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Query: HUMANGGP:034761 (insulin)
 211,843 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin is a small globular protein with a well defined tertiary structure which is closely similar in all species with the exception of certain hystricomorphs such as the guinea pig. Insulin-like growth factor is homologous with insulin and probably has an insulin-like tertiary structure. In contrast glucagon is not a globular protein. It exists as an equilibrium population of conformers with low helix content at physiological concentrations but attains a largely helical conformation on association to trimers. The receptor binding of insulin depends critically on the correct three-dimensional juxtaposition of groups (A1, A21, B25, etc) and involves both hydrophobic and polar interactions. In insulin-like growth factor part of the insulin receptor region is thought to be buried in extra peptide, so explaining its weak binding to insulin receptors. In contrast the glucagon receptor complex probably involves largely hydrophobic contacts which are possible when a helical conformer is formed.
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PMID:Polypeptide hormone-receptor interactions: the structure and receptor binding of insulin and glucagon. 21 91

A model for the three-dimensional structure of insulin-like growth factor (IGF) is proposed based on the close sequence homology of IGF with insulin, the tertiary structure of which is known. The IGF molecule is postulated to have an insulin-like main chain conformation for residues equivalent to B6--B27 and A1--A21 and a hydrophobic core nearly identical to that of insulin. A short connecting peptide of twelve residues and an extension at the COOH-terminus are easily accommodated on the molecular surface. The surface involved in dimer formation in insulin is largely conserved, but the zinc-binding histidine and many residues involving hexamerization are very different from those of insulin and it is unlikely that IGF forms zinc hexamers. The model provides a ready explanation for the inability of IGF to bind antibodies to insulin and for its ability to bind insulin receptors with low affinity.
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PMID:Insulin-like growth factor: a model for tertiary structure accounting for immunoreactivity and receptor binding. 27 33

Relaxin is an ovarian peptide that is released just prior to parturition to effect changes in the tissues of the birth canal that aid in the delivery of the fetus. Structural studies established that the two constituent polypeptide chains, composed of 22 and 30 amino acids, are joined by two interchain disulfide bonds with an additional third intrachain bridge. As well as the identical pattern of disulfide bonds, relaxin shows an overall 25% identity with insulin. Furthermore, the sequence of relaxin can be incorporated into the known three-dimensional structure of insulin without significant distortion of the main polypeptide chain backbone. The discovery of the insulin-relatedness of relaxin brings to three the number of growth factors that share a common structural gene precursor with insulin. Nerve growth factor and insulin-like growth factor have already been so identified. Inclusion in this hormone family suggests that the mechanism of action may involve internalization as well as complexation with cell surface receptors of target cells.
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PMID:Relaxin: an insulin-related growth factor. 39 38

Explants of 19- to 20-day fetal rat liver synthesize polypeptides biochemically and immunologically related to the well characterized somatomedin (insulin-like growth factor) BRL-MSA, multiplication-stimulating activity. Fetal MSA was purified from media conditioned by fetal liver explants by chromatography on Sephadex G-75 under acid conditions. Partially purified fetal MSA: 1) inhibited the binding of BRL-MSA to the MSA receptor of rat liver plasma membranes, to somatomedin-binding proteins from rat serum, and to rabbit anti-BRL-MSA serum; 2) had a molecular weight of 4,500 to 12,500 determined by polyacrylamide gel electrophoresis in sodium dodecyl sulfate; 3) stimulated the incorporation of [3H]thymidine into the DNA of chick embryo fibroblasts and induced cell multiplication; 4) stimulated glucose oxidation in rat adipocytes and weakly inhibited the binding of insulin to the insulin receptors of IM-9 lymphocytes; and 5) stimulated sulfate uptake in costal cartilage from hypophysectomized rats. These activities were associated with the same molecular species in fetal MSA preparations following disc acrylamide electrophoresis and co-migrated with active BRL-MSA peptides.
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PMID:Characterization of a somatomedin (insulin-like growth factor) synthesized by fetal rat liver organ cultures. 46 99

