Pancreatic Neural Circuitry in Obesity and Diabetes

项目摘要/摘要： 肥胖症在美国极为普遍，线性趋势预测表明，超过50%的 到20301，人口将遭受肥胖之苦。肥胖增加了发展慢性健康的风险 病情，如2型糖尿病(T2D)。肥胖症和糖尿病的生物学及其机制 将它们联系起来是复杂的，而且人们对此知之甚少，这影响了我们有效治疗T2D的能力。仅限 三分之一的糖尿病患者达到了适当的血糖控制，这表明需要更有效的血糖控制。 治疗1，35.进一步研究肥胖对胰腺内分泌的影响势在必行 了解T2D的病因和发病机制，可能为未来T2D的发病机制和治疗提供基础 旨在预防和治疗T2D的药理研究。胰腺，尤其是胰岛，富含 糖尿病和肥胖症患者神经支配和神经密度异常。然而，由于之前发表的研究 主要使用2D成像和极端肥胖模型，我们没有详细的胰腺图谱 临床相关模型中的神经支配。我们的方法将通过确定效果来克服这些限制 HFD对清除组织中胰腺神经的结构和区域变化的影响。我们的初步研究 表明60%的HFD增加了小鼠胰岛的交感神经支配，也可能会减少 副交感神经支配。由于结构和功能是相关的，因此决定HFD如何影响神经 结构将为HFD对胰岛功能的影响提供新的见解。神经信号在脑损伤中的重要性 控制胰腺激素的释放已经在包括人类在内的许多物种中得到了证明。然而，许多人 研究使用神经刺激策略，影响多个器官，以及感觉和运动通路，所以它 目前尚不清楚胰腺内的神经信号是否影响胰岛激素的分泌。我们的初步研究表明 胰腺副交感神经细胞的特异性激活改善了葡萄糖刺激的胰岛素分泌， 并显著降低喂养HFD后3天和7天的GTT期间的血糖水平(45%)。我们的 初步研究有力地支持了这一假设，即HFD增加胰岛交感活性并降低 胰岛的副交感神经活动，导致胰岛素不足，无法维持正常的血糖。这一假设 将在以下目标中进行测试：目标1-在 结合高分辨率成像，确定高频辐射对胰岛三维结构的影响 交感神经和副交感神经。目的2-利用DREADD技术调节胰腺的活动 并确定HFD对副交感神经和交感神经控制胰岛激素分泌的影响。 这一建议的发现将决定正常胰腺神经群的结构和功能。 生理学和高脂饮食喂养后，最终提供了新的洞察机制和 T2D的病理生理学，可以促进针对预防的更有效的治疗方法的发展 和T2D的治疗。

Project Summary/Abstract: Obesity is extremely prevalent in the United States, and linear trend forecasts suggest that more than 50% of the population will suffer from obesity by 20301. Obesity increases the risks for developing chronic health conditions, such as Type 2 diabetes (T2D). The biology of obesity and diabetes, as well as the mechanisms linking them, are complex and poorly understood, which has impacted our abilities to effectively treat T2D. Only one third of people living with diabetes achieve adequate glycemic control, suggesting a need for more effective therapies1,35. Further investigation into the impact of obesity on the endocrine pancreas is imperative to understanding the etiology and pathogenesis of T2D, which may provide a foundation for future mechanistic and pharmacological studies aimed at preventing and treating T2D. The pancreas, and especially islets, are richly innervated and nerve density is abnormal in diabetes and obesity. However, since previously published studies predominantly use 2D imaging and extreme models of obesity, we do not have detailed mapping of pancreatic innervation in a clinically relevant model. Our approach will overcome these limitations by determining the effect of a HFD on structural and regional changes in pancreas innervation in cleared tissue. Our preliminary studies indicate that a 60% HFD increases sympathetic innervation within mouse islets, and may also decrease parasympathetic innervation. Since structure and function are related, determining how a HFD impacts nerve structure will provide novel insight into the effect of a HFD on islet function. The importance of neural signals in controlling pancreatic hormone release has been shown in many species, including humans. However, many studies use nerve stimulation strategies, which impact multiple organs, and sensory and motor pathways, so it is unknown if neural signaling within the pancreas impacts islet hormone secretion. Our preliminary studies show that the specific activation of pancreatic parasympathetic neurons improves glucose stimulated insulin secretion, and significantly reduces plasma glucose levels during a GTT after 3 and 7 days of HFD feeding (45%). Our preliminary studies strongly support the hypothesis that a HFD increases islet sympathetic activity and decreases islet parasympathetic activity, leading to insufficient insulin to maintain normal plasma glucose. This hypothesis will be tested in the following aims: Aim 1- to use iDisco+, a whole mount immunolabeling technique, in conjunction with high resolution imaging, to determine the effects of a HFD on the 3D structure of islet sympathetic and parasympathetic nerves. Aim 2- To utilize DREADD technology to regulate activity in pancreatic nerves and determine the effect of a HFD on parasympathetic and sympathetic control of islet hormone secretion. The findings of this proposal will determine the structure and function of pancreatic neural populations in normal physiology and after high fat diet feeding, ultimately providing new insight into the mechanisms and pathophysiology of T2D, which can promote the development of more effective therapies aimed at the prevention and treatment of T2D.