Growth Hormone and Insulin-Like Growth Factor Flashcards
1
Q
GHRH
A
- somatocrinin
- released from hypothalamus
-effects on growth hormone release and synthesis in the anterior pituitary somatotroph
*derived by proteolysis from an amino acid precursor produced in the arcuate nucleus
- long half life (50 min)
- The GHRH-receptor complex interacts with Gs protein to promote activation of adenylyl cyclase and thus increase the intracellular cAMP concentration
- cAMP activates protein kinase A that in turn promotes both the secretion and synthesis of growth hormone.
- Activated protein kinase A stimulates GH biosynthesis by phosphorylating CREB (Cyclic AMP Responsive Element Binding protein), a nuclear transcription factor.
- CREB binds upstream of the promoter in the GH gene and enhances its transcription
2
Q
GHIH
A
- somatostatin
- released from hypothalamus
-periventricular area
- GHIHreceptor complex interacts with Gi protein to favor decreased production of cAMP by inhibition of adenylyl cyclase.
- GHIH blocks both synthesis and secretion of GH by lowering the concentration of cAMP.
3
Q
GH
A
- Growth hormone (somatotropin) is much higher in concentration than any other pituitary hormone
- Accounts for ~2% of weight of the pituitary.
- Species specific - nonhuman forms inactive in humans; cannot bind to the human GH receptor.
- GH secreted from the somatotrophs signals release of IGF-I from the liver (Figure 1). GH secretion is controlled in part through feedback inhibition by IGF-I on the somatotrophs and on the arcuate nucleus (decreases GHRH release) and via stimulation of the release of GHIH.
4
Q
GH Secretion
A
- GH secretion is influenced by a variety of stimuli (e.g., sleep, exercise, stress) and, like that of many of the pituitary hormones, is episodic.
- In contrast, hyperglycemia and elevated circulating fatty acids reduced GH secretion.
- Plasma GH concentration may change as much as 10-fold within a few minutes.
- Interacting with or overriding the basic control system of the hypothalamus is a well-characterized diurnal (circadian) rhythm of GH secretion.
- Throughout most of the day, the plasma GH concentration is fairly low (<5 mcg/L). However, approximately one hour after the onset of deep sleep, plasma GH is markedly increased. In the early morning before waking, the plasma concentration decreases.
-Therefore one of the largest increases (70% of daily secretion) occurs shortly after the onset of sleep, lending support to the adage “If you don’t get your sleep, you won’t grow”.
5
Q
Metabolic Control of GH Secretion
A
- Metabolic control of GH secretion relates to the nutritional status.
- Excess glucose (hyperglycemia) suppresses release while hypoglycemia promotes release to help restore glucose concentration to normal.
- Because a high protein diet is low in glucose, amino acids (especially arginine) from the protein meal cause the release of GH to promote gluconeogenesis.
- Fatty acids, likely because they are an alternate fuel supply, suppress the effects of GH.
- With food deprivation the increased GH helps mobilize fats as an energy source to limit the loss of muscle protein.
6
Q
GH Effects
A
- Direct effects are metabolic and are mediated by GH working via GH receptors on target tissues (i.e., adipose cells, skeletal muscle, and liver).
- Indirect effects of GH are exerted as a consequence of the stimulation of production of insulin-like growth factor-I (IGF-I, somatomedin C), that is an additional regulatory peptide primarily produced by the liver.
-Generally, indirect effects are related to growth and are exerted on skeletal muscle, boneepiphyseal cartilage, soft tissue and connective tissue.
7
Q
GH Receptors and Mechanism of Action I
A
- The human receptor for GH is a single membrane-spanning domain.
- Growth hormone receptor signaling requires activation of tyrosine kinase, but unlike the insulin receptor the growth hormone receptor does not possess intrinsic tyrosine-specific protein kinase activity.
- The GH molecule includes two distinct binding domains for its receptor.
-In this way GH can bind to each subunit of the preformed receptor dimer. This mechanism differs from insulin receptor in that only one receptor site is occupied by the insulin molecule.
