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Peptide and Protein Hormones ------7. Secretin Family 2

Author:N/A    | Post time:2012-05-26

7.6.3. Growth Hormone, Placental Lactogen, and Prolactin
The pituitary hormones prolactin (PRL) and growth hormone (GH) are structurally related to placental lactogen (PL) and two GH variants (GH-V and GH-V2) from the placenta. PL has lactogenic properties and some somatotropic activity (tibia test). PRL has no somatotropic activity, but GH has weak PRL activity.

Other substances related to PRL are somatolactin (pl-SL) [1616], proliferin (m-PLF), prolactin related cDNA (b-PRC I, II, and III), proliferin related protein (m-PRP), and prolactinlike proteins (r-PLP A and B, b-PLP I, II, and III) [1617].

There is great similarity in the structures of secretin-(5 – 20), h-GH-(1 – 16), and h-PL-(1 – 16). There is also amino acid homology between h-GH-(30 – 38), gastrin, and the C-terminus of the B-chain of insulin. Growth Hormone
  Occurrence. Growth hormone (GH) [9002-72-6], also known as somatotropin (STH), Mr 22 125 (h-STH), has 191 amino acids and is formed in the pituitary as pro-GH. Circulating GH occurs in several forms: monomeric (little GH), dimeric (big GH) and oligomeric (big-big GH, Mr > 60 000) [1618]. In addition, 20Kh-GH, a de-(32 – 46)GH, and the two GH variants from the placenta, GH-V and GH-V2 [1619] have also been found. The amino acid sequences of GH in various species are described in [1620], [1621].

  Release [1622]. GH is regulated primarily by the hypothalamic hormones galanine (GAL, see Section Galanine ), growth hormone releasing hormone (GHRH, see Section Growth Hormone Releasing Hormone ), and somatostatin (SRIH, see Section Somatostatin ). GAL and GHRH stimulate and SRIH inhibits the pituitary release of GH. Treatment with SRIH enhances the GHRH-stimulated release of GH [1623]. GH is also released in response to stimulation of 1-adrenergic receptors [1624] and cholinergic muscarinic receptors [1625], inhibition of 2-adrenergic receptors [1626], SKF-110 679, insulin, hypoglycemia, glucagon, arginine, physical stress [1627], -melanotropin, opioids [1628], angiotensin II [1629], pentagastrin [1630], GIP, neurotensin, combined application of thyroliberin with ACTH [1631], slow wave sleep [1632], intracerebroventricular application of delta-sleep-inducing peptide, interleukin-1 [1633], serotonin [1634], dopamine and dopamine agonists [1635], and indomethacin [1636].

In women, the release of GH is dependent on estrogen. Thus, the plasma level of GH falls during menopause [1637] and in suppression therapy with high doses of GnRH agonists [1638]. In young hypogonadal males, testosterone stimulates the GH formation and growth [1639]. Glucocorticoids also regulate the synthesis of GH. Hypoadrenalism [1640] and high doses of glucocorticoids [1641] lower the release of GH. However, glucocorticoids and triiodothyronine (T3) enhance the release of GH in vitro through GHRH.

GH release is inhibited by recombinant Met-GH [1642], centrally applied gastrin releasing peptide [1643], corticoliberin [1644], calcitonin [1645], calcitonin gene related peptide [1646], and by TRH [1647], mainly via the secretion of SRIH.

Plasma GH levels in persons with acromegaly and type I diabetes [1648] are higher than in healthy persons, but are reduced in depressive patients with an increased level of somatomedin C [1649]. TRH has no influence on the release of GH in normal subjects, but it causes a paradoxical increase in the plasma level of GH in patients suffering from acromegaly [1650], depression [1651], or metastatic testicular cancer [1652]. GnRH also raises the plasma GH level in type I and type II diabetics [1653].

Receptors. The amino acid sequences of the GH receptors from humans, rabbits [1654], and rats [1655] have been elucidated via their cDNA.

GH binding proteins are mainly the extracellular fragments of GH receptor [1656]. In patients with Laron-type dwarfism (high plasma GH level and low IGF-I level), the GH receptor is defective [1657] and the high-affinity GH binding protein is missing [1658]. African pygmies have a low plasma level of GH-binding protein [1659].

  Biological Effects. GHRH is species specific and promotes the longitudinal growth and regeneration of bone. It has a strong mitogenic effect on osteoblasts [1660] and pancreatic -cells [1661], increases the osteocalcin level [1662], and enhances DNA, RNA, and protein synthesis. It possesses lipolytic, diabetogenic, and insulinotropic properties; it also has an antidiuretic and antinatriuretic effect because it activates renin and increases the plasma level of aldosterone [1663].

In a negative feedback mechanism, GH inhibits the release of GHRH in the hypothalamus [1664] via the release of SRIH [1665].

Pulsatile intravenous GH stimulates the formation of somatomedin C [1666] in the liver and skeletal tissue. This substance is identical to the insulin-like growth factor I (IGF-I) and is largely responsible for the growth effect of GH [1667].

In vitro, GH stimulates the release of insulin from pancreatic islet cells [1668] and the insulin-dependent uptake and oxidation of glucose in adipose and muscle tissues [1669]. The insulin-like effect of GH is only found in vivo in GH deficiency models or children suffering from GH deficiency. Chronic therapy with GH or very high doses of GH have a diabetogenic effect in hypophysectomized animals. After prolonged GH treatment the fasting plasma glucose level in humans is raised [1670] and in patients with acromegaly, glucose metabolism is reduced in spite of the increased release of insulin [1671].

