Neuroendocrine Control of Glucose Metabolism

葡萄糖代谢的神经内分泌控制

• 批准号: 8104986
• 负责人: GREGORY J MORTON
• 金额: $ 42.75万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 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/8104986
• 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; response; urinary

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. PUBLIC HEALTH RELEVANCE: While treatment of hyperglycemia in type 1 diabetes is generally held to require exogenous insulin, recent evidence suggests that pharmacological doses of leptin can also induce this effect. Our recent findings implicate the brain in this effect and demonstrate that leptin action in the brain normalizes diabetic hyperglycemia in a model of uncontrolled, insulin-deficient diabetes (uDM) by increasing glucose uptake and reducing glucose output by the liver. The overarching goal of this proposal is to determine how the brain communicates to peripheral tissues to mediate the anti-diabetic effects of leptin and the data generated is expected to facilitate the development of new approaches for the control of blood sugars.

描述(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，诱导高瘦素血症完全改善了链脲佐菌素(STZ)诱导的糖尿病大鼠的高血糖，我们最近的发现表明这一效应与大脑有关。我们新的初步数据显示，这种瘦素效应涉及一种新的胰岛素非依赖性机制，其特征是肝脏葡萄糖生成率(HGP)降低和组织葡萄糖摄取率增加，并确立了UDM患者大脑有能力使血糖水平正常化。这些观察结果不同于之前描述的任何中枢神经系统(CNS)瘦素的作用，支持本提案的首要目标是描绘由瘦素激活的神经回路和外周机制，这些机制介导了瘦素的抗糖尿病效果。具体地说，我们假设瘦素抑制交感神经流出到肝脏和胰腺可以减少UDM患者的HGP，并且这种作用涉及黑素皮质素途径。此外，我们假设瘦素激活室旁核(PVN)中促甲状腺激素释放激素(TRH)神经元的亚群，刺激葡萄糖摄取，从而参与瘦素在UDM中的降糖作用。为了实现这些目标，我们将使用复杂的示踪稀释技术，结合药理学、外科和免疫组织化学方法，并使用Cre-loxP重组技术建立条件性基因敲除小鼠模型。因此，这项提案中产生的数据有望确定瘦素作用下游的特定神经元亚群，这些亚群将大脑和周围组织之间的通信联系起来，以控制HGP和葡萄糖的摄取。这些研究的实施有可能促进糖尿病治疗新方法的开发。 公共卫生相关性：虽然治疗1型糖尿病的高血糖通常被认为需要外源性胰岛素，但最近的证据表明，药理剂量的瘦素也可以诱导这种效应。我们最近的发现表明大脑参与了这一效应，并证明大脑中的瘦素通过增加肝脏对葡萄糖的摄取和减少肝脏的葡萄糖输出来使未控制的胰岛素缺乏糖尿病(UDM)模型中的糖尿病高血糖正常化。这项建议的首要目标是确定大脑如何与周围组织沟通，以调节瘦素的抗糖尿病效果，所产生的数据有望促进控制血糖的新方法的开发。