Role of Glucokinase in GLP-1 Regulation of Energy and Glucose Homeostasis

葡萄糖激酶在 GLP-1 能量和葡萄糖稳态调节中的作用

• 批准号: 8417755
• 负责人: DARLEEN A. SANDOVAL
• 金额: $ 31.46万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8417755
• 关键词: Acids; Animals; Area; Beta Cell; Brain; Brain region; Cells; Data; Deoxyglucose; Dependence; Dependency; Down-Regulation; Eating; Effectiveness; Enzymes; Epidemic; Euglycemic Clamping; Fasting; Food Intake Regulation; Glucokinase; Glucose; Glucose Clamp; Goals; Hepatic; Hormones; Hypoglycemia; Hypothalamic structure; In Vitro; Infection; Infusion procedures; Insulin; Intervention; Intestines; Lead; Leucine; Link; Modeling; Molecular; Mus; Nervous system structure; Neuraxis; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Oleic Acids; Pancreas; Peptides; Peripheral; Pharmaceutical Preparations; Population; Rattus; Receptor Activation; Regulation; Role; Signal Transduction; Skeletal Muscle; Stimulus; Structure of beta Cell of islet; System; Techniques; Testing; Work; analog; base; blood glucose regulation; clinically relevant; exenatide; glucagon-like peptide; glucagon-like peptide 1; glucose metabolism; glucose output; glucose production; glucose sensor; glucose uptake; in vivo; insight; insulin secretion; knock-down; novel; nutrient metabolism; prevent; receptor; research study; small hairpin RNA; tool

DESCRIPTION (provided by applicant): Obesity and type 2 diabetes mellitus (T2DM) are worldwide epidemics and the mechanisms that lead from obesity to abnormal glucose homeostasis remain elusive. Accumulating evidence suggests that the neurons within the hypothalamus that sense peripheral nutrients and hormones to regulate food intake also regulate glucose homeostasis. This raises the possibility that CNS mechanisms could link obesity and T2DM. Glucagon-like peptide-1 (GLP-1), secreted by the intestine, is a potent stimulus for insulin secretion and is essential for normal glucose homeostasis. Several long-acting GLP-1 analogs have recently been developed for the treatment of T2DM. These new GLP-1 based drugs are presumed to work directly on the pancreatic beta- cell to promote insulin release. However, GLP-1 is also made in the brain, with receptors in several key regions implicated in the control of food intake and glucose homeostasis. Our preliminary data indicate that GLP-1 signaling within the hypothalamus regulates peripheral glucose levels and that the ability of CNS GLP-1 to regulate both glucose levels and food intake is dependent on glucose availability. In the beta-cell, the ability of GLP-1 to induce insulin secretion is dependent on elevated ambient glucose concentrations, a key control for homeostatic regulation. Glucokinase (GK) has been proposed to function as a glucose sensor, and we propose that the ability of central GLP-1 to regulate energy and glucose homeostasis is dependent upon glucose availability and that this in turn is regulated via GK. Specifically, the goals of this proposal are to determine which populations of GLP-1r within the CNS are linked to GK function and glucose sensing in regulation of both food intake and glucose homeostasis. The long term goals of this proposal are to elucidate specific cellular and neuronal mechanisms that link obesity to type 2 diabetes mellitus.

描述（由申请人提供）：肥胖和2型糖尿病（T2DM）是全球流行病，并且从肥胖到异常的葡萄糖稳态导致的机制仍然难以捉摸。积累的证据表明，下丘脑内的神经元感知外周营养素和激素来调节食物摄入量也调节葡萄糖稳态。这增加了CNS机制可以将肥胖和T2DM连接起来的可能性。由肠道分泌的胰高血糖素样肽-1（GLP-1）是胰岛素分泌的有效刺激，对于正常的葡萄糖稳态至关重要。最近已经开发了几种长效GLP-1类似物来治疗T2DM。假定这些新的基于GLP-1的药物可以直接在胰腺β细胞上起作用，以促进胰岛素释放。但是，GLP-1也是在大脑中制造的，几个关键区域的受体与食物摄入和葡萄糖稳态的控制有关。我们的初步数据表明，下丘脑内的GLP-1信号传导调节外周葡萄糖水平，并且CNS GLP-1调节葡萄糖水平和食物摄入的能力取决于葡萄糖的可用性。在β细胞中，GLP-1诱导胰岛素分泌的能力取决于升高的环境葡萄糖浓度，这是稳态调节的关键控制。葡萄糖酶（GK）已被提议充当葡萄糖传感器，我们提出中央GLP-1调节能量和葡萄糖稳态的能力取决于葡萄糖的可用性，而这反过来又通过GK调节。具体而言，该提案的目标是确定中枢神经系统内的GLP-1R种群与GK功能和葡萄糖感应有关，以调节食物摄入和葡萄糖稳态。该提案的长期目标是阐明将肥胖与2型糖尿病联系起来的特定细胞和神经元机制。