Quantitation of Factors Regulating Glucose Tolerance

葡萄糖耐量调节因素的定量

• 批准号: 7920587
• 负责人: RICHARD Nathan BERGMAN
• 金额: $ 10.06万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7920587
• 关键词: Acarbose; Adrenal Cortex Hormones; Binding; Blood Circulation; Canis familiaris; Carbohydrates; Cell physiology; Cells; Denervation; Diabetes Mellitus; Diet; Down-Regulation; Employee Strikes; Energy Intake; Equilibrium; Failure; Fasting; Fatty acid glycerol esters; Financial compensation; Functional disorder; GLP-I receptor; Gastrointestinal tract structure; Glucocorticoids; Glucose; Glucose Intolerance; Hepatic; Hormone Antagonists; Hormones; Hydrocortisone; Hyperglycemia; Individual; Infusion procedures; Ingestion; Insulin; Insulin Resistance; Intake; L Cells; Lead; Liver; Measurable; Measures; Mediating; Mediator of activation protein; Metabolic; Metformin; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Normal Range; Nutrient; Obesity; Oral; Pathogenesis; Pattern; Peptides; Peripheral; Physiologic pulse; Play; Portal vein structure; RU-486; Reflex action; Resistance; Role; Secondary to; Signal Transduction; Simulate; Somatotropin; Somatotropin-Releasing Hormone; Testing; Third ventricle structure; Time; Up-Regulation; Viscera; Visceral; diabetes risk; disorder prevention; fasting glucose; feeding; gastrointestinal; glucagon-like peptide 1; glucose disposal; glucose output; glucose tolerance; impaired glucose tolerance; inhibitor/antagonist; insulin secretion; intravenous administration; islet; prevent; receptor; receptor upregulation; response; subcutaneous

Normal glucose tolerance is maintained by a balance between insulin secretion and insulin action to enhance glucose disposal and regulate glucose output. In normal individuals basal and postprandial insulinemia increases so that glycemia does not exceed the normal range at basal and with meals. This compensation is due to upregulation of 13-cell sensitivity to secretagogues, as well as downregulation of first-pass liver insulin clearance. Impaired glucose tolerance results when there is inadequate compensation for insulin resistance, and as this dysfunction progresses, diabetes develops. The precise mechanisms by which resistance results in 13-cellupregulation are not known. We are examining several mechanisms which may play a role in hyperinsulinemic compensation for insulin resistance. We exploit the isocaloric or hypercaloric fat-fed dog model, which develops visceral adiposity, insulin resistance and a well-defined pattern of compensation. We will determine whether postprandial or nocturnal glucose or free fatty acids explain upregulation of p-cell function. We will counter increases in postprandial nutrients with pharmacological agents (acarbose and/or metformin). We examine the relationship between cortisol and growth hormone and metabolic compensation, and disrupt the secretion/action of these hormones with antagonists infused systemically or into the third ventricle of the brain. We consider whether gastrointestinal peptide GLP-1 is an important mediator of the compensatory response to insulin resistance. We hypothesize that GLP-1 is stimulated in the fat-fed model and acts via specific receptors in the portal vein. The putative GLP-1 reflex will be blocked by denervation of the portal vein, or with portal infusion of GLP- 1 antagonists. We will examine whether portal GLP-1 plays a vital role in the putative action of the peptide to upregulate islets in the insulin resistant state. Failure of "compensatrins" to upregulate may be the earliest change in the pathogenesis of Type 2 diabetes. Identification of the origin and metabolic actions of such molecules should lead to more accurate identification of those at risk for diabetes, and allow for prevention of the disease.

正常的葡萄糖耐量通过胰岛素分泌和胰岛素作用之间的平衡来维持 增强葡萄糖处置并调节葡萄糖输出。在普通人中，基础和餐后 胰岛素血症增加，因此血糖不超过基础和进餐时的正常范围。 这种补偿是由于对13细胞的敏感性的上调以及 第一通通肝胰岛素清除的下调。当有葡萄糖耐受性受损时 胰岛素抵抗的补偿不足，随着这种功能障碍的发展，糖尿病 发展。不知道抗性导致13个细胞调节的确切机制。 我们正在研究几种可能在高胰岛素补偿中起作用的机制 胰岛素抵抗。我们利用了发展的等级或高脂肪喂养的狗模型 内脏肥胖，胰岛素抵抗和明确的补偿模式。我们将确定 无论是餐后还是夜间葡萄糖或游离脂肪酸，可以解释P细胞功能的上调。 我们将用药理学剂（Acarbose和/或 二甲双胍）。我们检查皮质醇与生长激素与代谢之间的关系 补偿，并破坏这些激素对注入的拮抗剂的分泌/作用 全身或进入大脑的第三个心室。我们考虑胃肠道肽是否 GLP-1是胰岛素抵抗的补偿性反应的重要介体。我们假设 该GLP-1在脂肪喂养的模型中刺激，并通过门静脉中的特定受体起作用。这 假定的GLP-1反射将通过门静脉的神经来阻止，或者输注GLP- 1个对手。我们将研究门户网站GLP-1是否在推定行动中起着至关重要的作用 肽在胰岛素抵抗状态下上调胰岛。 “补偿蛋白”无法上调 可能是2型糖尿病发病机理的最早变化。识别起源和 这种分子的代谢作用应导致更准确地识别有风险的人 糖尿病，允许预防疾病。