Physiological doses of GH also stimulate the production of peroxide anions in macrophages. It increases the activity of cytolytic T-cells and of natural killer cells, stimulates the formation of antibodies and thymulin synthesis [1672], and regenerates the thymus in dogs [1673].

Structure – Activity Relationships. Similar to h-GH, recombinant Met-h-GH, which acts like natural h-GH in children with GH deficiency [1674], has diabetogenic and insulin-like activity [1675]. Met-h-GH has a somewhat higher tendency to initiate antibody formation [1676]. Other acidic GH derivatives (deamidated h-GH) are as active as h-GH [1620].

The epiphyseal plate of the long bones of the rat declines following hypophysectomy and increases after treatment with GH. This increase in the width of the plate of the proximal end of the tibia has been used for the quantitative measurement of GH. Various GH fragments exhibit biological activity in the tibia test in hypophysectomized animals, e.g., GH-(88 – 124), GH-(125 – 156), b-GH-(96 – 133), and GH-(151 – 191). h-GH, but not 20K-h-GH, reduces the concentration of free fatty acids in children deficient in GH [1677]. The binding of 20K-h-GH to lactogenic receptors is about 500 times less than that of GH [1678]. The lactogenic activity of h-GH and o-PRL is competitively inhibited by [Met14]h-GH-(14 – 191) [1621].

h-GH-(4 – 15) and h-GH-(6 – 13) stimulate glucose oxidation, glucose uptake in adipose tissue, and the synthesis of glycogen [1679]. The minimal GH sequence with this insulin-potentiating effect is h-GH-(8 – 13). An artifact, the aspartoylimide variant of these peptides, appears to be responsible for this effect [1680]. Other insulinotropic GH fragments are h-GH-(31 – 44), h-GH-(32 – 38) [1681], and h-GH-(32 – 46) [1682]. Both h-GH-(177 – 191) and h-GH-(178 – 191) have diabetogenic activity.

  Uses. Met-h-GH and h-GH are produced by genetic engineering and are now used instead of natural h-GH in the therapy of hypophyseal dwarfism. Trade names include Genotropin (Pfrimmer Kabi), Grorm, Saizen (Serono), Humatrop (Lilly), and Norditropin (Nordisk).

h-GH has also been used to activate growth in persons with Turner\\\'s syndrome where growth is reduced in spite of normal GH formation [1683]. h-GH also finds application for the healing of wounds [1684] and for increasing the mass [1685] and density of bones [1686]. In older patients with low plasma GH levels, GH increases bone density, lean body mass, and skin thickness, and reduces the amount of adipose tissue [1687]. Prolactin
  Occurrence. Prolactin (PRL) [9002-62-4], Mr 22 806 (h-PRL, protein part), has 198 amino acids and is formed in the pituitary where it is glycosylated at Asn31 [1688] or dimerized via disulfide bridges [1688]. Other sites of synthesis are the placenta, myometrium, ovaries [1689], and hypothalamus. The sequences of PRL from various species are listed in [1690].

  Release [1691]. The pulsatile secretion of PRL from the pituitary is regulated by hypothalamic factors. It is stimulated by TRH and VIP and inhibited by dopamine. The C-terminal glycopeptide of vasopressin-neurophysin, which contains 39 amino acids, is a specific PRL-releasing factor [1692]. PRL is also released in response to K+ [1693], hypocalcemia [1694], calcitriol [1695], cholecystokinin, insulin, arginine [1696], epidermal growth factor [1697], the sucking stimulus through endogenous opioids [1698] and VIP [1699], stress and physical exercise [1700] through serotoninrgic mechanisms [1701], -endorphin [1702], AT II [1703], gonadoliberin [1704] through the formation of AT II [1705], neurotensin [1706], and to glutamate [1707]. It is also released by the stimulation of 1-adrenergic receptors [1708] or histamine H1-receptors [1709].

Dopamine from the hypothalamus and pituitary [1710] which is released by PRL is probably one of the most important inhibitors of PRL release.

The secretion of PRL is also inhibited by ascorbic acid [1711],  opiates [1712], hypercalcemia [1713], the prolactin inhibiting factor (PIF), PRL itself [1714], stimulation of 2-adrenergic [1708], GABA-A- [1715], or histamine H2-receptors [1709], chronic nicotine intake [1716], somatostatin and its analogues [1717], calcitonin [1718], IL-1 [1719], T3 [1720], melatonin [1721], glucocorticoids [1722], vasopressin (presumably via a dopaminergic pathway [1723]), and central neurotensin. A competitive antagonist of PRL is a recombinant h-GH, which lacks the 13 amino acids at the N-terminus [1724].

The steroid sex hormones modulate the release of PRL. Estrogen potentiates the secretion of PRL in experimental animals [1725], but can also potentiate the dopamine-stimulated inhibition of PRL release in humans. 17--estradiol potentiates the somatostatin-stimulated inhibition of PRL in pituitary cells [1726]. Testosterone appears to inhibit the secretion of PRL because the TRH-stimulated release of PRL is greatly enhanced in delayed puberty (males) [1727].

