We have investigated the relationship between the plasma distribution of infused recominant insulin-like growth factor-I across the insulin-like growth factor binding proteins and the resultant effects on glucose and fat metabolism. The studies were performed in 24-h fasted ram lambs which received primed constant infusions of 3H labelled glucose tracer. When isotopic equilibrium had been reached, the animals received 90-min infusions of human insulin-like growth factor-I at various doses (2.5, 20, 40 and 120 gg. kg-l.h-% n=3 for each dose). Total plasma insulin-like growth factor-I was significantly elevated by infusion at a rate of 40 gg. kg-1. h i (from 185 + 14 ~tg/1 to 442 _+ 41 gg/1, p<0.05) and 120gg.kg-~.h -1 (from 181+2gg/1 to 953 + 39 gg/1, p < 0.005). The plasma concentrations of insulin-like growth factor-I not associated with binding proteins remained undetectable ( < 15 ~tg/1) at the end of the 2.5 and 20 ~tg. kg 1. h-1 doses, but were significantly elevated at the end of the 40 and 120~tg.kg-l.h -1 infusions (to 71 + 14 gg/1,p < 0.05 and 176 + 55 gg/1,p < 0.01 respectively).
The infused insulin-like growth factor-I associated primarily with 35-60 kilodalton binding proteins. Glucose kinetics were significantly altered only by the highest dose infusion, during which there was a fall in plasma glucose concentration from 3.5 + 0.2 mmol/1 to 1.9 + 0.2 mmol/1 (p < 0.05). This was due to a 51% increase in the rate of glucose clearance. There was no significant change in the rate of glucose production. The plasma concentrations of glycerol and non-esterified fatty acid were not changed by any of the doses infused. We conclude that the hypoglycaemic action of infused recombinant insulin-like growth factor-I relates to a marked elevation of free insulin-like growth factor-I in the plasma, but that a threshold concentration of free insulin-like growth factor-I must be exceeded before this action is observed. The hypoglycaemic action of recominant insulin-like growth factor-I results primarily from an increase in glucose clearance while glucose metabolism was more sensitive than fat metabolism to infused recominant insulin-like growth factor-I. Both these actions contrast with those of insulin, and suggest that the acute metabolic effects of recombinant insulin-like growth factor-I are not mediated simply by cross-reaction with insulin receptors.