Shoubridge C A, Read L C
Child Health Research Institute and Cooperative Research Centre for Tissue Growth and Repair, North Adelaide, South Australia 5006, Australia.
Endocrinology. 2003 May;144(5):1887-93. doi: 10.1210/en.2002-220643.
During early postnatal development, the intestine is highly responsive to LR(3)IGF-I administration but refractory to IGF-I, in contrast to the mature intestine. Given that LR(3)IGF-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 LR(3)IGF-I in the intestine during postnatal development. IGF-I or LR(3)IGF-I (2.6 microg/kg) was spiked with corresponding (125)I-labeled peptide (10 x 10(6) 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 (125)I-IGF-I retained in the blood at both 5 and 10 min were higher than the levels of (125)I-LR(3)IGF-I, consistent with the slower clearance rate for the native peptide. In the gastrointestinal tract, the levels of (125)I-LR(3)IGF-I per gram of tissue were 37-50% higher than (125)I-IGF-I. Surprisingly, there was little difference in the relative delivery of LR(3)IGF-I to IGF-I to the intestine, across developmental age. Although bolus iv-injected LR(3)IGF-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 LR(3)IGF-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 (125)I-LR(3)IGF-I in stimulating growth of the preweaning vs. adult intestine.
在出生后早期发育阶段，与成熟肠道相比，肠道对注射LR(3)IGF-I有高度反应，但对IGF-I却无反应。鉴于LR(3)IGF-I是一种与IGF结合蛋白结合能力较弱的IGF-I类似物，肠道的这种反应可能反映了IGF结合蛋白对IGF-I生物活性的调节作用。本研究测定了断奶前（第19天）和成年大鼠中外源性IGF-I肽向肠道的递送情况，以确定其与出生后发育期间LR(3)IGF-I在肠道中的效力优势是否存在相关性。将IGF-I或LR(3)IGF-I（2.6微克/千克）与相应的（125）I标记肽（10×10⁶ 计数/分钟）混合，静脉推注给药（每组n = 5 - 6只），并在注射后5分钟和10分钟采集血液和组织样本。在两个年龄组中，5分钟和10分钟时血液中保留的（125）I-IGF-I水平均高于（125）I-LR(3)IGF-I水平，这与天然肽的清除率较慢一致。在胃肠道中，每克组织的（125）I-LR(3)IGF-I水平比（125）I-IGF-I高37 - 50%。令人惊讶的是，在不同发育年龄阶段，LR(3)IGF-I与IGF-I向肠道的相对递送几乎没有差异。尽管静脉推注的LR(3)IGF-I比IGF-I从循环中清除得更快，随后向肠道的递送量也比天然肽更高，但在两个年龄组中，肠道组织中LR(3)IGF-I与IGF-I的比例均约为2:1。因此，选择性递送至肠道不太可能解释（125）I-LR(3)IGF-I在刺激断奶前肠道与成年肠道生长方面明显更高的效力。