A period of breast feeding is followed by a reduced PRL level for at least 12 – 13 years [1728], which could be related to the low risk of breast cancer after pregnancies. Women who are not lactating have a pronounced PRL deficiency [1729]. In humans, the PRL response to TRH falls with age [1730]. Patients with chronic kidney damage and rats with experimentally induced kidney damage develop hyperprolactinemia. The plasma level of PRL is raised in spontaneously hypertensive rats and in patients with hypertension.

Receptors. Receptors for PRL are widely distributed: in the mammary gland, liver, kidneys, brain, prostate, testes, ovaries, and lymphocytes [1731]. The receptors have a similar structure to that of the GH receptors [1732], [1733].

In the rat, the number of PRL receptors in the mammary gland increases on the day of estrus. Together with estradiol, LH stimulates the formation of PRL receptors [1734]. The number of testicular PRL receptors in the golden hamster is increased by PRL, FSH, and LH; ovariectomy and hypophysectomy reduce the synthesis of PRL receptors [1735].

PRL is displaced from the receptors on lymphocytes by cyclosporin [1731].

  Biological Effects. In female mammals, PRL increases the production of milk and initiates maternal behavior. The PRL-stimulated biosynthesis of casein and lipid is reduced by inhibitors of phospholipase A2 [1736].

PRL stimulates the synthesis of dopamine and increases the density of dopamine receptors [1737]. Thus, the dopamine level in the central nervous system and the dopaminergic inhibition of aldosterone are increased in patients suffering from hyperprolactinism [1738].

Similar to placental lactogen, PRL also has luteotropic properties and stimulates the synthesis of progesterone [1739], but inhibits the formation of estradiol and testosterone [1739]. In men with chronically elevated PRL levels, the plasma level of testosterone is low and the excretion of LH in the urine is reduced [1740]. In women, hyperprolactinemia leads to irregular menstruation or even amenorrhea [1741].

PRL increases the blood pressure of experimental animals which is dependent on the adrenal glands and presumably occurs via the potentiation of noradrenaline activity. As a stress hormone, PRL potentiates the antidiuretic activity of Arg-vasopressin [1742] and the AT IIinduced uptake of water and retention of fluids [1743].

Hyperprolactinemia increases the production of androgens [1744] in the adrenal gland, DNA synthesis in the liver [1745], the susceptibility to chemically induced tumors [1746] and spontaneous mammacarcinoma, and the number of estrogen receptors in the mammary gland [1747]. It also prevents stress-induced stomach ulcers [1748], induces hypercalcemia in several species [1749], and reduces the mineral content of the bone [1750].

PRL is also immunostimulatory. Thus, the reactivity of the lymphocytes is reduced by blocking pituitary PRL release with bromocryptin. The immunosuppressive effect of cyclosporin can be abolished by PRL [1731]. Placental Lactogen
Placental lactogen (PL) [9035-54-5], Mr 22 212 (h-PL), is formed in the placenta in the first trimester of pregnancy and can be detected in the blood and urine of pregnant women. Secretion of PL decreases after birth.

h-PL first stimulates the development of the breast tissue. When the level of h-PL decreases after birth, pituitary h-PRL stimulates the secretion of milk.

h-PL has luteotropic properties: it stimulates the release of progesterone and estrogen from the corpus luteum. This effect is potentiated by h-choriogonadotropin (h-CG). The growth-promoting effect of h-PL is somewhat weaker than that of h-STH, but appears to play a more important role in the development of the fetus.

7.6.4. Somatomedins, Insulin, and Relaxin
Somatomedins of the IGF type (insulin-like growth factors I and II) are structurally related to insulin and relaxin. They are synthesized as single-chain prepropeptides. In the case of insulin and relaxin, three disulfide bridges are formed and the C-peptide (connecting peptide) between the N-terminal B-chain and the C-terminal A-chain is enzymatically removed to give two chains joined together by two disulfide bridges. In the case of IGF-I (Mr = 7648.8), and IGF-II (Mr = 7469.5), the C-peptide is not cleaved. Relaxin has no influence on the level of glucose but IGF-I, IGF-II, and insulin are functionally related. Somatomedins [1751]
  Occurrence. The somatomedins C [67763-96-6] and A [62046-94-0] (SM-C and SM-A) were previously called the sulfation factor, thymidine factor, nonsuppressible insulin-like activity in serum (NSILA-S), or the multiplication stimulating activity (MSA). The insulin-like growth factor I (IGF-I) is identical to SM-C, SM-A appears to be a deamidated IGF-I [1752]. Somatomedin B [63774-77-6] (SM-B) has a completely different structure which is similar to the N-terminal 44 amino acids of vitronectin.

The somatomedins are found in the liver, lungs, prostate, testes, seminal and follicular fluid [1753], thymus, thyroid gland [1754], skeleton, brain, heart, kidneys [1755], gastrointestinal tract, saliva [1756], milk [1757], fibroblasts, chondrocytes [1758], skeletal muscles, and in adipose deposits. A large number of tumors produce the messenger RNA for IGF-I and/or IGF-II [1759].

h-IGF-I, Mr 7649, and h-IGF-II, Mr 7470, each consists of a peptide chain linked with three disulfide bridges. Analogous to proinsulin, the peptide chain is divided into the N-terminal B-chain, the connecting C-peptide, the A-chain, and the C-terminal D-chain. The propeptides also contain the C-terminal E-peptide and the prepropeptides, the N-terminal prepeptide. The structures of IGF-I and IGF-II in various species are described in [1760][1761][1762][1763][1764].