•Additionally while the GH receptor is associated with kinase molecules (i.e., JAK2) these are not intrinsic domains of the receptor but rather are soluble and interact with the receptor.
- With binding of GH, the JAK2 proteins move closer in proximity to each other.
- This movement allows them to trans phosphorylate each other rendering them permanently active until the phosphates are removed.
- This phosphorylation also allows GH to dissociate to bind to another receptor.
8
Q
GH Receptors and Mechanism of Action II
A
- More important than receptor phosphorylation is that JAK phosphorylates downstream components of the signal transduction pathway to mediate GH bioeffects.
- Notably, one pathway includes latent transcription factors, STATs (Signal Transducers and Activators of Transcription).
- STATs are initially associated with the GH receptor ([A]). After tyrosine phosphorylation by JAK2 ([B]), they form a dimer ([C]) and then translocate to the nucleus [D].
- JAK2 and STAT activation are associated with both GH and prolactin receptors.
- STATs are therefore a major downstream target of activated JAK2, and are responsible for turning on gene expression for IGF-I release (liver), promoting lipolysis (adipose), and accelerating amino acid uptake (muscle) ([E].
9
Q
Metabloic Effects of GH
A
- In line with its role in growth, GH increases uptake of amino acids by skeletal muscle, in concert with the ability of its mediator, IGF-I, to promote formation of DNA and RNA leading to increased protein synthesis.
- In addition, in this way, GH mimics some effects of insulin.
-For the most part the effects of GH are counter regulatory to insulin.
- In line with the increased need for glucose during growth, GH diminishes peripheral glucose utilization and increases hepatic gluconeogenesis.
- As in starvation, fuel is provided by mobilizing fatty acids from triacylglycerol stores by increasing lipolysis.
- If this occurs over a long enough period of time, the elevated fatty acids can boost ketogenesis.
-Recall that elevated blood fatty acids and ketone bodies diminish muscle oxidation of glucose.
- Furthermore, in liver, fatty acid oxidation is obligatory for gluconeogenesis to occur.
- In these various ways, GH promotes elevation of blood glucose concentration.
10
Q
IGF-I
A
- somaomedin
- GH acts on skeletal tissues (bone and cartilage), and in part on muscles, by inducing the formation in liver of a direct acting intermediary growth factor. IGF-I (insulin-like growth factor-I or somatomedin C) has 85% structural homology with proinsulin. IGF-I is a continuous peptide chain unlike the A and B chain motif of insulin.
- IGF-I is produced in the liver and other tissues and is secreted in response to GH.
- Thus IGF-I is a secondary hormone or mediator of GH action. IGF-I in the circulation is bound to IGF-binding proteins (IGFBPs).
11
Q
IGF-I and Starvation or SYstemic Illness
A
- Starvation or systemic illness inhibits the ability of the liver to synthesize and secrete IGF-I in response to GH.
- This situation explains why growth ceases during severe illness, and “catch-up growth” occurs when the illness is resolved.
- Nevertheless, starvation activates the release of GHRH, which in turn stimulates GH secretion.
- During starvation, elevated GH exerts its glucagon-like metabolic effects to mobilize fuels and to promote glucose formation for survival. Of course, only the metabolic effects of GH are employed, since IGF-I-triggered growth would not be prudent during starvation.
12
Q
Coordination of GH and IGF-I Actions
A
- growth of muscle, growth of bone (via prliferation of the epiphyseal cartlage) and dissapation of fat
- Liver and kidney contain a high concentration of GH receptors consistent with their role in glucose production.
- GH receptors occur on adipose cells mediating the direct lipolytic (fat mobilizing) action of GH, and in muscle cells for the direct effect of GH on amino acid uptake and protein synthesis.
- Muscle cells also contain high amounts of the IGF-I receptor that activate a cascade resulting in muscle cell proliferation.
- Bone and cartilage are unique in possessing mainly IGF-I receptors that mediate the growth response.
