Role of neuropeptide Y in diabetes and obesity

描述(申请人提供)：肥胖症已经达到了世界范围内的流行水平，人们担心它的共同发病率会造成巨大的损失，特别是2型糖尿病。2型糖尿病的发病机制包括胰岛素抵抗和胰岛衰竭。尽管有几个假说将肥胖和胰岛素抵抗联系在一起，但肥胖症中胰岛衰竭的发生机制尚不清楚。有趣的是，神经肽Y(NPY)，大脑中已知在肥胖发展中发挥作用的多肽，也在胰岛中发现，并减少胰岛素的分泌。因此，大脑和胰腺中的NPY都可能导致胰岛功能障碍，并可能成为糖尿病和肥胖症之间的联系。 本研究的目的是阐明NPY在2型糖尿病胰岛衰竭发生中的作用。通过将NPY缺陷的小鼠置于高脂饮食中诱导肥胖和糖尿病，将研究NPY对大脑和胰腺中胰岛素分泌的调节。我们将分析NPY缺乏是否会阻止饮食诱导的糖尿病的发展，并改善NPY缺陷小鼠的胰岛素分泌。NPY在大脑中的作用将通过给大脑注射NPY和测量葡萄糖刺激的胰岛素分泌来测试。通过在分离的胰岛中加入NPY来分析胰腺NPY的抑制作用。这项研究将提供一个独特的机会来测试NPY在胰岛衰竭中的作用及其与肥胖的联系。除了加深我们对2型糖尿病胰岛功能障碍的了解外，该项目还将为首席研究员Imai博士提供极好的培训，以发展糖尿病/内分泌学的学术生涯。这项研究将在宾夕法尼亚大学糖尿病中心和内分泌学、糖尿病和新陈代谢部门进行，由Rexford Ahima博士和Franz Matschinsky博士监督。该司在糖尿病和肥胖症研究方面拥有专业知识，并将为实施拟议的项目提供一个出色的环境。

DESCRIPTION (provided by applicant): Obesity has reached epidemic levels worldwide and is feared to cause significant toll with its co-morbidity, especially type 2 diabetes. Pathogenesis of type 2 diabetes includes both insulin resistance and islet failure. Although several hypotheses link obesity and insulin resistance, the mechanism responsible for the development of islet failure in obesity is not well understood. Interestingly, neuropeptide Y (NPY), the peptide in the brain that is known to play a role in the development of obesity, is also found in the pancreatic islets and decreases insulin secretion. Therefore both NPY in the brain and the pancreas may contribute to islet dysfunction and potentially serves as a link between diabetes and obesity. The goal of this study is to clarify the role of NPY in the development of islet failure in type 2 diabetes. The regulation of insulin secretion by NPY in the brain and the pancreas will be studied by placing NPY deficient mice on high fat diet to induce obesity and diabetes. We will analyze whether the lack of NPY prevents the development of diet-induced diabetes and improves insulin secretion in NPY deficient mice. The role of NPY in the brain will be tested by administration of NPY to the brain and measurement of glucose stimulated insulin secretion. The inhibitory effect of pancreatic NPY will be analyzed by adding NPY to isolated islets. The study will provide a unique opportunity to test the role of NPY in islet failure and its link with obesity. In addition to deepening our knowledge of islet dysfunction in type 2 diabetes, the project will provide superb training for the principal investigator, Dr. Imai, to develop an academic career in Diabetes/ Endocrinology. The study will be carried out in the Penn Diabetes Center and the Division of Endocrinology, Diabetes, and Metabolism at the University of Pennsylvania under the supervision of Dr. Rexford Ahima and Dr. Franz Matschinsky. The division has expertise in diabetes and obesity research, and will provide an outstanding environment to conduct the proposed project.