A B S T R A C T Insulin and130 glucose oxidation through noninisulini receptor pathways, were not affected by the blockade of insulin receptors with Fah antibody fragmenits. These data suggest that this acute metabolic effect of both insulin and MSA is mediated via the insulin receptor.In cultured human fibroblasts, 10 ,sg/ml of Fab inhibited insulin binding by 90% and MSA binding by 15%. In fibroblasts, however, blockade of the insulin receptor did not alter the close response for stimulation of thymidine incorporation into DNA by either insulin or MSA. Furthermore, intact antireceptor antibody immunoglobulin (1g)G, which produces multiple other insulinlike effects, and Fab fragments of antireceptor antibody did not stinmulate thymidine incorporation. These data demonstrate directly that the insulin receptor mediates the metabolic effects of insulin and MSA, whereas the groxvth-promoting action of both peptides is mediated by the MSA receptor or other growth factors.
The serum half-life of somatomedin (SM) activity has been measured following the intravenous injection of SM activity into hypophysectomized rats. A [3H]thymidine incorporation assay in chick embryo fibroblasts (CEFs) has been utilized to measure SM activity. Cell cycle analysis data obtained with the flow microfluorometer shows that the [3H]thymidine incorporation data reflects actual DNA synthesis. When normal rat serum was injected, a half-life for SM activity of approximately 3 h was determined. In marked contrast, when serum from hypophysectomized (hypox) rats acutely treated with growth hormone (GH) was used as the source of SM actively, the half-life of the SM actively was short, approximately 8 min. However, when serum from hypox rats chronically treated with GH was injected, the half-life was again long, approximately 4 h. SM activity has been separated from its binding proteins by boiling under acid conditions or chromatography on Sephadex G-50 in 1 n acetic acid. The halflife of this partially purified SM activity was short, in the range of 10–30 min. Finally, recombination of the partially purified SM activity with the large proteins in normal serum extended the half-life of the SM from 10–30 min to about 2 h. These data indicate that the serum half-life of SM activity is GH dependent and suggest that the serum binding protein, like SM itself, is under GH control.
Insulin-like growth factor-I (IGF-I) and IGF-II are mitogenic polypeptides of relative molecular mass (Mr) approximately 7,500 isolated from human plasma each containing four peptide domains in a single chain and identical at more than 60% of their amino acid loci. The B- and A-domains of the IGFs are approximately 40% identical to the B- and A-chains of human insulin. IGF-I and IGF-II have similar in vitro biological activities and receptor reactivity, but are immunologically distinct. IGF-I appears to mediate the effects of growth hormone on cartilage to promote skeletal growth whereas IGF-II may have a special role in fetal development and in the central nervous system. To investigate the in vivo role of IGF-II, we have studied IGF-II biosynthesis in the BRL-3A rat liver cell line. BRL-3A cells synthesize and secrete a 7,484 Mr protein 93% identical to human IGF-II and representing rat IGF-II (rIGF-II). Rat IGF-II is synthesized as a approximately 22,000 Mr prepro-rIGF-II (ref. 12) from 12 S poly(A)+mRNA. In addition, approximately 20,000 Mr pro-rIGF-II has been identified in lysates of biosynthetically labelled intact BRL-3A cells. We report here the isolation of an almost complete cDNA clone for rIGF-II. Our results indicate that pro-rIGF-II is synthesized as a 156 amino acid peptide precursor (17,619 Mr) containing mature rIGF-II 1-67 at its amino-terminus and an 89-residue carboxy-terminal peptide extension.
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