REGULATION OF FFA METABOLISM IN NORMAL & DIABETIC HUMANS

拟议的研究将继续我们在活体领域的工作 人体内脂肪分解的调节。更好地理解这一点 鉴于游离脂肪酸的异常，很需要进行加工 与肥胖和糖尿病控制不佳有关的代谢，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。建议数 研究将初步比较甘油和游离脂肪酸作为潜在的 内源性脂解示踪剂，结合同位素稀释方法学 测量前臂和腹部的动静脉差值 脂肪组织。这些实验将检验是否在现场 游离脂肪酸的再酯化发生在脂肪组织中，以及 甘油被释放到血液循环中，这是由于 肌肉中的甘油三酯。后续研究将评估这些影响。 脉冲式与持续性输注生长激素和胰岛素的比较 脂肪分解。将进行研究，以调查是否有 生理性或药理性的血浆生长抑素增加会导致 降脂作用。其他研究将确定循环 底物(酮体、乳酸、谷氨酰胺和游离脂肪酸 本身)有直接的抗脂作用，不依赖于胰岛素。 具体地说，这些研究将1)确定甘油或游离 脂肪酸示踪剂在量化全身速率方面更具优势 脂肪分解；2)确定是否需要脉冲式递送以获得最佳 生长激素的降脂作用；3)确定胰岛素是否 与连续的相比，脉冲式的降脂作用更强。 脉冲式给药是否改善胰岛素抵抗 关注非胰岛素依赖型糖尿病患者的脂肪分解；4) 确定生长抑素输液是否有降脂作用 与胰岛素或生长激素的变化无关；以及5)确定 酮体、乳酸、谷氨酰胺和游离脂肪酸是否直接 抑制内源性脂肪分解。因此，这个项目代表着一个 全面调查以优化示踪方法，以表征 总而言之，两种关键的脂类调节剂(生长激素和 胰岛素)，并确定生长抑素和底物的作用 脂肪分解的调节剂。这些研究将为我们提供对 体内脂解的调节，并将导致对 底物和激素相互作用在燃料调节中的作用 人类的新陈代谢。

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.