  Release. The release of SM is stimulated by growth hormone, prolactin (in the liver [1765]), insulin, injuries [1766], exercise [1767], increased vascular strain [1768], gonadoliberin, follitropin, lutropin, h-choriogonadotropin [1769], estradiol [1770], [1771], ACTH, androgens, parathyroid hormone [1759] and by cAMP (in osteoblast cultures [1772]). Prior to birth, neither IGF-I nor IGF-II appears to be dependent on GH [1773]. Here, placental lactogen, but not GH, insulin, or other growth factors stimulates the synthesis of IGF-II.

SM secretion is reduced by insufficient food intake [1774], low-protein diet [1773], chronic alcohol consumption [1775], and suppression treatment with GnRH agonists [1776].

Serum SM levels fall in patients with hypophyseal insufficiency, diabetes mellitus, and after the age of sixty. Women taking contraceptives and patients with hyperthyroidism have elevated SM levels [1777]. In Cushing\\\'s syndrome, the SM level in the spinal fluid is raised [1777].

Receptors [1759]. IGF-I and IGF-II bind with high affinity to specific receptors [1778].

Like the insulin receptor, the IGF-I receptor has two - and two -subunits. The -subunit binds the hormones in the cysteine-rich domain between His223 and Met274 [1779]. The -subunit contains tyrosine kinase which phosphorylates intracellular proteins after ligand binding.

The IGF-II receptor is very similar to the mannose 6-phosphate receptor and also binds mannose 6-phosphate [1780]. It consists of a single polypeptide chain, has no kinase activity, does not bind insulin, and binds only poorly to IGF-I.

An IGF binding component found in the serum is the extracellular part of the IGF-II receptor [1781]. In addition, four structurally related IGF binding proteins (IGFBP 1, 2, 3, and 4) have been characterized [1782], [1783]. IGFBP-1 binds IGF-I and IGF-II with similar affinity. IGFBP-2 preferentially binds IGF-II. The majority of serum IGF is bound in a complex consisting of IGF-I or IGF-II (-subunit), IGFBP-3 (-subunit), and an -subunit that does not bind IGF.

The serum IGF bioactivity is inhibited by h-IGFBP-1 and h-IGFBP-2 [1784], [1785]. In contrast, IGFBP-3 has a stimulating effect on the activity of IGF-I [1759].

  Biological Effects. IGF-I stimulates intracellular synthesis of 1,2-diacylglycerol and induces the degradation of phosphatidyl choline, a process which involves protein kinase [1786].

In hypophysectomized animals, administration of IGF-I, like GH, increases body weight and bone growth. GH stimulates the proliferation of osteoblasts via the local synthesis of IGF-I [1787]. The GH-dependent increase in calcitriol after a low-phosphate diet is mediated by IGF-I [1788].

IGF-I and IGF-II bind 100 – 200 times less tightly to insulin receptors than insulin but, like insulin, they increase glucose uptake and oxidation in adipose and muscle tissue. In humans, they have about 6 % of the hypoglycemic activity of insulin [1789] and inhibit endogenous insulin release [1790].

The basal and GHRH-stimulated release of GH is inhibited by a negative feedback mechanism by IGF-I. It acts directly on the pituitary, where it inhibits transcription of the GH gene [1791]. It also releases somatostatin in the hypothalamus [1773]. IGF-II does not have a negative feedback effect on the basal or GHRH-stimulated GH [1751]. IGF-I inhibits the secretion of PRL in the pituitary [1792], but stimulates the release of PRL in cells of the human decidua [1793].

In Leydig cells, IGF-I stimulates the growth of h-CG receptors [1794] as well as the basal and h-CG-stimulated secretion of testosterone [1795]. IGF-I stimulates progesterone synthesis and pregnenolone in ovarian cells [1796].

IGF-I and IGF-II also act as autocrine growth factors in muscle development [1797] and cause proliferation of tumor cells [1798]. They increase the motility of melanoma cells and, therefore, could also increase the metastatic potential [1799].

IGF-I has a modulating effect on the immune system: it stimulates the growth of the thymus [1800], but inhibits the IL-2-induced proliferation and antibody formation of splenocytes in vitro [1801].

Structure – Activity Relationships. The A-chain domains of IGF-I are of importance for receptor binding and the growth effect [1802], the B-chain sequences play a role in the interaction with IGFBPs [1803].

Tyr24, Tyr31, and Tyr60 are important for binding of IGF-I to the IGF-I receptor and Tyr60 for binding to the IGF-II receptor [1804].

IGF-I-(6 – 70) has only one hundredth of the activity of IGF-I (in stimulating protein synthesis in rat myoblasts), IGF-I-(4 – 70) and IGF-I-(5 – 70) are ten times and twice as active as IGF-I, respectively [1805].

  Uses. IGF-I reduces the blood sugar and insulin levels in Mendenhall\\\'s syndrome with severe insulin resistance [1806] and in Laron-type dwarfism with a defective GH receptor [1807]. Insulin
  Occurrence. Insulin [9004-10-8], Mr 5808 (h-insulin), was first used in 1921 as a therapeutic agent in diabetes mellitus. It is synthesized in the -cells of the pancreatic islets of Langerhans. However, immunoreactive insulin has also been found in other tissues (e.g., brain, testes, and liver).

