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41 Cards in this Set
- Front
- Back
Growth hormone (GH, hGH)
aka Somatotropin |
GH is not highly conserved between species
GH in cows, pigs, sheep is not effective in humans |
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hGH
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single polypeptide chain of 191 AA, with 2 intrapeptide disulfide bonds
Variants of growth hormone have been isolated from humans, produced by post translational modifications and distinct mRNA with seq ommited from the N terminal region |
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GH: origin
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GH is synthesized in the anterior lobe of the pituitary gland; is stored in large dense granules and can account for up to 10% of the dry weight of the tissue
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GH: circulation
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GH circulates bound to a protein similar in structure to target cell growth hormone receptor
half life 20-30mins aging not associated with dramatic decline in amt of circulating GH |
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GH: effects
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- pulsatile GH is more effective than continuous GH
- growth hormone promotes growth in size of limbs and internal organs. Net linear bone growth occurs near the ends of bones in epiphyses |
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Epiphyses
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epiphyseal plate (cartilage) that proliferates, cartilage forms a matrix --> bone
faster rate of growth the larger the epiphyseal space assays for GH measure ability to inc size of space |
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GH: effects
metabolism |
- long term tx with GH makes tissue resistant to effects of insulin to stimulate gluocse uptake
-GH is diabetogenic -- even though it promots release of insulin like GF that promote glu uptake |
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Growth hormone
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1. spares glucose utilization
2. inc availability of free FA 3. promotes AA uptake and protein synthesis Generally - dec adiposity - inc lean body mass Acute administration of GH inc circulating gree FA and glycerole (acute promotion of lipolysis) |
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Other effects (enrichment) of GH include
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1. Inc Ca absorption from the gut
2. Inc urinary Ca excretion 3. Inc urinary hydroxyproline excretion 4. Inc retention of phosphate, potassium, and Na (Na can be bc of aldosterone--> inc intersitial V --> HTN |
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Syndromes of growth hormone excess:
Gigantism |
-hypersecretion of GH result from pituitary tumors
- if hypersecretion before bony epiphyses close--> inc linear growth --> long arms/ legs - size of visceral organs inc, amt of adipose tissue dec |
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Syndromes of growth hormone excess:
Acromegaly |
- if hypersecretion occurs after epiphyses close --> bone growth in fingers, toes, hands, feet, jaw, around eyes
- size of visceral organs inc, amt of adipose tissue dec |
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Syndromes of growth hormone deficiency:
Dwarfism |
- lack of GH from failure of pituitary to release the hormone, or removal of gland
- lack of GH prevent kids from reaching normal stature - mild obesity common, puberty delayed -Adults- lack of GH is not known to cause any physical signs |
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Laron type GH reistance
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defects with GH receptor or post recepto steps that mediate hormone action
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GH
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- two bindings sites (sites 1 and 2) that cause dimerization of GH receptors
- dimerization appears to be req for GH to produce a biological effect |
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First research
Somatomedins |
growth hormone promoted the expression of a somatomedin (factor in serum)--> promotes bond growth
factors that mediated somatic growth |
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Second research
MSA multiplication stimulating activity |
responsible for promoting the division of cells grown in culture
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Third research
Non suppressible insulin like activities NSILA |
Antibodies that blocked insulin action in bioassay failed to block the majority of insulin - like activity (activity taht promotes glu uptake and metabolism) in serum from fasted animals
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All three research -->
insulin like growth factor (IGF) |
IGF1- somatomedin A or C or basic somatomedin, GH inc level of IGF 1 mRNA in liver and peripheral tissues
IGF2 aka MSA |
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IGF-1
IGF-2 |
Molecular weights 7500
similar in structure to insulin, except that the C peptide (removed form insulin) remains major site syn--> liver mRNA coding for IGF also at other sites |
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Circulation of somatomedins
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IGF-1 and IGF-2 circulate bound to larger proteins.
after dissociation they are more active half life--> hours |
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IGF's (somatomedins) effect
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similar to insulin
mediate effect of growth hormone |
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IGF receptors
Type 1 |
- preferentially binds IGF 1 compared to IGF-2
- binds insulin weakly - has instrinsic tyrosin protein kinase activity and a structure similar to insulin receptor |
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IGF receptor
Type 2 |
- preferentially binds IGF-2 compared to IGF-1
- do not bind insulin - structurally distinct from type 1 and insulin receptors |
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Insulin and IGF-1
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-Insulin, inc amt of IGF-1
-Insulin deficiency dec IGF-1 (dec restored by admin of insulin not GH) -Insulin act directly on liver to inc IGF-1 rather than by inc GH - Admin IGF-1 to insulin deficient animals restores growth but does not restore blood glucose |
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Hypopituitary dwards
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-have depressed IGF-1 and IGF-2
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Tx of hypophysectomized rates with IGF-1 not IGF-2
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restores growth
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Pygmies
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- normal amts of GH
- slightly depressed amts of IGF-2 - low amts IGF-1 |
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Standard, miniature, toy levels of GH
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IGF-1 highest in the standard strain, intermediate in the minature, lowest in the toy
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Clincal use of IGF's
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- cDNA coding for IGF-1 and IGF-2
- short kids fail to respond to GH therapy may fail to syn normal amts of IGF-1, tx with IGF-1 - if kids respond GH but have adverse side effects |
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Glucoreceptors in hypothalamus sense changes in blood glucose
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--> a fall in blood glucose --> promotes secretion of GHRH
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GHRH
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- stimulates a pituitary adenylate cyclase--> cAMP --> promotes release of GH
- somatic mutations in pituitary (Gs- alpha) cause constitutively elevated cAMP--> cause GH releasing tumors - age dec response to GHRH |
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Somatostatin
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- acts via Gi and diminishes GHRH action bc its a general inhbitor of hormone stimulated (not basal) adenylate cyclase)
- somatostatin overrides GHRH stimulation of GH release |
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Release of GH into circulation is pulsatile and periodic
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- Feeding dec daytime circulating levels of GH
- large peak 1-2 hrs after commencing nocturnal sleep |
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Test for normal release response
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- insulin induced hypoglycemia
- basal levels of plasma GH are 1-5ng/ml - after exercise rise 15-50ng/ml - hormone assayed by RIA |
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GHRH- Growth hormone release hormone
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- 44AA
- normal source of GHRH is in the brain - pancreatic tumors produce and secrete GHRH --> lead to GH excess and cause acromegaly |
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GHRH: circulation
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- little GHRH in the plasma
- if injected it effectively release GH |
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GHRH: administration
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-GHRH used to treat slow glowing children w/ low amts of circulating GH
- effective for pts that lack effective regulation of normal pituitary |
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Somatostatin refers to small peptide
Somatostatin: origin |
- 28AA precursor
- synthesized in brain but also in peripheral tissues (pancrease) where it suppresses insulin release |
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Somatostatin: circulation
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- found free in plasma and is rapidly cleared
Half life- somatostatin 14 -->2-3 mins |
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Somatostain: Administration
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- surgical removal of pituitary does not reduce excess GH production
- treat problem with somatostatin but 1. somatostain has short hlaf life 2. it inhibits adenylate cyclase in a variety of tissues --> inhbition leads to inhbition of insulin release |
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Growth hormone, insulin and growth
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--circulating levels of GH may be elevated during stress when there is little growth
-Insulin also influences production of IGF-1 - GH is critical factor regulating growth via IGF-1 --> should not be assumed that GH is sole regulator of the process. |