METABOLIC FUELS, DIABETES, AND SOMATOMEDIN ACTIVITY

尽管糖尿病和营养不良的不良增长归因于 营养物质利用率降低，这种缺陷的机制不是 为人所知。骨骼的生长归因于对软骨的刺激 生长原子素，具有广泛的合成代谢作用的循环因子。其他 循环因子，抑制物，限制生长抑素的作用；两者 反映在净生长原子素活性的生物测定中，以及 两者似乎都是由肝脏根据胰岛素和 营养状况。而生长抑素和抑制剂的变化可能 直接利用养分朝向或远离生长、控制 人们对流程知之甚少。为了阐明其作用机制，我们提出：1. 为了检查循环中的生长抑素抑制剂的性质，a) 人血浆中高相对分子质量抑制物和大鼠血清中低相对分子质量抑制物 将是孤立的和具有特征的；以及b)试图提高 抗体可用于加强纯化，阐明生物学 行动，并改进对体内调节的评估。2.定义 养分利用的潜在调节--根据养分平衡 生长原子素及其抑制剂，a)对生长原子素及其受体的抑制作用 胰岛素的作用将在骨骼伸长和骨骼延伸的模型中进行检验 卡路里储存；b)以可逆性为特征的相互作用， 影响生长原子素和胰岛素的动力学和时间序列 作用；以及c)被测试为可能的拮抗点的结合的影响 胰岛素的作用。3.评估肝脏代谢决定因素 生长抑素和生长抑制素的贡献， 将使用灌流模型来量化形成(含量和释放)。 生长抑素和抑制剂a)对供体代谢变化的反应 状态；b)与肝糖原、糖异生有关，以及 酮的发生；以及c)可能受酶调节因子影响 它既能控制燃料代谢，又能控制生长抑素/抑制剂 队形齐鸣。4.为了评估体内的代谢调节，燃料- 和/或胰岛素受限的调制将根据a)来描述 “天然”(载体结合型)生长激素及其抑制剂的高效液相色谱分离 并通过生物测定进行定量；b)提取并测定血清IGF-1总量 (C)尿液中IGF-1所反映的“游离”生长抑素。这些 研究应该提供对正常的调节的更好的理解 生长，对生长受损的病理生理学的洞察，以及新的 糖尿病和营养不良的生长障碍的治疗概念。

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.