Role of Free Fatty Acids on Human Insulin Metabolism

游离脂肪酸对人体胰岛素代谢的作用

• 批准号: 7565067
• 负责人: DANIEL T STEIN
• 金额: $ 13.88万
• 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 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7565067
• 关键词: Anabolism; Area; Beta Cell; Biological Assay; C-Peptide; Cell physiology; Data; Defect; Development; Diabetes Mellitus; Dose; Dyslipidemias; Early Diagnosis; Enteral; Esterified Fatty Acids; Event; Exposure to; Failure; Family history of; Fatty acid glycerol esters; Financial compensation; Functional disorder; Glucose; Glucose Intolerance; Goals; Hour; Human; Insulin; Insulin Resistance; Leucine; Light; Link; Lipids; Maintenance; Measures; Metabolic; Metabolism; Methods; Nicotinic Acids; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nutrient; Obesity; Plasma; Prediabetes syndrome; Process; Proinsulin; Rate; Relative (related person); Risk; Role; Structure of beta Cell of islet; Surrogate Markers; Syndrome; Testing; Time; Tracer; Triglycerides; base; diabetic; glucagon-like peptide 1; glucose tolerance; human subject; impaired glucose tolerance; improved; in vivo; insight; insulin secretion; liquid chromatography mass spectrometry; novel; research study; response; size

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. Increased availability of lipid substrates, particularly plasma non-esterified fatty acids and intracellular triglyceride stores have been linked to many aspects of the insulin resistance syndrome including obesity, dyslipidemia and 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 are worsened by excess lipid availability leading to a decreased size of the readily releasable pool of insulin. Incretin action may preserve beta cell function by maintenance of the synthetic rates sufficient to meet metabolic demands. Insulin biosynthetic rates will be measured for the first time in subjects with normal and impaired glucose tolerance by the novel method of mass isotopomer distribution analysis. Lay Summary: 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. We will further determine whether the failure to handle increased fat exposure with more insulin insulin secretion in those at high risk of diabertes is due to decreased insulin synthesis, lack of adequate insulin stores, or an inability to release insulin in a timely fashion.

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。 脂质底物的利用率增加，特别是血浆非酯化脂肪酸 细胞内甘油三酯的储存与胰岛素的许多方面有关， 抵抗综合征，包括肥胖、血脂异常和2型糖尿病。的 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，这些缺陷会因脂质过多而恶化 导致易于释放的胰岛素池的尺寸减小。肠促胰岛素作用可能 通过维持足以满足以下要求的合成速率来保护β细胞功能： 代谢的需求。胰岛素的生物合成率将在2010年首次测量。 正常和受损的葡萄糖耐量受试者通过新的方法质量 同位素分布分析 2型糖尿病的发病率是多少？ 胰腺β细胞无法产生足够的胰岛素，或者只是无法 识别葡萄糖并适当地释放胰岛素。该提案将衡量 第一次在正常受试者、高危受试者和2型糖尿病患者中合成胰岛素 糖尿病我们将进一步确定是否未能处理增加的脂肪暴露 在糖尿病高危人群中，胰岛素分泌增加是由于 胰岛素合成，缺乏足够的胰岛素储备，或不能在一个特定的时间内释放胰岛素。 及时的时尚。