Harnessing Innervation to Promote Pancreatic Islet Function

周围自主神经系统的三个组成部分，即副交感神经、交感神经和 感觉神经，共同努力，防止危及生命的葡萄糖稳态波动。他们这样做是在 部分是通过调节胰岛的胰岛素分泌。用电极刺激自主神经有 最近被认为是治疗疾病(神经调节)的一种潜在方法。鉴于它在 然而，要提出电刺激神经来治疗糖尿病，关键是要了解胰岛是如何 神经影响胰岛β细胞的胰岛素分泌。此应用程序的目标是确定 神经控制胰岛素分泌的机制。最近的解剖学研究表明，交感神经和 重要的是，这些神经 不要直接接触β细胞，而是密集地支配胰岛血管。因此，我们假设 自主神经控制血液流动和血管通透性，以调节胰岛素释放到血液中。 这项拟议研究的基本原理是，这些神经作用机制可能成为干预目标。 人类的神经调节，这与美国国立卫生研究院的任务有关。在初步数据的指导下， 我们的假设将通过追求两个具体目标来检验：(1)确定交感神经的功能作用 以及(2)确定感觉神经对胰岛素分泌的功能作用。 在第一个目标下，我们将测试交感神经靶向血管周细胞以改变血流。我们会 类似于胰腺中的胰岛。我们将刺激、抑制和消融对胰岛的交感神经传入 移植并测定对胰岛血流量的影响，同时测定对胰岛素血浆的影响 血糖值和血糖。我们还将测试交感神经的慢性激活是否会阻止 渗透性。 我们还将激活 建议数 并利用小鼠胰岛神经支配的那些方面代表人类的情况。知道怎么做 神经控制胰岛素分泌是提出神经调节作为糖尿病治疗方法的关键。

The three components of the peripheral autonomic nervous system, the parasympathetic, sympathetic and sensory nerves, work together to prevent life-threatening fluctuations in glucose homeostasis. They do so in part by regulating insulin secretion from the pancreatic islet. Stimulating autonomic nerves with electrodes has recently been recognized as a potential way to treat diseases (neuromodulation). Given its central role in glucose metabolism and diabetes, the pancreatic beta cell is considered a primary target for neuromodulation. To propose electrical stimulation of nerves to treat diabetes, however, it is essential to understand how islet nerves impact insulin secretion from the beta cell. The objective of this application is to determine the mechanisms nerves use to control insulin secretion. Recent anatomical studies show that sympathetic and sensory nerves innervate the human islet, but parasympathetic innervation is sparse. Importantly, these nerves do not contact beta cells directly but densely innervate the islet vasculature. We therefore hypothesize that autonomic nerves control blood flow and vascular permeability to adjust insulin release into the bloodstream. The rationale for the proposed research is that these mechanisms of nerve action could be intervention targets for neuromodulation in human beings, which is relevant to the mission of the NIH. Guided by preliminary data, our hypothesis will be tested by pursuing two specific aims: (1) determine the functional role of sympathetic innervation for insulin secretion, and (2) determine the functional role of sensory nerves for insulin secretion. Under the first aim, we will test that sympathetic nerves target vascular pericytes to change blood flow. We will transplant human and mouse islets into the eye of diabetic mice. In the eye, islet grafts restore normoglycemia and can be monitored non-invasively. Importantly, islet grafts are revascularized and reinnervated in patterns that resemble those of islets in the pancreas. We will stimulate, inhibit, and ablate sympathetic input to islet grafts and determine the effects on islet blood flow and simultaneously measure the effects on insulin plasma levels and glycemia. We will also test whether chronic activation of sympathetic nerves prevents the derangement of islet vasculature in mouse models of type 2 diabetes. Under the second aim, we will test that sensory nerves respond to local perturbations in the islet microenvironment to change the vascular permeability. To determine what activates sensory nerves in the islet, we will use mice that express functional indicators in sensory neurons and measure activity in nerve terminals in the islet in living pancreas slices and in vivo in neuronal cell bodies of the nodose ganglion after stimulating or injuring the islet. We will also activate sensory nerve chronically to test the impact on islet health in mouse models of type 2 diabetes. The proposed research is significant because the research plan takes into account the innervation pattern of the human islet and uses those aspects of mouse islet innervation that are representative of the human situation. Knowing how nerves control insulin secretion is crucial to propose neuromodulation as a therapeutic approach in diabetes.