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Preferential Intestinal Delivery of Long[Arg³] Insulin-Like Growth Factor (LR³IGF-I) over IGF-I in Preweaning and Adult Rats

Child Health Research Institute and Cooperative Research Centre for Tissue Growth and Repair, North Adelaide, South Australia 5006, Australia

Address all correspondence and requests for reprints to: Dr. Cheryl Shoubridge, Centre for Molecular Genetics, Department of Cytogenetics and Molecular Genetics, Women and Children’s Hospital, 72 King William Road, North Adelaide, South Australia 5006. E-mail: cheryl.shoubridge{at}adelaide.edu.au.

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.