In vivo actions of IGF analogues with poor affinities for IGFBPs: Metabolic and growth effects in pigs of different ages and GH responsiveness

Abstract

IGF-I analogues that bind poorly to IGFBPs are substantially more potent than IGF-I at stimulating growth in rats. However, rodents differ from other mammals because they contain only minimal circulating levels of IGF-II and they are poorly responsive to GH. In this report we review a series of experiments carried out in pigs, a species that is both GH responsive and has high blood concentrations of IGF-II. Intravenous bolus administration of IGFs to 55 kg pigs depressed blood glucose with the potency greatest for analogues such as des(1–3)IGF-I, R³IGF-I and LongR³IGF-I that showed the weakest binding to pig IGFBP-3, a similar efficacy pattern to that reported in the rat. Chronic subcutaneous administration of LongR³IGF-I, however, reduced growth rates, led to a depression in food intake and lowered concentrations of IGF-I, IGF-II and IGFBP-3. IGF-I itself depressed IGF-II concentrations and did not stimulate growth. Subcutaneous infusion of IGFs over a 3-day period, also in 55 kg pigs, demonstrated that analogues that bound least well to IGFBP-3 were the most effective at reducing the concentration of this binding protein, suggesting that the inhibition of growth was related to the depression of IGFBP-3. On the other hand, IGF-I and LongR³IGF-I increased growth rats in neonatal pigs, especially under conditions of reduced food intake. As these anabolic effects occur at a developmental stage where the animals are insensitive to GH in a manner analogous to the situation in rats, it is plausible that the feed-back inhibition of GH secretion explains the catabolic response to IGFs in older pigs.