REGULATION OF FFA METABOLISM IN NORMAL & DIABETIC HUMANS

这项研究将继续我们在体内领域的工作， 调节人体脂肪分解。 对这一点的更好理解 鉴于游离脂肪酸的异常， 与肥胖和控制不良的糖尿病相关的代谢，以及 游离脂肪酸在胰岛素发病机制中的潜在关键作用 抵抗、非胰岛素依赖型糖尿病和高脂血症。 拟议 研究将首先比较甘油和游离脂肪酸作为潜在的 内源性脂解示踪剂，结合同位素稀释法 测量前臂和腹部的动静脉差异 脂肪组织 这些实验将研究是否在原位 游离脂肪酸的再酯化发生在脂肪组织中，以及 由于甘油的水解，甘油被释放到循环中， 肌内甘油三酯 后续研究将评估其影响 脉冲式与连续输注生长激素和胰岛素的比较， 脂肪分解 将进行研究，以调查 血浆生长抑素的生理学或药理学增加导致 抗脂肪分解作用。 其他研究将确定是否循环 底物（酮体、乳酸盐、谷氨酰胺和游离脂肪酸 本身）具有直接的抗脂肪分解作用，不依赖于胰岛素。 具体地说，这些研究将1）确定甘油或游离甘油 脂肪酸示踪剂是上级的量化率的全身 脂解; 2）确定是否需要脉动递送以获得最佳的 生长激素的脂肪分解作用; 3）确定胰岛素是否 抗脂肪分解作用通过脉冲，相对于连续， 以及脉冲式递送是否改善胰岛素抵抗， 关于非胰岛素依赖型糖尿病患者的脂解; 4） 确定生长抑素输注是否具有抗脂肪分解作用 独立于胰岛素或生长激素的变化;和5）确定 无论是酮体、乳酸盐、谷氨酰胺和游离脂肪酸， 抑制内源性脂解作用。 因此，该项目代表了一个 全面调查，以优化示踪方法， 两种关键的脂解调节剂（生长激素和 胰岛素），并确定生长抑素和底物的作用， 脂解的调节剂。 这些研究将提供新的见解， 调节体内脂肪分解，并将导致更多的研究， 底物和激素相互作用在调节燃料中的作用 人体新陈代谢

The proposed research will continue our work in the area of in vivo regulation of lipolysis in humans. An improved understanding of this process is greatly needed in view of the abnormalities in free fatty acid metabolism associated with obesity and poorly controlled diabetes, and the potential key role of free fatty acids in the pathogenesis of insulin resistance, noninsulin-dependent diabetes and hyperlipidemia. The proposed studies will initially compare glycerol and free fatty acids as potential tracers of endogenous lipolysis, combining isotope dilution methodology with measurement of arteriovenous differences in the forearm and abdominal adipose tissue. These experiments will examine whether in situ reesterification of free fatty acids occurs in adipose tissue, and whether glycerol is released into the circulation as a result of hydrolysis of intramuscular triglyceride. Subsequent studies will evaluate the effects of pulsatile versus continuous infusions of growth hormone and insulin on lipolysis. Studies will be undertaken to investigate whether either physiologic or pharmacologic increases in plasma somatostatin result in antilipolytic effects. Other studies will determine whether circulating substrates (ketone bodies, lactate, glutamine and free fatty acids themselves) have direct antilipolytic effects, independent of insulin. Specifically, these studies will 1) determine whether a glycerol or a free fatty acid tracer is superior for quantifying rates of whole body lipolysis; 2) determine whether pulsatile delivery is required for optimal lipolytic effects of growth hormone; 3) determine whether insulin's antilipolytic effects are enhanced by pulsatile, versus continuous, delivery and whether pulsatile delivery improves insulin resistance as regards lipolysis in patients with noninsulin-dependent diabetes; 4) determine whether somatostatin infusion has antilipolytic effects independent of changes in insulin or growth hormone; and 5) determine whether ketone bodies, lactate, glutamine and free fatty acids directly inhibit endogenous lipolysis. Thus, this project represents a comprehensive investigation to optimize tracer methodology, to characterize in full the effects of two key lipolytic regulators (growth hormone and insulin), and to determine the role of somatostatin and substrates as modulators of lipolysis. These studies will provide new insights into the regulation of lipolysis in vivo, and will lead to additional studies of the effects of substrate and hormonal interaction in the regulation of fuel metabolism in man.