Neuroendocrine Control of Glucose Metabolism

葡萄糖代谢的神经内分泌控制

基本信息

批准号：
8432470
负责人：
GREGORY J MORTON
金额：
$ 36.97万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8432470
关键词：
Adipose tissue Animal Model Animals Area Blood Glucose Body fat Brain Brown Fat Celiac ganglion Cells Collaborations Communication Data Development Diabetes Mellitus Dilution Techniques Dose Eating Fatty acid glycerol esters Genetic Recombination Glucagon Glucose Goals Heart Hepatic Homeostasis Human Hyperglycemia Hyperphagia Hypothalamic structure Infusion procedures Insulin Insulin Resistance Insulin-Dependent Diabetes Mellitus Knockout Mice Leptin Leptin deficiency Link Liver Mediating Modeling Motor Neurons Nerve Neuraxis Neurons Neurosecretory Systems Obesity Operative Surgical Procedures Pancreas Pathway interactions Performance Peripheral Plasma Play Publishing Rattus Recovery Regulation Reporting Rodent Model Role Signal Transduction Skeletal Muscle Spinal Cord Streptozocin Structure of alpha Cell of islet Technology Thyrotropin-Releasing Hormone Tissues Toxin Tracer Universities Weight Gain base blood glucose regulation diabetic diabetic rat energy balance glucose metabolism glucose output glucose production glucose uptake improved insulin sensitivity mouse model novel novel strategies paraventricular nucleus pituitary thyroid axis public health relevance response urinary

项目摘要

DESCRIPTION (provided by applicant): Although insulin remains the cornerstone of therapy for type 1 diabetes in humans, recent evidence suggests that induction of hyperleptinemia fully ameliorates hyperglycemia in streptozotocin (STZ)-induced diabetic rats and our recent findings implicate the brain in this effect. Our new Preliminary Data show that this leptin effect involves a novel, insulin-independent mechanism characterized by reduced rates of hepatic glucose production (HGP) and increased rates of tissue glucose uptake and establishes that the brain has the capacity to normalize blood glucose levels in uDM. These observations are distinct from any previously described central nervous system (CNS) leptin action and support the overarching goal of this proposal to delineate the neuronal circuits and peripheral mechanisms activated by leptin that mediate its anti-diabetic effects. Specifically, we hypothesize that leptin inhibition of sympathetic outflow to the liver and pancreas reduces HGP in uDM, and that this effect involves the melanocortin pathway. Moreover, we hypothesize that leptin-induced activation of a subset of thyrotropin-releasing hormone (TRH) neurons in the paraventricular nucleus (PVN) stimulates glucose uptake, and thereby contributes to the glucose-lowering effects of leptin in uDM. To accomplish these objectives, we will employ sophisticated tracer dilution techniques, in combination with pharmacological, surgical and immunohistochemical approaches and established conditional knockout mouse models using Cre- loxP recombination technology. The data generated in this proposal is therefore expected to identify specific neuronal subsets downstream of leptin action that link communication between the brain and peripheral tissues to control both HGP and glucose uptake. Performance of these studies has the potential to facilitate the development of new approaches to diabetes treatment.

描述（由申请人提供）：尽管胰岛素仍然是人类1型糖尿病治疗的基石，但最近的证据表明，诱导高勒敦血症的诱导完全可以完全缓解链霉菌素（STZ）糖尿病大鼠中的高血糖，而我们的最新发现则暗示了这种作用的大脑。我们的新初步数据表明，这种瘦素效应涉及一种新型的，胰岛素独立的机制，其特征是肝葡萄糖产生率降低（HGP）和组织葡萄糖摄取的速率增加，并确定大脑具有UDM中血糖水平归一化的能力。这些观察结果与任何先前描述的中枢神经系统（CNS）瘦素作用不同，并支持该提案的总体目标，即描述由瘦素介导其抗糖尿病作用的瘦素激活的神经元回路和外周手术机制。具体而言，我们假设瘦素对肝脏的交感流出抑制和胰腺可以减少UDM中的HGP，并且这种作用涉及黑色素质素途径。此外，我们假设瘦素诱导的甲状腺蛋白释放激素（TRH）神经元的激活（PVN）刺激了葡萄糖的摄取，从而有助于UDM中瘦素的葡萄糖降糖素作用。为了实现这些目标，我们将采用复杂的示踪剂稀释技术，结合药理学，外科和免疫组织化学方法，并使用CRELOXP重组技术建立了条件敲除小鼠模型。因此，预计该提案中产生的数据将鉴定瘦素作用下游的特定神经元子集，这些神经元子集将大脑和外围组织之间的通信联系起来，以控制HGP和葡萄糖摄取。这些研究的表现有可能促进开发糖尿病治疗的新方法。