OBESITY, LACTATE OVERPRODUCTION AND INSULIN RESISTANCE

肥胖、乳酸过量和胰岛素抵抗

• 批准号: 3239133
• 负责人: MARIO DI GIROLAMO
• 金额: $ 13.2万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-08-01 至 1992-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3239133
• 关键词: adipocytes; artificial endocrine pancreas; blood chemistry; enzyme mechanism; fatty acid biosynthesis; glucose; glucose metabolism; glucose tolerance test; hormone regulation /control mechanism; human subject; hyperinsulinism; insulin; insulin sensitivity /resistance; laboratory rabbit; laboratory rat; lactates; noninsulin dependent diabetes mellitus; obesity; pancreatic islet function; pyruvate dehydrogenase; radioimmunoassay

The proposed studies intend to explore indepth provocative new findings in obesity, namely, that with adipocyte enlargement a major shift occurs in the fat cells toward nonoxidative glucose metabolism and enhanced production of lactate, a water-soluble substrate easily exported from the fat cells and potentially capable of influencing hepatic glucose production and peripheral utilization of glucose. The applicant proposes to investigate the magnitude, regulation, and significance of lactate overproduction by adipocytes from progressively obese animals and humans, and to explore the mechanisms by which lactate overproduction may contribute to the carbohydrate intolerance, hyperinsulinemia and insulin resistance associated with the development of obesity and obesity-related non-insulin-dependent (Type II) diabetes mellitus. The investigation will include following objectives: a) To evaluate the relative and absolute production of lactate from glucose by adipocytes from different adipose regions in the rabbit and in the human, in relation to the degree of adiposity, and cell size and number. Adipocyte cellular enzymatic mechanisms and the experimental conditions which regulate fluxes of glucose into its major metabolic products (CO2, glyceride-fatty acids, glyceride-glycerol and lactate) will be studied in the rat. b) To determine, by studies with perfused adipose tissue of rats and rabbits in vivo, the quantitative contribution of adipose tissue to lactate economy, in relation to the animals's degree of adiposity, and glucose and insulin concentrations in the perfusing medium. c) To determine, in vivo in rats and in human volunteers, the effects of gradual elevation of circulating lactate levels on hepatic glucose production, peripheral utilization of glucose, plasma insulin levels, and degree of insulin resistance, by euglycemic clamp techniques. Obesity is a major health hazard in the western world due to its association with hypertension, hyperlipidemia, and diabetes. The health relatedness of this proposal resides in the elucidation of novel pathophysiologic and metabolic events accompanying the development of obesity and possibly contributing to the carbohydrate intolerance and insulin resistance of Type II diabetes.

拟议的研究旨在深入探索具有挑战性的新 肥胖症的发现，即脂肪细胞增大 脂肪细胞发生向非氧化葡萄糖的重大转变 新陈代谢和增强乳酸的产生，乳酸是一种水溶性物质 底物很容易从脂肪细胞中输出，并且有可能 能够影响肝脏葡萄糖的产生和外周血 葡萄糖的利用。 申请人提议调查 乳酸过量产生的程度、调节和意义 来自逐渐肥胖的动物和人类的脂肪细胞，以及 探索乳酸过量产生的机制 导致碳水化合物不耐受、高胰岛素血症和 胰岛素抵抗与肥胖的发展有关 肥胖相关的非胰岛素依赖型（II 型）糖尿病。 调查将包括以下目标： a) 评估乳酸的相对和绝对产量 来自不同脂肪区域的脂肪细胞从葡萄糖中提取 兔子和人类，就肥胖程度而言， 以及细胞大小和数量。 脂肪细胞细胞酶 调节机制和实验条件 葡萄糖流入其主要代谢产物（CO2、 甘油酯-脂肪酸、甘油酯-甘油和乳酸）将是 在老鼠身上进行了研究。 b) 通过对大鼠灌注脂肪组织的研究来确定 和兔子体内，脂肪组织的定量贡献 乳酸经济，与动物的程度有关 肥胖，以及灌注中的葡萄糖和胰岛素浓度 中等的。 c) 确定大鼠和人类志愿者体内的 循环乳酸水平逐渐升高的影响 肝葡萄糖产生、葡萄糖的外周利用、 血浆胰岛素水平和胰岛素抵抗程度 血糖正常钳夹技术。 肥胖是西方世界的主要健康危害，因为 与高血压、高脂血症、糖尿病有关。 这 该提案与健康的相关性在于阐明 伴随着新的病理生理和代谢事件 肥胖的发展并可能导致 II型碳水化合物不耐受和胰岛素抵抗 糖尿病。