Insulin consists of two peptide chains which are joined together by two disulfide bridges. It is formed from single-chain proinsulin by enzymatic removal of the C-peptide (connecting peptide) [1808] between the C-terminal A-chain and the N-terminal B-chain. In most species the A-chain (acid chain) contains 21 amino acids, while the B-chain (basic chain) contains 30 amino acids. The C-chain with its N- and C-terminal basic amino acids contains 35 amino acids. In vivo, the C-chain is found without the N- and C-terminal basic amino acids. In physiological concentrations, insulin occurs in human plasma as a monomer which does not bind to serum proteins [1809]. Insulin sequences of various species are given in [1810].

Insulin-like molecules are also observed in the silkworm Bombys mori [1811], in the mollusk Lymnaea stagnalis [1812], and in the brain of the insect Locusta migratoria [1813].  


  Release [1814]. Insulin is released by an increased plasma level of glucose or amino acids, cAMP, and Ca2+ (Mg2+). The plasma insulin level increases after ingestion of food. Incretins are postulated to stimulate the secretion of insulin from the pancreas in a glucose-dependent process. Incretin release from the intestine is increased by oral glucose and inhibited by insulin. The criteria for the postulated incretin are best fulfilled by the glucagon-like peptide 1-(7 – 36)-amide [1815], the glucose-dependent insulinotropic peptide, and oxyntomodulin [1816]. Glucose-dependent secretion of insulin is also stimulated by the gastrin releasing peptide, neurotensin, substance P, gastrin, pentagastrin, CCK-8 (sulfated or unsulfated), the C-terminal tetrapeptide of CCK, cholinergic substances, 2-adrenoreceptor antagonists [1817], TGF-1, TGF-2 [1818], oxytocin [1819], ACTH, glucagon, secretin [1820], calcitriol [1821], estradiol [1822], thyroid hormones [1823], prostaglandin D2, lipoxygenase products [1824], and phospholipase A2 products [1825].

Low doses of endogenous opioids and exorphins stimulate insulin secretion while high doses have a more inhibitory effect.

The glucose-stimulated release of insulin is inhibited by adrenaline [1826], prostaglandin E2 [1827], somatostatin, pancreastatin, pancreatic peptide, galanine [1828], calcitonin gene related peptide [1829], amylin, calcitonin, exogenous insulin [1830], growth hormone, interferon [1831], interleukin 1, and interleukin 6 [1832].

The cell-specific destruction of the pancreatic -cells, which precedes insulin-dependent diabetes mellitus occurs by an autoimmune mechanism. Autoantibodies have been found in more than 80 % of newly diagnosed patients. The target of the autoantibodies is a -cell autoantigen which has been identified as glutamic acid decarboxylase [1833] or as heat shock protein 65 [1834].

Receptors [1835]. The insulin receptor consists of two - and two - subunits joined together by disulfide bridges to give the configuration: (-chain-S-S--chain)-S-S-(-chain-S-S--chain). The cysteine-rich domain between Asn230 and Ile285 of the -chain is important for insulin binding [1836]. The -subunit is a transmembrane protein and contains a tyrosine-specific protein kinase. Insulin stimulates phosphorylation of the -subunit. Autophosphorylation of the insulin receptor is restricted by triiodothyronine [1837].

The receptor is synthesized in the form of a prepropeptide.

Diabetes, resistance to insulin, can result from receptor defects (e.g., a deletion in the tyrosine kinase domain [1838] or the subtitution of valine for Gly996 [1839]). Trp1200 is also important for the normal function of insulin receptor kinase [1840]. In Hodgkin\\\'s disease, antibodies against the insulin receptors can cause hypoglycemia because of their insulin-like activity [1841].

The formation of insulin receptors is stimulated by glucose [1842] and down regulated by insulin and proinsulin [1843]. In cancerous breast tissue, the concentration of insulin receptors is more than six times that in normal tissue and correlates with the size of the tumor and with the estrogen receptor concentration [1844].

The following positions in insulin appear to be important for receptor binding: A-chain: Gly1, Gln5, Tyr19, and Asn21; B-chain: Val12, Tyr16, Arg22, Gly23, Phe24, Phe25, and Tyr26.

Estrogen, progesterone [1845], h-GH, h-GH-(7 – 13) [1846], and relaxin [1847] increase the binding of insulin to the receptor; prolactin [1847], heparin [1848], or contraceptive therapy in women [1849] reduces binding.

  Biological Effects. Insulin lowers blood glucose by promoting glucose uptake in skeletal muscle, heart, and adipose tissue, by activating glycogen synthesis [1850], and by inhibiting glycogenolysis in the liver [1851]. Glucose transport proteins are involved in the uptake of glucose [1852]. Taurine [1853], the basic peptides Arg-Lys and Arg-Arg [1854], and somatostatin potentiate the insulin effect on the blood glucose level.

Apart from stimulating glucose and amino acid transport, insulin also increases the secretion of somatomedins, the affinity of the IGF-II receptors [1855], the proliferation and differentiation of cells (healing of wounds), ion transport, renal Na+/K+ ATPase [1856], lipogenesis, potentiates the FSH-stimulated synthesis of estrogen and progestin [1857] and the h-CG-stimulated synthesis of testosterone [1858], increases food intake [1859], stimulates the secretion of gastric acid [1860] and bile flow, and is important for postprandial cholecystokinin- or secretin-stimulated exocrine pancreatic secretion [1861].

Hypoglycemia induced by insulin is a stress reaction which leads to the release of ACTH and cortisol [1862]. Insulin also increases the K+-stimulated production of aldosterone [1863]. In type I diabetics, insulin lowers the level of cortisol raised by fasting [1864].

