IGFs

The liver represents the major site of synthesis of the IGFs, from where they enter the blood stream, thereby acting in a classical endocrine fashion. A wide variety of body cells express IGF receptors, of which there are two types. Furthermore, IGFs are also synthesized in smaller quantities at numerous sites in the body and function in an autocrine or paracrine manner at these specific locations. IGF activity is also modulated by a family of IGF binding proteins (IGFBPs), of which there are at least six. 

IGF-1 and -2 display identical amino acid residues at 45 positions, and exhibit in excess of 60% sequence homology. Both display A and B domains, connected by a short C domain — similar to proinsulin. However, unlike in the case of proinsulin, the IGF s C domain is not subsequently removed. The predicted tertiary structure of both IGFs closely resemble that of proinsulin. The overall amino acid homology displayed between insulin and the two IGFs is in excess of 40%. 

Hepatic transcription of IGF-1, in particular, is initiated upon binding of growth hormone (GH) to its hepatic receptors and, indeed, most of the growth-promoting actions of GH are directly mediated by IGF-1. 

IGFs induce their characteristic effects by binding to specific receptors present on the surface of sensitive cells. At least three receptor types have been identified the IGF-1 receptor, the IGF-2 receptor and the insulin receptor. As is evident from Table 7.4 (with one important exception), IGF-1, IGF-2 and insulin can bind the three receptor types, but with varying affinities. This renders delineation of which factor is inducing any one characteristic effect quite difficult. 

Recent studies also point to the existence of a fourth receptor species. This appears to be a hybrid structure, composed of an insulin receptor a-/l dimer crosslinked to an IGF-1 receptor oc-fi dimer. Although this receptor type displays a marked reduction in its affinity for insulin. 

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SEM = standard error of the means. IGF-I = insulin-like growth factor I. 

Insulin and Amylin. Insulin is a member of a family of related peptides, the insulin-like growth factors (IGFs), including IGF-I and IGF-II (60) and amylin (75), a 37-amino acid peptide that mimics the secretory pattern of insulin. Amylin is deficient ia type 1 diabetes meUitus but is elevated ia hyperinsulinemic states such as insulin resistance, mild glucose iatolerance, and hypertension (33). Insulin is synthesized ia pancreatic P cells from proinsulin, giving rise to the two peptide chains, 4. and B, of the insulin molecule. IGF-I and IGF-II have stmctures that are homologous to that of proinsulin (see INSULIN AND OTHER ANTIDIABETIC DRUGS). 

At the same time, however, considerable research was being done, especially in Germany, on a novel process called emulsion polymerization, in which the monomer was polymerized as an emulsion in the presence of water and soap. This seemed advantageous since the product appeared as a latex, just like natural mbber, leading to low viscosity even at high soHds content, while the presence of the water assured better temperature control. The final result, based mainly on work at the LG. Farbenindustrie (IGF) (10), was the development of a butadiene—styrene copolymer prepared by emulsion polymerization, the foremnner of the present-day leading synthetic mbber, SBR. 

Denusomab (anti-RANKL mAb) Growth factors (e.g. GH, IGFs, FGFs)... 

PTH has a dual effect on bone cells, depending on the temporal mode of administration given intermittently, PTH stimulates osteoblast activity and leads to substantial increases in bone density. In contrast, when given (or secreted) continuously, PTH stimulates osteoclast-mediated bone resorption and suppresses osteoblast activity. Further to its direct effects on bone cells, PTH also enhances renal calcium re-absorption and phosphate clearance, as well as renal synthesis of 1,25-dihydroxy vitamin D. Both PTH and 1,25-dihydroxyvitamin D act synergistically on bone to increase serum calcium levels and are closely involved in the regulation of the calcium/phosphate balance. The anabolic effects of PTH on osteoblasts are probably both direct and indirect via growth factors such as IGF-1 and TGF 3. The multiple signal transduction... 

CRP , complement , PLA2 , serum amyloid A , fibrinogen , c -acid glycoprotein , IL-1Ra , ceruloplasmin , ai-antichymotrypsin , LBP albumin , haptoglobin , IGF-1 , transferrin , u2-HS glycoprotein ... 

Studies with fenretinide in woman with stage I breast cancer did not show an overall effect of decreasing the risk of contralateral breast cancer. A protective effect could only be observed in premenopausal women, probably due to the modulation of the insulin-like growth factor 1 (IGF-1) by fenretinide in this population. 

Somatomedins are polypeptide mediators produced in response to growth hormone in the liver, e.g. insulinlike growth factors (IGFs). In particular, IGF-1 is the main mediator of growth hormone action. 

Other tissues/cells Inhibition of growth factor (IGF 1, EGF, PDGF)and cytokine (IL6, IFN-y) secretion... 

Figure 38-7. Activation of elF-4E by insulin and formation of the cap binding elF-4F complex. The 4F-cap mRNA complex is depicted as in Figure 38-6. The 4F complex consists of elF-4E (4E), elF-4A, and elF-4G. 4E is inactive when bound by one ofa family of binding proteins (4E-BPs). Insulin and mitogenic factors (eg, IGF-1, PDGF, interleukin-2, and angiotensin II) activate a serine protein kinase in the mTOR pathway, and this results in the phosphorylation of 4E-BP. Phosphorylated 4E-BP dissociates from 4E, and the latter is then able to form the 4F complex and bind to the mRNA cap. These growth peptides also phosphorylate 4E itself by activating a component of the MAP kinase pathway. Phosphorylated 4E binds much more avidly to the cap than does nonphosphorylated 4E.

ANF Atrial natriuretic factor IGF-I Insulin-like growth factor-I... 

Single protein kinases such as PKA, PKC, and Ca +-calmodulin (CaM)-kinases, which result in the phosphorylation of serine and threonine residues in target proteins, play a very important role in hormone action. The discovery that the EGF receptor contains an intrinsic tyrosine kinase activity that is activated by the binding of the hgand EGF was an important breakthrough. The insuhn and IGF-I receptors also contain intrinsic... 

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