Neuroendocrine Control of Glucose Metabolism

葡萄糖代谢的神经内分泌控制

• 批准号: 8826104
• 负责人: GREGORY J MORTON
• 金额: $ 38.37万
• 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/8826104
• 关键词: Adipose tissue; Animal Model; Animals; Area; Beta Cell; Blood Glucose; Body fat; Brain; Brown Fat; Celiac ganglion; Cells; Collaborations; Communication; Cre-LoxP; Data; Development; Diabetes Mellitus; Dilution Techniques; Dose; Eating; Fatty acid glycerol esters; Genetic Recombination; Glucagon; Glucose; Goals; Health; 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; neuronal circuitry; 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.

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，诱导高瘦素血症可完全改善链脲佐菌素 (STZ) 诱导的糖尿病大鼠的高血糖，并且我们最近的发现表明大脑参与了这种效应。我们的新初步数据表明，这种瘦素效应涉及一种新颖的、独立于胰岛素的机​​制，其特征是肝葡萄糖生成率 (HGP) 降低和组织葡萄糖摄取率增加，并确定大脑有能力使 uDM 中的血糖水平正常化。这些观察结果与之前描述的任何中枢神经系统（CNS）瘦素作用不同，并支持该提案的总体目标，即描绘瘦素激活的神经元回路和外周机制，介导其抗糖尿病作用。具体来说，我们假设瘦素对肝脏和胰腺交感神经流出的抑制会降低 uDM 中的 HGP，并且这种效应涉及黑皮质素途径。此外，我们假设瘦素诱导的室旁核（PVN）中促甲状腺素释放激素（TRH）神经元子集的激活刺激葡萄糖摄取，从而有助于瘦素在uDM中的降血糖作用。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、手术和免疫组织化学方法，并使用 CreloxP 重组技术建立条件敲除小鼠模型。因此，该提案中生成的数据有望识别瘦素作用下游的特定神经元子集，这些神经元子集连接大脑和周围组织之间的通讯，以控制 HGP 和葡萄糖的摄取。这些研究的进行有可能促进糖尿病治疗新方法的开发。