Insulin inhibits the synthesis and release of somatostatins and enteroglucagon [1865], reduces the basal and PTH-stimulated excretion of phosphate in the urine [1866] as well as renal Ca2+ reabsorption, stimulates the synthesis of collagen [1867], and potentiates the PTH-stimulated synthesis of calcitriol in the kidney [1868].

Insulin inhibits the noradrenaline- or AT II-stimulated contraction of arteries and veins (hypotensive effect [1869]), increases the heart rate [1870], and is positively inotropic [1871].

The inability of a given concentration of insulin to produce an expected biological effect is called insulin resistance. This resistance can be caused by circulating antagonists of insulin activity (antibodies, prostaglandins, and glucocorticoids [1872]), down regulation of the receptors, or receptor defects.

Structure – Activity Relationships. The biological activity of insulin is expressed in international units (IU). The activity is measured in the mouse cramp test or by determining the decrease in the blood sugar level in the rabbit. Crystalline insulin contains 26 – 28 IU/mg.

Proinsulin is only about one-third as active as insulin in lowering the blood sugar level, but its action is significantly prolonged [1873]. The antilipolytic activity of h-proinsulin is higher than that of h-insulin [1874].

Hydrophobic interactions are responsible for the formation of insulin dimers. The hexamer of insulin is formed from three dimers with two or four zinc atoms [1875]. Monomeric insulin is assumed to be the biologically active form, i.e., binds to the receptor. The regions around A1, A2, A19, A21, and B22 – B25 are important for biological activity.

Fully active insulin is obtained when the B-chain is shortened at the N-terminus by two amino acids and at the C-terminus by three amino acids.

[AspB10]h-insulin [1876] and de-(B26–B30)-[AspB10, Tyr-NH2B25]insulin [1877] are more active than h-insulin. GlyB23 can be replaced by d-Ala without loss of activity, but [AlaB23]insulin has a greatly reduced biological activity [1878]. Both [d-PheB24]b-insulin and [d-AlaB24]b-insulin still possess activity [1879]. Substitution of Glu for TyrB26 or ThrB27 or of Asp for ProB28 leads to monomeric analogues having a slightly higher activity [1880]. ThrB29 can be replaced by many different amino acids and still retain activity [1881].

The N-terminal Gly of the A-chain can only be replaced by d-amino acids without loss of activity. [d-LeuA1]insulin possesses full insulin activity and [d-TrpA1]insulin is even slightly more potent than native insulin. The hydroxyl group of TyrA19 forms a hydrogen bond with the carboxyl group of GlyA1 and stabilizes the molecule. Modifications of AsnA21 lead to less active compounds. The cysteines are exremely important for the tertiary structure.

Less soluble analogues with prolonged activity are obtained by introducing Arg into the molecule [1882][1883][1884], amidating the Glu--carboxyl groups and the C-terminus of the B-chain [1885], and by the palmitoylation of the A-chain [1886]. Long-acting analogues include [GlyA21,ArgB27,ThrB30-amide]h-insulin (NovoSol-Basal) [1882]. [AspB9,GluB27]h-insulin [1887] and [AspB10]h-insulin [1887] are monomeric derivatives that act especially quickly.

  Uses [1888], [1889]. Many insulin preparations are available for the parenteral treatment of diabetes mellitus. Bovine, porcine, and human insulin are generally used. Commercially available h-insulin preparations are either enzymatically modified p-insulin [H-Insulin, Depot-H-Insulin, Komb-H-Insulin (Hoechst); Insulin Monotard HM, Insulin Actrapid HM (Novo); Insulin Velasulin Human, Insulin Mixtard Human (Nordisk)] or chain recombinant insulin produced by genetic engineering in bacteria (Huminsulin, Eli Lilly). In enzymatically modified products the C-terminal alanine of p-insulin is substituted by a threonine ester with the aid of trypsin. The ester function is then hydrolyzed to give h-insulin. In chain recombinant h-insulin, the A- and B-chains are synthesized separately and subsequently linked by oxidation, see also  Genetic Engineering.

De-PheB1-insulin derivatives (Insulin Defalan, Hoechst) have full insulin activity, but are more soluble and less antigenic than insulin. In patients with insulin allergy, de-PheB1-p-insulin has been used successfully because it has a low antigenicity [1890]. However, de-Phe-insulins are no longer on the market.

Insulin pumps have been developed for better insulin adjustment, pulsatile infusion appears to be more efficient than continuous infusion [1891].

Treatment with insulin is also recommended in total parenteral feeding [1892], in cancer-induced anorexia, and loss of weight [1893]. Topically applied insulin promotes the healing of wounds [1894]. Relaxin [1895]
  Occurrence. Relaxin (RLX) [9002-69-1], Mr 6333 (h-RLX 2), is found primarily in the serum and tissues of pregnant mammals. It occurs in especially high concentrations in the corpus luteum of pregnant animals, and is isolated from this source. In addition, RLX is found in the endometrium during pregnancy, breast [1896], testes, prostate, and seminal fluid.

RLX, like insulin, consists of an A- (24 amino acids in humans) and a B-chain (32 amino acids in humans) linked by sulfide bridges and is synthesized as a single-chain prohormone. h-RLX occurs in two forms, h-RLX-2 is formed in the ovaries during pregnancy [1897]. p-RLX occurs in three forms. RLX sequences from various species are described in [1897]. 


