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Insulin stimulates fetal growth and postnatal growth by stimulating secretion of IGF-1. Stimulates proteinsynthesis. Important actions on carbohydrate and fat metabolism and growth regulation. Children withdiabetes fail to grow even though their GH levels are normal, whereas infants of diabetic mothers with islet-hyperplasia and hyper-insulinism are of increased stature. Insulin is required for the full anabolic effect ofGH

Growth Hormone and Insulin-like Growth factor1 (IGF-1)Growth hormone, secreted by anterior pituitary, has little or no effect on fetal growth, but is the single mostimportant hormone for postnatal growth. It indirectly stimulates cell division in its many target tissues. Forexample it stimulates maturation and cell division of chrondocytes in the epiphyseal plates, thus wideningplates and providing more cartilaginous material for bone formation. Excess of growth hormone in childhoodproduces giantism whereas deficiency produces dwarfism ( achrondoplasia ). Excess growth hormone inadulthood produces acromegaly , a disfiguring bone thickening and overgrowth of other organs. GH-replacement in GH deficient adults alters body composition and energy metabolism, decreasing fat mass,increasing fat-free mass, retaining sodium, and increasing energy expenditure. After cessation of somatic

growth, GH exerts significant diverse metabolic actions in adult life, and lack of GH may be accompanied byabnormalities in body composition and energy metabolism. GH has direct anti-insulin effects on some targetcells, causing glucose formation.

GH secretion is regulated by stimulating (GHRH) and inhibiting (SST = somatostatin) factorsfrom the hypothalamus . IGF-I stimulates hypothalamic SST release and inhibits stimulated pituitary GHrelease. 40-50% of circulating GH is complexed to the BP in normal human plasma. GHBP complexrepresents a hormone reservoir, and presence of BP modifies the amount of hormone that can have accessto receptors. GHBP generation in the human probably results from proteolytic cleavage of the livermembrane receptor.

Growth hormone works by inducing synthesis and release of IGF-1 (aka somatomedin C)secreted by the liver and many other types of cells and thought to act at these sites as paracrine orautocrine agent. It may also act as a blood-borne endocrine. IGF-II is three times more abundant in adultcirculation than IGF-I, but its role is not clear.Several hormones affect IGF-I production in the liver, e.g.prolactin and placental lactogen can maintain IGF-I levels in pregnant rats even hypophysectiomised, butlevels drop promptly postpartum.

Injected radio labelled GH rapidly localizes to the liver rather than to the epiphyses of the long bones. ButGH injected into epiphyseal plates induces unilateral longitudinal bone growth, and the number if IGF-Iimmunoreactive cells in the proliferative zone is increased. Locally-infused IGF-1 is able to increaseepiphyseal width as well as bone length. This suggests that the target cells for IGF-I are in the proliferativecell layer, whereas GH stimulates multiplication of the slowly cycling cells in the germinal layer of theepiphyseal plate, and stimulates IGF secretion and IGF responsiveness. So germinal layer can be regardedas stem cells of growth layer. GH stimulates their differentiation to chrodocytes which express and arestimulated by IGF-I. In the paracrine layer, IGF-I stimulates a clonal expansion of these chrondocytes byautocrine and paracrine signalling. In the hypertrohic layer, these cells increase in size and undergocytoplasmic maturation.

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Somatomedin is generally used to refer to those growth factors found in the plasma that are under the

control of GH, have insulin-like propert ies, and promotethe incorporation of sulphate into cartilage ( sulphonation factors ) = IGF-1 and IGF-2. These peptides bearsome structural relationship to proinsulin and threfore exhibit some affinity for insulin receptors, and insulinat high concentrations will bind to somatomedin receptors. Growth activity present in the blood cannot beneutralised by antibodies against insulin. IGF-1 circulates in the blood in a complex together with acid labilesubunit and IGFBP-3. There is some suggestion that IGFBP may actually be the active form, rather than free

IGF.

Amino Acid sequence of IGF-1, from http://www.drugs.com/pro/increlex.html . Starting from amino end, B2 B30, C1-C12, A1-A21, and 8 amino acid tail, Insulin is similar but B chain has 30 not 29 amino acids, andC chain has 33. The sulphur bridges are in the same places.

Current concepts of how growth hormone and IGF-1 interact on epiphyseal plate:

GH stimulates chrondocyte precurrsor cells (pre-chrondocytes) and/or young differentiatingchrondocytes in epiphyseal plates to differentiate into chrondocytes.