- IGF-II (somatomedin A) is important in development of skeletal muscle.
- It seems to be regulated by microRNA.
- A number of studies demonstrated the presence of IGF-II and its receptor in a variety of tumors. Cancer patients who over express IGF-II generally have a poor prognosis. Clearly IGF-II does not play a role in normal growth because GH-deficient dwarfs or pygmies have normal circulating concentration of IGF-II. Therefore, pathological lack of growth associated with GH deficiency must be mediated through IGF-I.
13
Q
IGF-I receptors adn Mechanism of Action
A
- IGF-I is not related structurally to GH but, instead, as its name “insulin-like growth factor” implies, it is similar in amino acid sequence to insulin.
- The IGF-I receptor contains intrinsic tyrosine kinase activity in the same subfamily with the insulin receptor.
- Insulin and IGF-I stimulate mitogenesis (cell growth) and glucose utilization (glycolysis) via a tyrosine kinase initiated intracellular kinase cascade that, for regulating metabolic enzymes, terminates with the activation of phosphatases.
- These phosphatases dephosphorylate and activate enzymes involved in regulation and metabolism of glucose, fatty acids and cholesterol.
- Another important effect of IGF-I is the regulation of production and release of GH.
- When IGF-I is overproduced in response to GH, a logical feedback loop would lead to decreased synthesis and release of GH.
- Accordingly, IGF-I increases the release of GHIH and decreases the output of GHRH to lower cAMP in the somatotroph by inhibition of adenylyl cyclase.
- IGF-I also exerts a short feedback loop to suppress GH synthesis and release from the somatotroph.
14
Q
Direct Effects of GH
A
- increased Muscle amino acid uptake resulting in protein synthesis (similar to insulin)
- increased Glucose use peripherally by lowering tissue uptake (anti-insulin)
- increased Glucose output from liver (anti-insulin)
- increased Fat Mobilization (anti-insulin)
- increased Ketogenesis in liver (anti-insulin)
- increased IGF-I release from liver (and other tissues)
15
Q
Direct Effects of IGF-I
A
- increased Cartilage/bone growth
- increased Muscle growth/proliferation
21
Q
Laron-type Dwarfs
A
- Genetic defects in GH receptors expressed in the liver and other tissues occur in Laron-type dwarfs, who cannot produce IGF-I (somatomedin).
- These patients are resistant to therapy with hGH, a distinguishing feature from isolated GH deficiency.
- Because GH receptors are defective, Laron patients display metabolic problems such as hypoglycemia and increased triacylglycerol storage in adipose.
- Patients with Laron Syndrome respond to treatment with recombinant human IGF-I to restore growth and development.
- Their growth and development need to be monitored regularly.
- Nutritionally frequent meals are needed to avoid hypoglycemia with monitoring of their blood glucose concentration.
- Overall their diet is carefully planned to limit excessive weight gain.
22
Q
GHRH Receptor Defect - Dwarfism of Sindh
A
- a defect of the GHRH receptor on the somatotropic cells of the anterior pituitary
- This disorder is also refer to as Dwarfism of Sindh.
- Patients are treated with recombinant human growth hormone.
24
Q
Panhypopituitarism
A
- The boy in has panhypopituitarism (age 5), compared to another boy (age 4.3) who lacks the disorder.
- In addition to the dwarfism note the small genitalia.
- Although hypothyroid features are not prominent, hypothyroidism was documented via a low uptake of radioiodide (I131) by the thyroid.
- Adrenal insufficiency was demonstrated by the low excretion of products of steroid degradation, low serum sodium, and the initial failure in response to ACTH.
- The fasting blood sugar was found on occasion to be as low as 20 mg per 100 ml.
- The bone age was 20 months when the chronologic age was 4.5 years.
- X-ray examination showed the sella turcica to be normal, but pneumoencephalograms and electroencephalograms demonstrated organic brain disease.
- The boy showed a satisfactory response to treatment with cortisone, thyroid hormone, and growth hormone.