  Release. The plasma level of RLX increases greatly at the end of pregnancy and falls rapidly after birth. In hypophysectomized animals, endogenous RLX can be activated by estrogens and progesterone. The release of RLX is increased by h-CG [1898], oxytocin, and prostaglandin F2. Indomethacin prevents the increase in the RLX level and delays birth.

In trophoblastic disease, which is accompanied by an increase in the plasma h-CG level, RLX is detectable in the plasma [1899].

  Biological Effects. Purified RLX (NIH standard, RXN-P1) has about 3000 U/mg. One unit is the threshold dose which causes a softening of the interpubic disc in two-thirds of the guinea pigs tested.

In advanced pregnancy, RLX reduces the contraction of the uterus. This effect is supported by progesterone and is important for the maintenance of pregnancy. RLX has a growth-promoting and relaxing effect on the uterus and cervix and a growth-promoting and lactation-inhibiting effect on the mammary gland. RLX alone inhibits progesterone synthesis, but increases estrogen synthesis [1900]. RLX also appears to prepare the myometrium for parturition because without it oxytocin cannot induce birth. RLX inhibits prostaglandin synthesis during pregnancy, but stimulates it during birth [1901].

The relaxing effect of RLX on the interpubic disc (pelvic symphysis) occurs because the compact cartilaginous tissue between the two pubic bones is converted to a more flexible structure. The water content of the tissue is increased and the secretion of proteolytic enzymes is stimulated, loosening the network of collagen and glycosaminoglycan [1902]. Estrogen and hypophyseal hormones (e.g., growth hormone) are also involved in this deaggregation of collagen. Intravaginal RLX (2 mg/patient) causes cervical maturation in humans and induces birth.

RLX increases sperm motility and exerts a hypotensive effect [1903]. It inhibits the pressor activity of angiotensin II, vasopressin, and noradrenaline [1904].

Structure–Activity Relationships. The shortening of the A-chain of p-RLX by two amino acids at the N-terminus does not affect biological activity, whereas deletion of five or six amino acids halves the biological activity [1905].

Oxidation of TrpB27 in p-RLX with N-bromosuccinimide has no influence on biological activity. However, p-RLX becomes inactive when TrpB18 is oxidized.

7.6.5. Somatostatin [1906]
  Occurrence. Somatostatin [38916-34-6], also called somatotropin release inhibiting hormone or factor (SRIH or SRIF), Mr 1638, is formed as prepro-SRIH. The main product of gene expression in the stomach and pancreas of mammals is pro-SRIH-(1 – 64), which is cleaved at the C-terminus to form SRIH-28 with 28 amino acids and SRIH-14 with 14 amino acids [1907].

SRIH-14 and SRIH-like substances have been found in the hypothalamus, nervous system, pancreatic islet D-cells, gastrointestinal mucosa, thymus, extrahepatic bile ducts, plasma [1908], in the C-cells of the thyroid gland, ovaries, and in plants (e.g., spinach [1909]). Somatostatin sequences of various species are described in [1910].

  Release. SRIH is released in the antrum (lower part of the stomach) in response to fasting [1911], acid in the antrum, intraduodenal infusion of fat and HCl [1908], stress [1912], cholinergic and -adrenergic mechanisms, dopamine D2 agonists [1913], estrogen and androgens [1913], and numerous peptide hormones including growth hormone releasing hormone and somatomedins [1908], [1914][1915][1916][1917].

The secretion of SRIH is reduced shortly after meals [1911], by electrical stimulation of the vagus, sham feeding, -adrenergic stimuli, serotonin [1918], and various peptides (e.g., endogenous opioids, galanine, pancreatic peptide, and insulin).

The plasma level of SRIH is lower at night [1919]. The plasma SRIH level in children below the age of two is raised. Above two years its level is normal and increases continuously with age [1920].

The plasma SRIH level is increased in patients with chronic renal failure, cirrhosis [1921], and primary hypothyroidism [1922]. The level of SRIH is raised in the cerebrospinal fluid of patients with brain tumors, metabolic encephalopathy, spinal cord compression, and intracranial hypertension [1923].

The plasma level of SRIH is reduced in patients with pernicious anemia, achlorhydria [1920], cluster headache [1924], psoriasis [1925], obesity [1926], and in women who are taking estrogen-containing contraceptives [1927]. The level of SRIH in the cerebrospinal fluid is reduced in patients with Alzheimer\\\'s disease [1928], unipolar depression, and active multiple sclerosis [1912]. The level of SRIH is reduced in the cortex and hippocampus of patients suffering from Parkinson\\\'s disease [1929].

Receptors. Several SRIH types of receptors are found in the brain.

SRIH receptors are detected in most GH- and TSH-producing pituitary adenomas, carcinoids, islet cell carcinomas, EGF-receptor-negative glial tumors, and small cell lung carcinomas [1930]. The number of SRIH receptors is reduced in the cerebral cortex of patients with Alzheimer\\\'s disease [1931].

  Biological Effects. SRIH-14 [1932] stimulates phosphodiesterase, inhibits cAMP synthesis, blocks calcium influx, and the turnover of phosphoinositides in the cytosol [1933]. It also inhibits the release and action of hormones (e.g., growth hormone (GH), prolactin, thyrotropin, stress-induced corticotropin [1934]), calcitonin, insulin, glucagon, GIP, VIP, secretin, pancreatic polypeptide, gastrin releasing peptide [1908], gastrin, cholecystokinin, and motilin. GH is the most sensitive to SRIH inhibition, followed by thyrotropin [1935].

