L21 Metabolic Rate, Growth and Disease Flashcards
What does deficiency of GH lead to?
In children it promotes growth, deficiency leads to dwarfism. In adults, deficiency in GH shows no obvious disease but replacement therapy shows increases in lead body mass, decreased fat and increased vigour.
What does excess GH lead to?
Excess in children leads to gigantism. - In adults the epiphyses of the long bones are fused so you cannot grow any more, as a result there is no change in stature. Excess leads to acromegaly, the bones become thickened and enlarged, the soft tissue also over grows. This leads to an excessive load on the CVS and so typically patients die of heart failure.
How is GH regulated?
Growth hormone releasing hormone (GRH) is released from the hypothalamus. Foodstuff and ghrelin feed into here. In the hypothalamus there is the paraventricular nucleus (stimulates the anterior pituitary to produce GH) and the arcuate nucleus (inhibits the anterior pituitary). These have reciprocal inhibitory effect, leading to a cyclic response. The amount of GRRH and the amount of GH we produce shows a spiky pattern through the day. T3 also has an enhancing effect on GH. Lost of GRH leads to lots of growth hormone, providing a negative feedback model, enhancing somatostatin production, inhibiting GH which will inhibit GRH.
How is GH secreted?
GRH increases secretion whereas somatostatin suppress secretion from the anterior pituitary gland. GRH causes activation of adenylate cyclase and somatostatin inhibits it. GRH leads to activation of adenylate cyclase which activates protein kinase A leading to the secretion of GH by exocytosis. GH release is very pulsatile through the day and night however much is released at night.
How is GH synthesised?
GH is produced in two splice variants - 20 and 22 kDa. Both work and so the same thing. When released in circulation, half of it is bound to a carrier protein in circulation. This is its receptor and increases its half life.
What are the diabetogenic effects of GH?
- Antagonising the effect on insulin, increasing glucose level. Acts via trypsin kinase associated receptor, leading to protein phosphorylation. Produces fairly rapid effects,
- Increases lipolysis, insulin resistance, increases gluconeogenesis, and decreases muscle glucose uptake. The muscles instead use lipids.
Long term effects on growth mediated via insulin-like growth 1 (somatomedin) released from many tissues in response to GH (requires insulin to be present).
- Increases lipolysis, insulin resistance, increases gluconeogenesis, and decreases muscle glucose uptake. The muscles instead use lipids.
What are IGFs?
Insulin-like growth factors. There are 2: IGF1 main one stimulated by GH and IGF2 not controlled by GH and doesn’t work well on the receptor. IGF1 has a string homology to insulin - has similar receptors, IGF1 therefore will work okay at the insulin receptor. They enhance protein synthesis and growth. Due to the homology if IGF1 is present in very high concentrations, it can induce hyperglycaemia.
What factors, other than GH, effect growth?
Other factors that affect growth
- Insulin - in the foetus it is the main hormone that promotes growth. Also in the adult for GH for work, insulin must be around and so has a permissive effect.
- Steroid hormones - sex steroids accelerate growth but hasten maturity (fusion epiphyses of bones and so we reach the mature heights). Glucocorticoids typically slow growth as they act as stress hormones.
Thyroid hormones are essential for normal growth and response to GH.
What are thyroid hormones?
They are peptide hormones but act like steroids as their receptors are intracellular. - T3 (Triiodothyronine) is the main active form but T4 (Thyroxine) is the main form in circulation. T4 particularly is tightly bound to carrier proteins and so its free concentration is very low but it has a high half life. T3 is much less stable but comes into cells and has its effect.
How is TSH and thyroid hormone secretion regulated?
TSH is released from the anterior pituitary (Thyrotropin) which travels to the thyroid and stimulates it.
What is the function of the thyroid hormones?
Thyroid hormones increase metabolism and promote heat generate. They also promote growth. It is a nuclear receptor initiates gene transcription. It either induces or suppresses expression - the sodium-potassium pump for example by shunting ions as well to increase activity and enzymes for gluconeogenesis and respiration The beta adrenergic receptor also gets activated increasing our sensitivity to sympathetic activity.
What are the acute effects of thyroid hormones?
- Acutely, increase basal metabolic rate and heat production, via “futile cycles” and mitochondrial decoupling (pump electrons across and let them flow out again without producing ATP) particularly relevant in brown fat which is a type of adipose tissue used to generate warmth.
- Increases gluconeogenesis and glycogenolysis in the liver (freeing glucose)
- Causes both lipolysis (to free glycerol for gluconeogenesis), and lipogenesis at the same time.
- Increases proteolysis (to produce AA for gluconeogenesis), but also protein synthesis. Net muscle wasting.
- Increases Na/K ATPase activity - possibly by causing a sodium leak
- Increased β receptor expression
Usually no hyperglycaemia (insulin control normal)
What are the chronic effects of thyroid hormones?
- Crucial for normal brain development and growth
- Deficiency in infancy leads to cretinism (a condition characterized by physical deformity and learning difficulties that is caused by congenital thyroid deficiency) and dwarfism (suppression of GH response).
- Later in childhood there is severe impairment of growth: catch-up growth possible
TSH drives thyroid hypertrophy, so low TH (and lack of feedback) leads to a goitre: common in areas with low environmental iodine (e.g. “Derbyshire neck”)
What can result due to autoimmunity of the thyroid?
Hyperthyroidism and hypothyroidism.
How does negative feedback work in the regulation of glucocorticoids?
- CRH produced by the hypothalamus stimulates the anterior pituitary to produce ACTH (corticotropes produce this) which stimulates the adrenal gland to act via cAMP to activate a series of cascade to result in the production and release of corticosteroids.
- ACTH stimulates adrenal cortex (zona fasciculata and reticularis): hypertrophy and cortisol production.
The steroids feedback both to the pituitary and the hypothalamus to suppress the production of glucocorticoids.
- ACTH stimulates adrenal cortex (zona fasciculata and reticularis): hypertrophy and cortisol production.
