THE CIRCULATING MOLECULAR-WEIGHT FORMS OF INFUSED RECOMBINANT INSULIN-LIKE GROWTH FACTOR-I AND EFFECTS ON GLUCOSE AND FAT-METABOLISM IN LAMBS

We have investigated the relationship between the plasma distribution of infused recombinant 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 H-3 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-mu-g . kg-1 . h-1, n = 3 for each dose). Total plasma insulin-like growth factor-I was significantly elevated by infusion at a rate of 40-mu-g . kg-1 . h-1 (from 185 +/- 14-mu-g/l to 442 +/- 41-mu-g/l, p < 0.05) and 120-mu-g . kg-1 . h-1 (from 181 +/- 2-mu-g/l to 953 +/- 39-mu-g/l, p < 0.005). The plasma concentrations of insulin-like growth factor-I not associated with binding proteins remained undetectable ( < 15-mu-g/l) at the end of the 2.5 and 20-mu-g . kg-1 . h-1 doses, but were significantly elevated at the end of the 40 and 120-mu-g . kg-1 . h-1 infusions (to 71 +/- 14-mu-g/l. p < 0.05 and 176 +/- 55 mu-g/l, 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/l to 1.9 +/- 0.2 mmol/l (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 recombinant insulin-like growth factor-I results primarily from an increase in glucose clearance while glucose metabolism was more sensitive than fat metabolism to infused recombinant 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.