METABOLIC FUELS, DIABETES, AND SOMATOMEDIN ACTIVITY

代谢燃料、糖尿病和生长调节素活性

• 批准号: 3231873
• 负责人: LAWRENCE S PHILLIPS
• 金额: $ 21.25万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-08-01 至 1991-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3231873
• 关键词: adult human (21+); bioassay; blood chemistry; blood glucose; cartilage development; cellular pathology; child (0-11); diabetes mellitus; diabetes mellitus therapy; dietary constituent; gel filtration chromatography; growth inhibitors; high performance liquid chromatography; hormone regulation /control mechanism; human subject; insulin; insulin dependent diabetes mellitus; insulinlike factor; insulinlike growth factor; ion exchange chromatography; isolation perfusion; laboratory rabbit; laboratory rat; liver metabolism; malnutrition; medical complication; metabolism disorder; nutrient interaction; nutrition related tag; obesity; postnatal growth disorder; radioimmunoassay; urinalysis

Although poor growth in diabetes and malnutrition is attributed to decreased utilization of nutrients, the mechanism of the defect is not known. Skeletal growth is attributed to stimulation of cartilage by somatomedins, circulating factors with broad anabolic effects. Other circulating factors, inhibitors, limit the actions of somatomedins; both are reflected in bioassay measurements of net somatomedin activity, and both appear to be generated by the liver according to insulin and nutritional status. While alterations in somatomedins and inhibitors might direct utilization of nutrients toward or away from growth, control processes are poorly understood. To elucidate mechanisms, we propose: 1. To examine the nature of the circulating somatomedin inhibitors, a) the high-MW inhibitor in human plasma and the low-MW inhibitor in rat serum will be isolated and characterized; and b) attempts made to raise antibodies which can be used to enhance purification, elucidate biological actions, and refine assessment of regulation in vivo. 2. To define potential modulation of nutrient utilization according to the balance of somatomedins and inhibitors, a) inhibitor effects on somatomedin and insulin action will be examined in models of skeletal elongation and calorie storage; b) interactions characterized in terms of reversibility, kinetics, and temporal sequence of impact on somatomedin and insulin action; and c) effects on binding tested as a possible locus of antagonism of insulin action. 3. To assess metabolic determinants of hepatic contributions of somatomedins and somatomedins and somatomedin inhibitors, a perfusion model will be used to quantify formation (content and release) of somatomedins and inhibitors a) in response to changes in donor metabolic status; b) as related to hepatic glycogen, gluconeogenesis, and ketogenesis; and c) as potentially affected by enzymatic regulatory factors which could control both fuel metabolism and somatomedin/inhibitor formation in concert. 4. To evaluate metabolic regulation in vivo, fuel- and/or insulin-limited modulation will be delineated in terms of a) "native" (carrier-bound) somatomedins and inhibitors fractionated by HPLC and quantitated by bioassay; b) "total" serum IGF-1 extracted and measured by RIA; and c) "free" somatomedins as reflected by IGF-1 in urine. These studies should provide improved understanding of the regulation of normal growth, insight into the pathophysiology of impaired growth, and new concepts for therapy of growth failure in diabetes and malnutrition.

尽管糖尿病和营养不良的不良增长归因于 营养素利用率下降，缺陷的机制不是 知道的 骨骼生长归因于软骨的刺激 生长调节素，具有广泛合成代谢作用的循环因子。 其他 循环因子，抑制剂，限制生长调节素的作用;两者 反映在净生长调节蛋白活性的生物测定测量中， 两者似乎都是由肝脏根据胰岛素产生的， 营养状况 虽然生长调节素和抑制剂的改变可能 直接利用营养物质朝向或远离生长，控制 过程知之甚少。 为了阐明机制，我们建议：1。 为了检查循环生长调节素抑制剂的性质，a） 人血浆中的高分子量抑制剂和大鼠血清中的低分子量抑制剂 将被隔离和表征;和B）试图提高 可用于增强纯化、阐明生物学特性、 行动，并完善体内调节的评估。 2.以限定 根据平衡的养分利用的潜在调节 a）对生长调节素的抑制剂作用， 将在骨骼伸长模型中检查胰岛素作用， 热量储存; B）以可逆性为特征的相互作用， 动力学和对生长调节素和胰岛素影响的时间顺序 作用;和c）对结合的影响，作为拮抗作用的可能位点进行测试 胰岛素的作用。 3.评估肝脏的代谢决定因素， 生长调节素和生长调节素以及生长调节素抑制剂的贡献， 灌注模型将用于量化形成（含量和释放） 生长调节素和抑制剂a）响应供体代谢的变化 状态; B）与肝糖原、肝再生相关，以及 生酮;和c）可能受酶调节因子的影响 它可以控制燃料代谢和生长调节素/抑制剂 形成一致。 4.为了评估体内代谢调节，燃料- 和/或胰岛素限制性调节将根据以下描述：a） 通过HPLC分级分离的"天然"（载体结合）生长调节素和抑制剂 并通过生物测定法定量; B）提取并测量的"总"血清IGF-1 通过RIA测定;和c）尿中IGF-1反映的"游离"生长调节素。 这些 研究应该提供更好的理解正常的调节， 生长，深入了解受损生长的病理生理学，以及新的 治疗糖尿病和营养不良的生长障碍的概念。