During this differentiation the cells begin to secrete IGF-1 and to become responsive to IGF-1. IGF-1 then acts as an autocrine or paracrine agent to stimulate differentiating chrondocytes to

undergo cell division

It is likely that similar processes happen in other tissues.

Two main classes of IGF receptors:

1. IGF-I receptor exhibits ligand-dependent tyrosine kinase activity and autophosphorylation and hasconsiderable structural and functional similarity to insulin receptor, but higher affinity for IGF-I&IIthan for insulin.

2. IGF-II receptor has a different structure, homolygous with the human mannose-6-phosphatereceptor, has higher affinity for IGF-II than for IGF-I, and does not bind insulin.

Both IGF-I & II can bind, at low potency, to insulin receptors.

GH receptor is member of hematopoietic receptor superfamily. Like the tyrosine kinases, members of thehematopoietic superfamily have a three-domain organisation comprising an extracellular ligand bindingdomain, a single transmembrane segment, and an intracellular domain of unknown function which is nothomolygous within the family. Like the tyrosine kinases, the mechanism through which ligand binding eventinformation is transmitted through the membrane to evoke cellular response is unknown.

(brilliant diagrams illustrating cell signallin g http://219.221.200.61/ywwy/zbsw(E)/edetail6.htm )

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Dwarfism can be due to GH deficiency or due to decreased production of IGF-1, or failure of tissues torespond to IGF-1 e.g. short stature of Pygmies is likely to be due to a gene mutation that impairs theability of cells to produce IGF-1 in response to GH. Secretion and activity of IGF-1 is affected by theindividuals nutritional status and by many hormones , e.g. estrogen stimulates secretion of IGF-1 by cells ofthe uterus and ovaries.

In addition to its growth promoting effect, GH directly stimulates protein synthesis in various tissues andorgans, by increased amino acid uptake by cells, and synthesis of RNA and ribosomes. This effect facilitatesthe ability of cells to enlarge.

Major effects of Growth Hormone:

Promotes growth and induces precursor cells to differentiate and secrete insulin-like growth factor Iwhich stimulates cell division.

Stimulates protein synthesis. Anti-insulin effects renders adipocytes more responsive to lipolytic stimuli, stimulates

gluconeogenesis, reduces ability of insulin to stimulate glucose uptake.

Growth hormone secretion is stimulated by GHRH and inhibited by somatostatin. GH secretion happensmostly 1-2 hours after a person falls asleep , and very little in the day. Sex hormones and thyroidhormones have significant influence on secretion of GH. GH secretion rate is highest in adolescents, thenchildren, then adults. The decrease in GH associated with ageing is responsible at least in part for thedecrease in lean-body and bone mass, expansion of adipose tissue and thinning of skin with ageing.

Human GH produced by recombinant DNA is used to treat children with short stature due to deficiencyof GH. Controversial at present is the administration of GH to short children who do not have GH deficiency,to athletes in an attempt to increase muscle mass, and to elderly persons to reverse the growth-hormonerelated ageing changes.

Thyroid hormones T4 (thyroxine) and T3 (iodothyronine) are required for both synthesis of GH and itsgrowth-promoting effects. Infants and children with hypothyroidism manifest retarded growth. TH is alsopermissive for normal CNS development. Severe iodine deficiency during pregnancy can lead to inadequatematernal and fetal TH, one of the worlds most common preventable causes of mental retardation, termedendemic cretinism.

Insulin is required for growth. It is an anabolic hormone with stimulating effects on amino acid uptake andprotein synthesis. It also exerts direct growth-promoting effects on cell differentiation and cell divisionduring fetal life (and possibly childhood too). Insulin is also required for normal production of IGF-1.

[wiki]Kisspeptin (formerly known as Metastin ), the product of the gene Kiss1 is a G-protein coupled receptorligand for GPR54. Kiss1 was originally identified as a human metastasis suppressor gene that has the abilityto suppress melanoma and breast cancer metastasis. It is recently become clear that kisspeptin-GPR54signaling has an important role in initiating GnRH secretion at puberty, the extent of which is an area of

ongoing research.www.womens-health.co.uk/kisspeptin-hormone.html In March 2009, British scientists carrying out hormone research published exciting results which may offernew hope to infertile women around the world. These scientists are certain that the sex hormone kisspeptin,present in all healthy men and women, can restart the female reproductive system in women who havestopped ovulating due to an imbalance in their sex hormones. Kisspeptin is therefore a potential basis for anew infertility treatment .Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1761-6. Epub 2005 Jan 21 Kisspeptin directly stimulatesgonadotropin-releasing hormone release via G protein-coupled receptor 54 Messager S, Chatzidaki EE, Ma

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