Role of Insulin Biosynthesis in Glucose Tolerance

胰岛素生物合成在葡萄糖耐量中的作用

• 批准号: 8305143
• 负责人: DANIEL T STEIN
• 金额: $ 41.28万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8305143
• 关键词: Anabolism; Animal Model; Area; Behavior; Beta Cell; Biological Assay; Blood; C-Peptide; Cell physiology; Defect; Development; Diabetes Mellitus; Dose; Early Diagnosis; Equilibrium; Event; Exocytosis; Failure; Functional disorder; Glucose; Glucose Intolerance; Goals; Hepatic; Human; Hyperglycemia; Insulin; Insulin Resistance; Lead; Leucine; Light; Measures; Methods; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Peripheral; Prediabetes syndrome; Process; Proinsulin; Rattus; Relative (related person); Risk; Role; Somatostatin; Stimulus; Streptozocin; Structure of beta Cell of islet; Surrogate Markers; Testing; Time; Tracer; base; diabetic; diabetic rat; exenatide; glucagon-like peptide 1; glucose tolerance; high risk; human subject; impaired glucose tolerance; improved; in vivo; insight; insulin secretion; insulin sensitivity; liquid chromatography mass spectrometry; novel; response

The ultimate goal of this proposal is to determine the cause(s) of impaired glucose tolerance leading to type 2 diabetes. An improved understanding of the underlying pathophysiology of the early events should provide a rational basis for the development of improved methods of early diagnosis and ultimately treatments for type 2 diabetes. The pancreatic beta cell response to nutrient oversupply and obesity associated insulin resistance is compensatory insulin hypersecretion in order to maintain euglycemia. Diabetes, and early states of glucose intolerance only develop in those who develop beta cell dysfunction. Although beta cell mass has been found to decline by ~50% in those with prediabetic states of glucose intolerance, controversy exists as to whether defects in the beta cell secretory response is due to deficient synthetic machinery or functional defects in glucose sensing and insulin secretion. This proposal will test the hypothesis that intrinsic or acquired defects in insulin biosynthesis characterize states of glucose intolerance, that these defects result in depletion of a rapidly mobilizable pool of insulin necessary for fully efficient beta cell function in response to nutrient stimuli. Insulin biosynthetic rates and relative sizes of intracellular beta cell pools will be measured for the first time in vivo in streptozotocin treated rats, and in subjects with normal, impaired glucose tolerance and diabetes by the novel method of mass isotopomer distribution analysis.

本提案的最终目标是确定血糖受损的原因 导致2型糖尿病。更好地理解潜在的 早期事件的病理生理学应该提供一个合理的基础， 2型糖尿病的早期诊断和最终治疗的改进方法。 胰腺β细胞对营养过剩和肥胖相关胰岛素的反应 抵抗是代偿性胰岛素分泌过多，以维持正常。 糖尿病和葡萄糖耐受不良的早期状态只在那些 β细胞功能障碍尽管已经发现β细胞质量在24小时内下降了约50%， 对于那些患有葡萄糖耐受不良的糖尿病前期状态的患者， β细胞分泌反应的缺陷是由于合成机制的缺陷， 葡萄糖感应和胰岛素分泌的功能缺陷。这项提案将考验 胰岛素生物合成中固有或获得性缺陷表征状态假说 葡萄糖耐受不良，这些缺陷导致消耗的快速动员池 对营养刺激作出反应时，β细胞充分发挥有效功能所必需的胰岛素。 胰岛素生物合成速率和细胞内β细胞池的相对大小将被 首次在链脲佐菌素治疗的大鼠体内测量， 正常，受损的葡萄糖耐量和糖尿病的新方法的质量 同位素分布分析