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biopharmaceuticals biochemistry and biotecnology - Walsh G.

Walsh G. biopharmaceuticals biochemistry and biotecnology - John Wiley & Sons, 2003. - 572 p.
ISBN 0-470-84327-6
Download (direct link): biochemistryandbiotechnology2003.pdf
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Several experiments utilizing transgenic animals confirm the importance of IGFs in promoting longitudinal body growth and increasing body weight. Transgenic mice overexpressing IGF-1 grow faster and larger than non-transgenic controls. Furthermore, transgenic mice whose IGF-2 gene was rendered dysfunctional, grew only to 60% of their ultimate expected body weight. Such effects render IGFs likely therapeutic candidates in treating the various forms of dwarfism caused by a dysfunction in some element of the GHIGF growth axis (Table 7.2). Initial trials show that s.c. administration of recombinant human IGF-1 over a 12 month period significantly increases the growth rate of Laron type dwarfs (LTD; a condition caused by a mutation in the GH receptor, rendering it dysfunctional; as a result, GH cannot promote any of its usual effects, including promotion of IGF synthesis). GH in turn functions as a primary regulator of IGF-1 synthesis. Unlike the pulsatile nature of GH secretion, however, serum IGF levels tend to remain relatively constant. Nutritional status also affects IGF-1 levels, which are significantly decreased during starvation, despite concurrently elevated GH levels.
284 BIOPHARMACEUTICALS
In addition to promoting fetal and childhood growth, IGFs play a core role in tissue renewal and repair (e.g. wound healing) during adulthood, e.g. these growth factors play a central role in bone remodelling (i.e. reabsorption and rebuilding — which helps keep bones strong and contributes to whole body calcium homeostasis). Reabsorption of calcified bone is undertaken by osteoclasts, cells of haemopoietic origin whose formation is stimulated by IGFs. These mitogens may, therefore, influence the development of osteoporosis, a prevalent condition (especially amongst the elderly), which is characterized by brittle, uncalcified bone.
IGFs also stimulate a more generalized short- and long-term whole body anabolic effect. Studies in calorie-restricted animals and humans show that IGF administration can retard or reverse catabolic events, such as tissue degradation and catabolism of body protein. Such effects have attracted the interest of some athletes who have used it illegally as a performance-enhancing drug. Detection is rendered complex, due to the relatively wide range of IGF concentrations classified as ‘normal’ and the fact that exercise naturally boosts endogenous IGF-1 production. IGF effects have also prompted speculation that these growth factors might be of clinical use in retarding/preventing/reversing cachexia, the generalized wasting of body tissues associated with chronic disease and many cancer types. Many IGF metabolic effects (particularly IGF-1) exhibit similarities to several metabolic effects induced by insulin. These similarities (particularly IGF’s ability to enhance cellular glucose uptake), suggests a possible role for this growth factor in the treatment of certain forms of diabetes, most notably noninsulin dependent diabetes (type II diabetes; Table 7.2). Initial studies have shown that IGF can reduce hyperglycaemia in patients unresponsive to insulin and further more detailed studies are now ongoing.
Renal and reproductive effects
IGFs (in particular IGF-1 and also IGFBP-1) are localized within various areas of the kidney. Direct infusion of IGF-1 influences (usually enhances) renal function by a number of means, including promoting:
• increased glomerular filtration rate;
• increased renal plasma flow;
• increased kidney size and weight.
These responses are obviously mediated by multiple effects on the growth and activity of several renal cell types and suggest that IGFs play a physiological role in regulating renal function. Not surprisingly, IGF-1 is currently being assessed as a potential therapeutic agent in the treatment of various forms of kidney disease.
GH deficiency often leads to delayed puberty. This condition often responds to exogenous GH administration. IGFs, as well as their receptors and binding proteins, are widespreadly expressed in the male and female reproductive tissue. Thus, IGFs are believed to affect reproductive function by both (GH-stimulated) endocrine action and via paracrine- and autocrine-based activity.
In the human female, IGF-1 is expressed by follicular theca cells, while IGF-2 is synthesized by granulosa cells (Chapter 8). The IGF-1 and -2 receptors are widely expressed in ovarian tissue, and synthesis of both growth factors and their receptors are influenced by circulating gonadotrophin levels. IGF-1 exerts a direct mitogenic effect on human granulosa cells, and promotes increased androgen and oestradiol synthesis by these cells. IGF-1 also promotes increased expression of FSH and LH receptors in ovarian tissue.
GROWTH FACTORS 285
In the male, IGF-1 is synthesized by the Sertoli and Leydig cells of the testes. It also stimulates testosterone production by the Leydig cells, and promotes growth and maintenance of various additional testis cell types.
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