Insulin stimulates fetal growth and postnatal growth by stimulating secretion of IGF-1. Stimulates protein synthesis.

. Important actions on carbohydrate and fat metabolism and growth regulation. Children with diabetes fail to grow even though their GH levels are normal, whereas infants of diabetic mothers with islethyperplasia and hyper-insulinism are of increased stature. Insulin is required for the full anabolic effect of GH

Growth Hormone and Insulin-like Growth factor 1 (IGF-1)

Growth hormone, secreted by anterior pituitary, has little or no effect on fetal growth, but is the single most important hormone for postnatal growth. It indirectly stimulates cell division in its many target tissues. For example it stimulates maturation and cell division of chrondocytes in the epiphyseal plates, thus widening plates and providing more cartilaginous material for bone formation. Excess of growth hormone in childhood produces giantismwhereas deficiency produces dwarfism (achrondoplasia). Excess growth hormone in adulthood produces acromegaly, a disfiguring bone thickening and overgrowth of other organs. GHreplacement 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 by abnormalities in body composition and energy metabolism. GH has direct anti-insulin effects on some target cells, causing glucose formation. GH secretion is regulated by stimulating (GHRH) and inhibiting (SST = somatostatin) factors from the hypothalamus. IGF-I stimulates hypothalamic SST release and inhibits stimulated pituitary GH release. 40-50% of circulating GH is complexed to the BP in normal human plasma. GHBP complex represents a hormone reservoir, and presence of BP modifies the amount of hormone that can have access to receptors. GHBP generation in the human probably results from proteolytic cleavage of the liver membrane 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 or autocrine agent. It may also act as a blood-borne endocrine. IGF-II is three times more abundant in adult circulation 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, but levels drop promptly postpartum. Injected radio labelled GH rapidly localizes to the liver rather than to the epiphyses of the long bones. But GH injected into epiphyseal plates induces unilateral longitudinal bone growth, and the number if IGF-I immunoreactive cells in the proliferative zone is increased. Locally-infused IGF-1 is able to increase epiphyseal width as well as bone length. This suggests that the target cells for IGF-I are in the proliferative cell layer, whereas GH stimulates multiplication of the slowly cycling cells in the germinal layer of the epiphyseal plate, and stimulates IGF secretion and IGF responsiveness. So germinal layer can be regarded as stem cells of growth layer. GH stimulates their differentiation to chrodocytes which express and are stimulated by IGF-I. In the paracrine layer, IGF-I stimulates a clonal expansion of these chrondocytes by autocrine and paracrine signalling. In the hypertrohic layer, these cells increase in size and undergo cytoplasmic maturation.

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 promote the incorporation of sulphate into cartilage (sulphonation factors) = IGF-1 and IGF-2. These peptides bear some structural relationship to proinsulin and threfore exhibit some affinity for insulin receptors, and insulin at high concentrations will bind to somatomedin receptors. Growth activity present in the blood cannot be neutralised by antibodies against insulin. IGF-1 circulates in the blood in a complex together with acid labile subunit 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, and C 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 differentiating chrondocytes 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 has considerable structural and functional similarity to insulin receptor, but higher affinity for IGF-I&II than for insulin. IGF-II receptor has a different structure, homolygous with the human mannose-6-phosphate receptor, has higher affinity for IGF-II than for IGF-I, and does not bind insulin.

2.

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 the hematopoietic superfamily have a three-domain organisation comprising an extracellular ligand binding domain, a single transmembrane segment, and an intracellular domain of unknown function which is not homolygous within the family. Like the tyrosine kinases, the mechanism through which ligand binding event information is transmitted through the membrane to evoke cellular response is unknown. (brilliant diagrams illustrating cell signallinghttp://219.221.200.61/ywwy/zbsw(E)/edetail6.htm)

Dwarfism can be due to GH deficiency or due to decreased production of IGF-1, or failure of tissues to respond to IGF-1 e.g. short stature of Pygmies is likely to be due to a gene mutation that impairs the ability of cells to produce IGF-1 in response to GH. Secretion and activity of IGF-1 is affected by the individuals nutritional status and by many hormones, e.g. estrogen stimulates secretion of IGF-1 by cells of the uterus and ovaries. In addition to its growth promoting effect, GH directly stimulates protein synthesis in various tissues and organs, by increased amino acid uptake by cells, and synthesis of RNA and ribosomes. This effect facilitates the ability of cells to enlarge. Major effects of Growth Hormone:

Promotes growth and induces precursor cells to differentiate and secrete insulin-like growth factor I which 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 happens mostly 1-2 hours after a person falls asleep, and very little in the day. Sex hormones and thyroid hormones have significant influence on secretion of GH. GH secretion rate is highest in adolescents, then children, then adults. The decrease in GH associated with ageing is responsible at least in part for the decrease 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 deficiency of 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-hormone related ageing changes. Thyroid hormones T4 (thyroxine) and T3 (iodothyronine) are required for both synthesis of GH and its growth-promoting effects. Infants and children with hypothyroidism manifest retarded growth. TH is also permissive for normal CNS development. Severe iodine deficiency during pregnancy can lead to inadequate maternal and fetal TH, one of the worlds most common preventable causes of mental retardation, termed endemic cretinism. Insulin is required for growth. It is an anabolic hormone with stimulating effects on amino acid uptake and protein synthesis. It also exerts direct growth-promoting effects on cell differentiation and cell division during 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 receptor ligand for GPR54. Kiss1 was originally identified as a human metastasis suppressor gene that has the ability to suppress melanoma and breast cancer metastasis. It is recently become clear that kisspeptin-GPR54 signaling 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 offer new 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 have stopped ovulating due to an imbalance in their sex hormones. Kisspeptin is therefore a potential basis for a new infertility treatment. Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1761-6. Epub 2005 Jan 21 Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54 Messager S, Chatzidaki EE, Ma

D, Hendrick AG, Zahn D, Dixon J, Thresher RR, Malinge I, Lomet D, Carlton MB, Colledge WH, Caraty A, Aparicio SA. We have recently described a molecular gatekeeper of the hypothalamic-pituitary-gonadal axis with the observation that G protein-coupled receptor 54 (GPR54) is required in mice and men for the pubertal onset of pulsatile luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion to occur. In the present study, we investigate the possible central mode of action of GPR54 and kisspeptin ligand The localization and GnRH release effects of kisspeptin thus define GPR54 as a major control point in the reproductive axis and suggest kisspeptin to be a neurohormonal effector.