Preferential intestinal delivery of long[arg(3)] Insulin-like growth factor (LR(3)IGF-I) over IGF-I in preweaning and adult rats

Abstract

During early postnatal development, the intestine is highly responsive to LR3IGF-I administration but refractory to IGF-I, in contrast to the mature intestine. Given that LR3IGF-I is an IGF-I analog that binds poorly to IGF binding proteins, the response of the intestine is likely to reflect regulation of IGF-I bioactivity by IGF binding proteins. This study measures the delivery of exogenous IGF-I peptides to the intestine in preweaning (d-19) and adult rats to determine whether a correlation exists with the potency advantage of LR3IGF-I in the intestine during postnatal development. IGF-I or LR3IGF-I (2.6 µg/kg) was spiked with corresponding 125I-labeled peptide (10 x 106 cpm) and administered iv as a bolus (n = 5–6/group) with blood and tissue samples collected 5 and 10 min post injection. In both age groups, the levels of 125I-IGF-I retained in the blood at both 5 and 10 min were higher than the levels of 125I-LR3IGF-I, consistent with the slower clearance rate for the native peptide. In the gastrointestinal tract, the levels of 125I-LR3IGF-I per gram of tissue were 37–50% higher than 125I-IGF-I. Surprisingly, there was little difference in the relative delivery of LR3IGF-I to IGF-I to the intestine, across developmental age. Although bolus iv-injected LR3IGF-I was cleared more rapidly from the circulation than IGF-I and was subsequently delivered to the intestine in higher amounts than the native peptide, the ratio of LR3IGF-I to IGF-I in gut tissues was approximately 2:1 in both age groups. Hence, selective delivery to the gut is unlikely to explain the markedly higher potency of 125I-LR3IGF-I in stimulating growth of the preweaning vs. adult intestine.