SRIH inhibits exocrine secretion of gastric acid, pepsin (anti-ulcer effect), pancreatic enzymes, pancreatic bicarbonate, colonic fluid (reduction of secretory diarrhoea [1936]), bile flow (patients with somatostatinoma usually have gall-stones [1937]). It also potentiates human platelet aggregation stimulated by collagen and arachidonic acid [1938] (control of upper gastrointestinal hemorrhage).

SRIH enhances gastric emptying [1939] and intestinal transit [1940]. It may be useful in the management of the dumping syndrome [1941]. SRIH inhibits cell proliferation in the exocrine pancreas [1942], rabbit jejunum [1943], liver after hepatectomy [1944], and tumor growth. The antitumor effect of SRIH is mediated by the stimulation of a tyrosine phosphatase [1945].

Immunomodulatory actions include increase of leukocyte migration inhibitory factor [1946], enhancement of human lymphocyte natural killer activity [1947], and mouse spleen lymphocyte proliferation [1948].

Structure – Activity Relationships. The substitution of d-Trp for Trp8 produces an analogue that has 8 times the activity of SRIH in inhibiting GH release.

Potent, long-acting SRIH analogues of the urotensin II type are of tremendous interest [1949][1950][1951][1952]. For instance, octreotide [49474-41-2], [79517-01-4] is 70 times more effective than SRIH-14 in inhibiting GH. It has a long duration of action when given intramuscularly [1949].  


Cyclic peptides without a disulfide structure are also potent, long-acting compounds. Examples are cyclo-(N-Me-Ala-Tyr-d-Trp-Lys-Val-Phe) (seglitide) and cyclo-(Pro-Phe-d-Trp-Lys-Thr-Phe).

Cyclic retropeptides of the latter, e.g., cyclo-(Phe-Thr-Lys-Trp-Phe-d-Pro), inhibit the uptake of cholate and phallotoxin in liver cells [1953] and protect against taurocholate- and ceruletide-induced pancreatitis [1954], and against ethanol-induced stomach lesions [1955], without possessing true SRIH activity.

Analogues of octreotide which usually contain penicillamine instead of Cys7 are poor ligands for SRIH receptors, but exhibit stronger binding to opioid receptors [1956]. They act as selective antagonists for -opioid receptors, i.e., they inhibit morphine induced analgesia [1957].

  Uses. SRIH-14 infusions (Stilamin, Serono; Aminopon, UCB; Somatostatin Ferring, Ferring; Somatostatin Labaz, Sanofi) have proved useful for the treatment of bleeding peptic ulcers and gastrointestinal lesions, for preventive treatment against stress-induced ulcers, and in the healing of fistulae of the small intestine and gallbladder.

Octreotide (Sandostatin, Sandoz) [1958] is used in the treatment of GH- and thyrotropinsecreting pituitary tumors, carcinoid tumors, glucagonomas, insulinomas, and gastrinomas. The use of octreotide in acute esophageal variceal bleeding, pancreatic pseudocysts, external gastrointestinal and pancreatic fistulae, short bowel syndrome, dumping syndrome, and refractory hypersecretory diarrhoea related to the acquired immunodeficiency syndrome has provided encouraging results. Preliminary reports indicate the efficiency of octreotide in the treatment of psoriasis, autonomic neuropathy [1959] and of carcinoid flush [1960], and its ability to reduce growth in tall adolescents. Other potential applications include the control of pain [1961], rheumatoid arthritis, and diabetic microangiopathy as well as the prevention of postoperative pancreatic complications (fistulae, pancreatitis, and abscess).

7.6.6. Pancreastatin
  Occurrence. Pancreastatin (PST) [117148-67-1] from the pancreas of the pig contains 49 amino acids [1962]. Sequences from other species are given in [1963]. h-PST contains 52 amino acids, Mr 5509.

The precursor of pancreastatin is chromogranin A, an acidic glycoprotein which is widely distributed in the neuroendocrine system and released in large amounts from the chromaffin cells of the adrenal medulla [1963]. Pancreastatin contains the penta-Glu sequence of gastrin (GT) and has a C-terminus that is similar to that of gonadoliberin (GnRH).

In patients with non-insulin-dependent diabetes mellitus, the plasma pancreastatin level increases after the digestion of glucose, which is not the case in healthy persons [1964].

  Biological Effects. Pancreastatin inhibits the first phase of glucose- or arginine-induced release of insulin and the arginine-induced release of somatostatin, but potentiates the arginine-induced secretion of glucagon [1965] from the rat pancreas. These changes are reminiscent of non-insulin-dependent diabetes.

In the rat, pancreastatin lowers the plasma insulin level and increases the plasma level of glucose in response to intragastric glucose [1966] and raises the plasma glucagon level in response to intravenous arginine [1967]. Like glucagon, it stimulates hepatic glycogenolysis [1968].

Pancreastatin also inhibits the CCK-stimulated secretion of protein and fluid from the pancreas [1967] and the CCK-stimulated growth of human pancreatic adenocarcinoma [1969].

Structure–Activity Relationships. The inhibitory effect on the glucose-stimulated release of insulin is restricted to the C-terminal region of the molecule [1962]. The shortest, active C-terminal fragment is p-PST (35 – 49) [1970]. The C-terminal amide function is required for biological activity [1970].

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