In vivo isotopic studies of the metabolic effects of recombinant human growth hormone and insulin-like growth factors I and II

Abstract

The continued loss of protein from patients with severe sepsis, trauma or cancer cachexia, which occurs despite the provision of adequate calories and nitrogen, remains a challenge for surgeons and intensivists involved in their care. Prolonged loss of protein may impair cardiopulmonary and immune function and wound healing, and so its effective treatment may represent a considerable clinical advance. In this thesis, studies have been performed in both Patients and laboratory animals which investigate the potential of human growth hormone and insulin-like growth factors to slow or reverse the accelerated protein catabolism associated with severe surgical illness. In the patient studies, the following issues have been addressed: i) The effects of a short course of recombinant human growth hormone (rhGH) on the rate of net protein loss, whole body protein turnover, glucose kinetics, free fatty acid and glycerol concentrations and total carbohydrate and fat oxidation have been measured in septic and injured patients in both postabsorptive and parenterally fed states. ii) The effects of a short course of recombinant human growth hormone on the rate of protein synthesis has been determined in tissues removed from patients with cancer. In the animal studies the following issues have been addressed; i)The effects of acute infusions of recombinant human insulin-like growth factor I (rhIGF-I) on the rate of net protein loss, whole body protein turnover, tissue protein synthesis, glucose kinetics and free fatty acid and glycerol concentrations have been measured. The actions of rhIGF-I infusion were then compared to those of an insulin infusion of equivalent hypoglycaemic potential and to an equimolar infusion of recombinant human insulin-like growth factor II (rhIGF-II). ii) The difficulty in achieving nitrogen accretion in patients with critical surgical illness or cancer cachexia may result from metabolic derangements caused by release of inflammatory mediators such as tumour necrosis factor (TNF). In order to determine whether recombinant human insulin-like growth factor I (rhIGF-I) preserved its protein sparing effects in the face of high plasma TNF concentrations, rhIGF-I was infused into lambs which were simultaneously receiving infusions of recombinant human tumour necrosis factor (rhTNF), and the change in the rate of net protein loss compared to control animals who received rhIGF-I alone. The major findings of the human studies were as follows: i) In parenterally fed patients, rhGH treatment almost halved the rate of net protein loss, although a positive nitrogen balance was not achieved. The rate of whole body protein turnover was not altered, suggesting that the reduction in net protein loss was due to an increase in the rate of protein synthesis rather than reduced catabolism. In the post absorptive group, rhGH treatment increased the rate of appearance and oxidation of free fatty acids and reduced the rate of protein oxidation, from which it was concluded that fat was being oxidized in preference to protein. ii) The rate of protein synthesis in skeletal muscle tissue removed from patients with cancer undergoing resection to whom a short course of rhGH had been administered was significantly greater than that of a matched group of control patients, however the rate of protein synthesis in the tumour per se was not increased. It appears that rhGH favourably alters host tissue protein kinetics without accelerating the rate of tumour protein synthesis. The important results from the animal studies were as follows: i) Infusion of rhIGF-I reduced the rate of net protein loss by both increasing the rate of protein synthesis and reducing the rate of protein catabolism. The rate of protein synthesis was increased by a greater extent in the heart and in the diaphragm than in other skeletal muscles. High rates of rhIGF-I infusion which saturated the plasma IGF-I binding capacity lowered the blood glucose concentration by enhancing peripheral glucose uptake. Infusion of an equimolar dose of rhIGF-II did not influence protein kinetics but did result in a small increase in the rate of glucose clearance. Insulin infused at a dose which resulted in the same degree of hypoglycaemia as the rhIGF-I infusion caused a similar reduction in the rate of net protein loss but did not accelerate the rate of protein synthesis in any of the tissues examined. ii) Recombinant human TNF infusion resulted in pyrexia and increased the plasma glucose, cortisol, glucagon and insulin concentrations. The reduction in the rate of net protein loss following rhIGF-I infusion in rhTNF infused lambs was identical to that seen in control animals infused with rhIGF-I alone. We conclude that as rhIGF-I preserves its protein anabolic action in the face of high rhTNF levels, further investigation into a possible clinical role for rhIGF-I in severe surgical illness is warranted. In general terms, these studies demonstrate that rhGH administration to septic or injured patients significantly reduces their rate of loss of protein, and that rhIGF-I infusion similarly conserves protein in an animal model of sepsis. These findings present the challenge to determine whether the favourable changes in protein kinetics brought about by the administration of anabolic peptide hormones will realize tangible improvements in the clinical course of severely ill surgical patients.