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ABSTRACT
The effects of insulin-like growth factor-I (IGF-I) on the gut of 150 g dexamethasone-treated rats were compared with those of two analogues with reduced affinity for IGF-binding proteins, des(1–3)IGF-I and LR3IGF-I, an N-terminal-extended variant. Administration of IGF-I for 7 days to rats made catabolic by co-treatment with dexamethasone induced a dose-dependent increase in total gut weight, with the highest dose of IGF-I (695 μg/day) increasing gut weight by up to 60%, and gut weight as a fraction of body weight by up to 32%. Effects were apparent in all regions of the gut examined, including the stomach, small intestine and colon. Histological and biochemical analyses of the intestine showed that cross-sectional mass, rather than gut length, was increased, and proportional increases in wet weight, protein and DNA content per unit length were measured in both the mucosa and muscularis layers. The rate of duodenal protein synthesis measured on day 7 of treatment was not increased by IGF-I treatment. The IGF-I analogues had qualitatively similar effects to IGF-I, but were consistently severalfold more potent, providing evidence that IGF-binding proteins reduce the biological activity of exogenous IGF-I in the gut. The results indicate that the gut is one of the most sensitive IGF-I target tissues, and that potency in vivo correlates with a reduced interaction with IGF-binding proteins.
Journal of Endocrinology (1992) 133, 421–431
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ABSTRACT
Incubation of 125I-labelled insulin-like growth factor-I (IGF-I) with rat plasma at 4 °C led to the transfer of approximately half the radioactivity to 150 kDa and smaller complexes with IGF-binding proteins. The extent of association was greater with labelled IGF-II and essentially absent with the truncated IGF-I analogue, des(1–3)IGF-I. A greater degree of binding of IGF peptides with binding proteins occurred after i.v. injection of the tracers into rats, but most of the des(1–3)IGF-I radioactivity remained free. Measurement of the total plasma clearances showed the rapid removal of des(1–3)IGF-I compared with IGF-I and IGF-II; the mean clearances were 4·59, 1·20 and 1·34 ml/min per kg respectively. The mean steadystate volume of distribution was larger for des(1–3)IGF-I than for IGF-I and IGF-II (461, 167 and 181 ml/kg respectively), probably because of the differences in plasma protein binding. With all tracers, radioactivity appeared in the kidneys to a greater extent than in other organs. The amount of radioactivity found in the adrenals, brain, skin, stomach, duodenum, ileum plus jejunum and colon was in rank order, des(1–3)IGF-I > IGF-I > IGF-II. Since this ranking is the opposite of the abilities of the three IGF peptides to form complexes with plasma binding proteins, we propose that the plasma binding proteins inhibit the transfer of the growth factors to their tissue sites of action. Moreover, we suggest that IGF analogues that are cleared rapidly from blood may have greater biological potencies in vivo.
Journal of Endocrinology (1991) 128, 197–204