Insulin binding to its receptor leads to negatively cooperative interactions among the receptor sites. Studies with 29 insulin analogues (animal insulins and proinsulin, insulin-like growth factor and chemically modified insulins) which vary 1,000-fold in their affinity for the receptor and in their biological potency, suggest that a discrete invariable region on the surface of the insulin monomer is responsible for including the negative cooperativity. This domain comprises some of the eight carboxy-terminal residues of the B-chain and the A21 asparagine. Burying of this 'cooperative site' in the dimerisation of insulin leads to a loss of negative cooperativity. A revised mapping of the insulin molecule is proposed, featuring distinct bioactive and cooperative sites.
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PMID:Mapping of the residues responsible for the negative cooperativity of the receptor-binding region of insulin. 66 60

The somatomedins, a group of serum growth factors, have in common the ability to stimulate proteoglycan synthesis in cartilage. All are growth hormone dependent and have insulinomimetic properties in extraskeletal tissues. All stimulate DNA synthesis and mitosis in a variety of cell lines. Somatomedin-A and multiplication-stimulating activity are neutral peptides of 7,000--10,000 daltons, whereas nonsuppressible insulin-like activity and somatomedin-C are basic peptides of 5,700--7,000 daltons. Whether some of these substances are identical remains to be established. By use of a highly specific radioimmunoassay for somatomedin-C and less specific radioreceptor assays for insulin-like activity and somatomedin-C, evidence has been obtained for the existence of two major classes of somatomedins: neutral somatomedin, which is more insulin-like, and basic somatomedin, which is more rigorously growth hormone dependent, and which, in some systems, is s more powerful stimulant of growth.
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PMID:The somatomedin group of peptide growth factors. 74 48

The amino-terminal sequences of two polypeptides with nonsuppressible insulin-like and cell-growth-promoting activities (NSILA I and II), isolated from human serum, were determined. Of the first 31 residues, 22 are identical in NSILA I and II. Moreover, a striking structural similarity was found between NSILA and insulin B chain: 47 and 57% of residues 1-30 in NSILA I are identical to those in insulin B chain from man and tuna fish, respectively. This high degree of sequence identity is presented as evidence for homology and thus for a common evolutionary origin of insulin and NSILA. Based on these results and on these results and on biological properties of NSILA described earlier, a new designation for NSILA is proposed: insulin-like growth factor (IGF).
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PMID:Amino-terminal sequences of two polypeptides from human serum with nonsuppressible insulin-like and cell-growth-promoting activities: evidence for structural homology with insulin B chain. 106 90

FSH, which stimulates cAMP in the Sertoli cell, markedly lowers the concentration of insulin-like growth factor-binding protein-3 (IGFBP-3) in Sertoli cell-conditioned medium; in contrast, insulin-like growth factor-I (IGF-I) increases BP-3 expression. In this study, the mechanisms controlling the contrasting effects of cAMP and IGF-I were investigated. The abundance of BP-3 mRNA was dramatically lowered by (Bu)2cAMP, but was unaffected by IGF-I. Analyzed by ligand blot of conditioned medium, coincubation of (Bu)2cAMP and IGF-I largely eliminated the increase observed with IGF-I alone. Based on the following evidence, the effect of IGF-I appeared to be solely related to the capacity of IGF-I to interact directly with BP-3. 1) Insulin at micromolar concentrations failed to increase BP-3 abundance despite documentation by affinity cross-linking that insulin displaced [125I]IGF-I from the IGF-I receptor. 2) A synthetic IGF-I analog, [Leu24,1-62]IGF-I, which has reduced binding affinity for rat IGF-I receptor but displays high affinity for rat Sertoli cell-conditioned medium BPs, increased BP-3 abundance. 3) A synthetic IGF-I analog, B-chain mutant, which has reduced affinity for rat Sertoli cell BPs but displays normal affinity for the rat IGF-I receptor, failed to increase BP-3 abundance. 4) Human recombinant glycosylated [125I]BP-3 when added to cultured Sertoli cells was preserved in the medium when IGF-I or analogs with BP-3 affinity were present. 5) IGF-I, in dose-responsive manner, both retarded the disappearance from the medium of exogenously added human recombinant nonglycosylated BP-3 and decreased the amount of membrane-associated BP-3. These results indicate that whereas cAMP lowers BP-3 abundance in medium, most likely by markedly decreasing synthesis, IGF-I increases BP-3 accumulation by retarding its clearance by the Sertoli cell.
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PMID:Mechanisms of Sertoli cell insulin-like growth factor (IGF)-binding protein-3 regulation by IGF-I and adenosine 3',5'-monophosphate. 128 Feb 4

