INSULIN-LIKE GROWTH FACTOR-I AND MORE POTENT VARIANTS RESTORE GROWTH OF DIABETIC RATS WITHOUT INDUCING ALL CHARACTERISTIC INSULIN EFFECTS

The effects of graded doses of insulin-like growth factor-I (IGF-I) and two variants which bind poorly to IGF-binding proteins were investigated in 160 g streptozotocin-induced diabetic rats. The two variants were the truncated form, des(1-3)IGF-I, and another with arginine at residue 3 and an N-terminal extension, termed LR3-IGF-I. The peptides were infused via mini-osmotic pumps. Reference groups received either vehicle or insulin (30 i.u. per day). Treatment led to a marked dose-dependent increase in growth rate and nitrogen balance. The highest dose (695 mug/day) of IGF-I increased body weight by 48.1 +/- 1.7 g/7 days, compared with 11.0 +/- 2.8 g/7 days for the vehicle-treated group. The two variants were 2.5-3 times more potent than IGF-I in restoring growth. The insulin-treated group gained more weight (64.5 +/- 1.6 g/7 days), but the added gain was fat (92.5 +/- 4.8 g of fat/kg carcass wet wt., compared with 32.2 +/- 2.1 for all other groups) rather than protein. All peptides increased muscle protein-synthesis rates and RNA levels by up to 50%, with IGF-I the least potent. These high doses of IGFs did not decrease either the glucosuria or the daily excretion rate of N(T)-methylhistidine (N(T)-MH). On the other hand, insulin treatment markedly decreased both glucosuria (from 82.7 +/- 5.4 to 4.5 +/- 3.3 mmol/day) and N(T)-MH excretion (from 9.3 +/- 0.3 to 7.1 +/- 0.4 mumol/day per kg). This experiment shows that, although IGF-I and variants can restore growth in diabetic rats, other insulin-dependent metabolic processes in liver, muscle and adipose tissue are not restored.