EFFECTS OF INSULIN AND INSULIN-LIKE GROWTH-FACTORS ON PROTEIN AND ENERGY-METABOLISM IN TUMOR-BEARING RATS

The effects of insulin-like growth factor-1 (IGF-I), and a more potent variant LR(3)-IGF-I, which binds poorly to IGF-binding proteins, were investigated in rats bearing a mammary adenocarcinoma. The effect of insulin, either alone or in combination with LR(3)-IGF-I, was also investigated. Peptides were infused via osmotic minipumps for 6-7 days after tumour size reached 5% of body weight. Infusion of IGFs alone at either 200 or 500 mu g/day significantly decreased food intakes as well as circulating levels of insulin and glucose, and consequently failed to promote muscle protein accretion in the host. Tumour growth was increased by the IGFs, especially by LR(3)-IGF-I, even though these peptides did not promote growth of the adenocarcinoma in cell culture. Infusion of LR(3)-IGF-I, and to a lesser extent IGF-I, led to decreased rates of muscle protein synthesis and increased muscle protein breakdown, but each of these measures was closely related to the final tumour burden (r(2) = 0.454 and 0.810 respectively; P < 0.01) and possibly resulted from a decrease in substrate supply to the host tissues. Insulin infusion (100 mu g/day) increased food consumption by more than 50% and significantly decreased tumour growth. Insulin and LR(3)-IGF-I had a synergistic effect on host weight, which increased by 19.1+/-1.9, -1.1+/-4.7 and 37.9+/-1.5 g for insulin, LR(3)-IGF-I and combined treatments respectively. Carcass protein was increased by more than 10% with insulin treatment, due to increased rates of synthesis and decreased rates of muscle protein breakdown, but LR(3)-IGF-I had no positive effect on carcass protein accretion, either alone or in combination with insulin. Similarly, the amount of carcass fat was increased almost 2-fold by insulin treatment, whereas it was decreased by 30% by LR(3)-IGF-I. These changes may have arisen either from direct hormone effects on metabolism or from the indirect effects of food intake, or both. Our results suggest that IGF administration may exacerbate an insulin insufficiency associated with the tumour-bearing state and further decrease metabolic substrate supply to the host. This can be overcome by co-infusion of insulin.