不依赖的机制。因此，GABA可以调节三角洲细胞的反应 其他本地信号。我们将使用人的胰岛和小鼠的胰岛来确定(1.1)效果 内源性GABA对基础SST分泌量的影响，(1.2)内源性GABA对Delta的影响 细胞对葡萄糖和其他局部信号的反应，以及(1.3)内源性GABA信号的丧失是如何起作用的 高BMI和2型糖尿病患者生长抑素分泌的变化。在目标2中，我们将考察 胰岛炎症中的三角洲细胞和SST信号转导。我们的初步发现表明，德尔塔细胞 来自免疫和神经隔间的信号，并分泌SST以对抗炎症和 神经炎。因此，三角洲细胞可以保护胰岛免受不受控制的和破坏性的免疫反应。 我们将测试(2.1)细胞因子和促炎神经肽对三角洲细胞的影响，以及(2.2)影响 SST对局部免疫细胞和感觉神经的影响。我们将使用一种新的体外培养(隔离胰岛)的组合， 体外(胰腺组织切片)和体内(眼内胰岛移植)方法结合药理学 工具，光遗传刺激，细胞消融，功能成像和系统代谢读数，以研究如何 三角洲细胞被激活，以及它们如何影响感觉神经和周围的内分泌和免疫 细胞。我们希望我们的研究能进一步加深我们对三角洲细胞在什么情况下 被招募来影响胰岛的内分泌和免疫细胞。如果SST作为免疫调节剂的作用得到证实， 三角洲细胞很可能会被重新考虑为糖尿病自然病程中的一个关键因素。因此， 我们对糖尿病发病机制的理解有望取得重大进展。

ABSTRACT The delta cell of the pancreatic islet has been barely investigated despite secreting somatostatin (SST), a powerful inhibitory peptide that is essential for the homeostasis of different tissues. In the islet, SST inhibits the secretion of insulin and glucagon, but little is known about the mechanisms that activate delta cell and SST secretion. No other roles have been investigated or even proposed for the delta cell in islet biology and glucose metabolism. The nervous system, endocrine organs, and local neighboring cells, including immune cells, could potentially interact with the delta cell as a “switch” or “brake” to modulate the function of the whole islet. It is clear that the relevance of this powerful inhibitory component in the islet has been overlooked. The position of the delta cell as a key element in the regulation of islet hormone secretion needs to be addressed to understand how islet hormone secretion is regulated. The general hypothesis of this proposal is that the delta cell is a signaling hub where paracrine, immune and nervous signals converge and are integrated to set the level of SST secretion that ultimately modulates overall islet activity. This hypothesis will be tested through two related but not interdependent aims. In Aim 1 we will study the role of GABA as a key paracrine signal in delta cell function. Our previous results suggest that delta cell function is tightly adjusted by GABA, a paracrine signal secreted by beta cells through glucose independent mechanisms. GABA could therefore modulate delta cell responses to other local signals. We will use human islets and, when translatable, mouse islets to determine (1.1) the effects of endogenous GABA on the magnitude of basal SST secretion, (1.2) the effects of endogenous GABA on delta cell responses to glucose and other, local signals, and (1.3) how loss of endogenous GABA signaling contributes to the changes in somatostatin secretion in high BMI and type 2 diabetes. In Aim 2 we will examine the role of the delta cell and SST signaling in islet inflammation. Our preliminary findings indicate that the delta cell responds to signals from the immune and neural compartments and secretes SST to counteract inflammation and neuroinflammation. Thus, the delta cell could protect the islet from unchecked and damaging immune responses. We will test (2.1) the effects of cytokines and proinflammatory neuropeptides on delta cells, and (2.2) the effect of SST on local immune cells and sensory nerves. We will use a combination of novel in vitro (isolated islets), ex vivo (pancreatic tissue slices), and in vivo (intraocular islet grafts) approaches together with pharmacological tools, optogenetic stimulation, cell ablation, functional imaging and systemic metabolic readouts to study how delta cells are activated and how they influence the sensory nerves and surrounding endocrine and immune cells. We expect our studies to further our understanding of the circumstances under which the delta cell is recruited to influence endocrine and immune cells in the islet. If SST’s role as an immunomodulator is validated, it is likely that the delta cell will be reconsidered as a key element in the natural history of diabetes. Therefore, important advances in our understanding of the pathogenesis of diabetes could be expected.