REGULATION OF FFA METABOLISM IN NORMAL & DIABETIC HUMANS

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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.