Insulin-like growth factors (IGFs) mediate the effects of growth hormone (GH), and the insulin-like growth factor-binding proteins (IGFBPs) modulate the actions of IGFs in tissues. We studied the circulating levels of IGFBP-1 in 6 children and 9 adults with Laron type dwarfism (LTD), in 11 children and 21 adults with growth hormone deficiency (GHD), and in 8 children with constitutional short stature. Compared with the situation in healthy children, the basal serum IGFBP-1 concentration was 5.4-fold higher in LTD children, 4.1-fold higher in GHD children, and 3.8-fold higher in children with short stature (p < 0.02 vs controls in all groups). In adult patients with multiple pituitary hormone deficiency (MPHD), the IGFBP-1 concentration was 2-fold elevated, but it was normal in adult LTD patients. Intravenous (N = 10) or subcutaneous (N = 9) administration of IGF-I (75 micrograms.kg-1 and 150 micrograms.kg-1, respectively) in LTD children resulted in a rapid 50-60% fall in serum insulin (p < 0.02), a decline in blood glucose and a concomitant 40-60% rise of IGFBP-1 levels (p < 0.05). Treatment for seven days with IGF-I (150 micrograms.kg-1 x d-1) resulted in a decrease by 34% and 44% of serum IGFBP-1 level in two out of three children with LTD. After prolonged GH therapy, the IGFBP-1 level fell in GHD children by 29% (p < 0.05), in GHD adults by 52% (p < 0.02) and in children with constitutional short stature by 17% (p < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Growth hormone and insulin-like growth factor regulate insulin-like growth factor-binding protein-1 in Laron type dwarfism, growth hormone deficiency and constitutional short stature. 128 Mar 92

Insulin-like growth factor-binding protein-3 (IGFBP-3) and insulin-like growth factor-1 (IGF-1) levels were measured by specific radioimmunoassays in children with all degrees of chronic renal failure (CRF). Study group 1 comprised 29 children (10 on dialysis) who had been studied one to four times over 2 years to determine whether IGF-1 and IGFBP-3 levels differed from those in age-matched healthy children and to examine the relationship between these levels and heights. IGF-1 and IGFBP-3 levels did not differ from those in normal children. IGF-1 and IGFBP-3 were significantly correlated, increased with pubertal stage in all children and with age in non-dialysis patients. IGF-1, but not IGFBP-3, correlated with age in dialysis patients. There was no correlation between IGF-1 or IGFBP-3 levels (corrected for age) and height standard deviation score (SDS) in either non-dialysis or dialysis patients. Study group 2 comprised 19 children (7 on dialysis) who were studied prospectively for 1-2 years to examine the relationship between IGF-1 and IGFBP-3 levels, growth rates and nutritional parameters. Mean values of IGF-1 and IGFBP-3 (corrected for age) did not change over 1-year periods, while height SDS fell by -0.38 +/- 0.21 SD/year in dialysis patients and by -0.11 +/- 0.29 SD/year in non-dialysis patients. No significant correlations were found between IGF-1 or IGFBP-3 levels and growth rates or nutritional parameters. Thus growth retardation in children with CRF is not related to circulating levels of IGF-1 or IGFBP-3.
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PMID:Insulin-like growth factor-1, growth hormone-dependent insulin-like growth factor-binding protein and growth in children with chronic renal failure. 128 Sep 88


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