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: 8121422
• 负责人: DANIEL T STEIN
• 金额: $ 41.4万
• 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/8121422
• 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; Health; 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Controversy exists whether in those at risk for Type 2 Diabetes, there is an inability of pancreatic beta cells to make enough insulin or there is simply a failure to recognize glucose and appropriately release insulin. This proposal will measure for the first time the synthesis of insulin in normal subjects, those at risk, and those with Type 2 Diabetes and compare the results to an animal model of diabetes. We hope to understand whether the failure to release insulin in a timely fashion in those at high risk of diabetes is due to decreased insulin synthesis, lack of adequate insulin stores, or an inability to recognize glucose in the blood.

描述（由申请人提供）：本提案的最终目标是确定导致2型糖尿病的葡萄糖耐量受损的原因。对早期事件的潜在病理生理学的更好的理解应该为2型糖尿病早期诊断和最终治疗的改进方法的发展提供合理的基础。胰腺β细胞对营养过剩和肥胖相关的胰岛素抵抗的反应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仅在那些发展为β细胞功能障碍的人中发展。虽然已经发现β细胞质量在具有葡萄糖耐受不良的糖尿病前期状态的那些中下降约50%，但是关于β细胞分泌应答的缺陷是否是由于合成机制缺陷或葡萄糖感知和胰岛素分泌的功能缺陷而存在争议。该提案将检验胰岛素生物合成中的固有或获得性缺陷表征葡萄糖耐受不良状态的假设，这些缺陷导致响应营养刺激的完全有效的β细胞功能所必需的可快速动员的胰岛素池的耗尽。胰岛素生物合成速率和细胞内β细胞池的相对大小将首次在链脲佐菌素治疗的大鼠体内测量，并在正常，葡萄糖耐量受损和糖尿病受试者中通过质量同位素分布分析的新方法。公共卫生相关性：对于那些有2型糖尿病风险的人来说，是否存在胰腺β细胞无法产生足够的胰岛素或只是无法识别葡萄糖并适当释放胰岛素的争议。该提案将首次测量正常受试者、高危受试者和2型糖尿病患者的胰岛素合成，并将结果与糖尿病动物模型进行比较。我们希望了解糖尿病高危人群中未能及时释放胰岛素是否是由于胰岛素合成减少、缺乏足够的胰岛素储备或无法识别血液中的葡萄糖。