CNS Mechanisms Controlling Blood Glucose Levels in Uncontrolled Diabetes Mellitus

未受控制的糖尿病中控制血糖水平的中枢神经系统机制

• 批准号: 8656055
• 负责人: THOMAS Harris MEEK
• 金额: $ 3.55万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8656055
• 关键词: Affect; Amputation; Area; Attenuated; Beta Cell; Blindness; Blood Glucose; Blood Vessels; Body fat; Brain; Brain-Derived Neurotrophic Factor; Cardiovascular Diseases; Characteristics; Complement; Cre-LoxP; Data; Development; Diabetes Mellitus; Dilution Techniques; Dose; Eating; Gene Expression; Genetic; Genetic Recombination; Glucagon; Glucose; Goals; Health; Hepatic; Homeostasis; Hormones; Hyperglycemia; Hyperphagia; Hypothalamic structure; Incidence; Infusion procedures; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Kidney Diseases; Knockout Mice; Leptin; Leptin deficiency; Liver; Mediating; Methods; Microinjections; Modeling; Mus; Neurons; Obesity; Operative Surgical Procedures; Performance; Peripheral; Plasma; Prevalence; Publishing; Rattus; Receptor Gene; Regulation; Research; Resolution; Rodent Model; Role; SF1; Signal Transduction; Study models; Technology; Testing; Tissues; Tracer; Universities; Vascular Diseases; Viral; Viral Genes; Washington; base; blood glucose regulation; diabetic; energy balance; gene therapy; glucose metabolism; glucose output; glucose production; glucose uptake; high risk; leptin receptor; mouse model; novel; promoter; public health relevance; treatment strategy; ventromedial hypothalamic nucleus; virus genetics

DESCRIPTION (provided by applicant): The incidence and prevalence of diabetes is increasing globally. This is a major health concern given that diabetes is associated with a higher risk of cardiovascular disease and both macro- and micro-vascular disease including blindness, amputation and renal disease. In addition to its role in energy homeostasis, the adiposity hormone, leptin, is strongly implicated in the control of glucose metabolism during uncontrolled insulin-deficient diabetes (uDM). In support of this, systemic administration of pharmacological doses of leptin normalizes blood glucose levels in a rodent model of uDM. Our data implicate the brain in this effect as infusion of leptin directly into the brain completely normalizes blood glucose levels in a rodent model of uDM independent of its effects to reduce food intake. Moreover, this effect involves a novel, insulin-independent mechanism characterized by reduced rates of hepatic glucose production (HGP) and increased rates of tissue glucose uptake. The primary goal of this proposal is to delineate the distinct hypothalamic neuronal subsets which mediate the specific actions of leptin to lower HGP and those that increase glucose uptake. Based on our Preliminary Data showing that leptin administration selectively to the VMN attenuates diabetic hyperglycemia in uDM and that this effect is accompanied by normalization of increased hepatic glucogenic gene expression, we hypothesize that the VMN mediates leptin-induced suppression of HGP. Moreover, we hypothesize that leptin-mediated suppression of HGP is mediated by hypothalamic brain-derived neurotrophic factor (BDNF) neurons. This hypothesis is supported by our Preliminary Data demonstrating that administration of BDNF directly into the brain lowers blood glucose levels in uDM via a potent suppression of HGP, without effects on tissue glucose uptake. To accomplish these objectives, we will employ advanced gene-therapy based approaches in combination with pharmacological, immunohistochemical and surgical approaches along with sophisticated tracer dilution techniques. Furthermore, we will utilize these approaches in combination with established conditional knockout mouse models using Cre-loxP recombination technology. Together, these studies will expand our understanding of the distinct hypothalamic neuronal subsets which mediate the specific actions of leptin to lower HGP or increase glucose uptake. Performance of these studies is thereby hoped to inform the development of more effective diabetes treatment strategies.

描述（由申请人提供）：糖尿病的发病率和患病率在全球增加。鉴于糖尿病与心血管疾病以及宏观和微血管疾病的风险更高有关，这是一个主要的健康问题，包括失明，截肢和肾脏疾病。除了其在能量稳态中的作用外，肥大激素瘦素还与不受控制的胰岛素缺陷型糖尿病（UDM）中的葡萄糖代谢控制很大。为此，在UDM的啮齿动物模型中，瘦素的药理学剂量的全身给药使血糖水平归一化。我们的数据暗示了大脑在这种作用中直接输注大脑，这完全使UDM啮齿动物模型中的血糖水平完全归一化，而与其作用无关以减少食物摄入。此外，这种作用涉及一种新型的，胰岛素独立的机制，其特征是肝葡萄糖产生速率降低（HGP）和组织葡萄糖摄取的速率增加。该提案的主要目的是描述独特的下丘脑神经元子集，这些下丘脑神经元子集介导瘦素对降低HGP的特定作用以及增加葡萄糖摄取的人。基于我们的初步数据，表明对VMN的瘦素给药可减弱UDM中的糖尿病性高血糖，并且这种作用伴随着增加的肝糖基因基因表达的归一化，我们假设VMN介导了HGP的瘦素诱导的HGP抑制。此外，我们假设瘦素介导的HGP抑制是由下丘脑脑源性神经营养因子（BDNF）神经元介导的。我们的初步数据证明，该假设的支持表明，直接在大脑中给药可通过有效的HGP抑制在UDM中降低血糖水平，而对组织葡萄糖摄取的影响没有影响。为了实现这些目标，我们将采用基于先进的基因治疗方法与药理，免疫组织化学和外科手术方法以及复杂的示踪剂稀释技术结合使用。此外，我们将使用CRE-LoxP重组技术结合建立的条件敲除小鼠模型来利用这些方法。总之，这些研究将扩展我们对独特的下丘脑神经元子集的理解，这些下丘脑介导瘦素降低HGP或增加葡萄糖摄取的特定作用。因此，这些研究的表现希望为更有效的糖尿病治疗策略的发展提供信息。