Metabolic Rate, Growth & Disease Flashcards
How is acute regulation of plasma glucose maintained?
Through the action of insulin and glucagon
There are some modifications by adrenaline
What is the role of growth hormone in children?
It promotes growth
What does deficiency and excess growth hormone in children lead to?
Deficiency leads to dwarfism after birth
Excess leads to gigantism
Why does growth deficiency only lead to dwarfism after birth?
Before birth, there are hormones related to growth hormone that produce the same growth response
Maternal insulin is also important
Why does growth hormone not have the same effect in adults?
The epiphyses of the long bones are closed, so there is no change in stature
What does an excess of growth hormone cause in adults?
Acromegaly
Bones become excessively thickened, soft tissues and other tissues overgrow
How does someone with acromegaly often die?
Through heart failure
This is due to the extra strain on the cardiovascular system from tissue overgrowth
What does growth hormone deficiency cause in adults?
How does this change when growth hormone is administered?
Deficiency gives no obvious disease
When GH is administered:
- increase in lean body mass
- decrease in fat
- increase in vigour and wellbeing
What is the role of the hypothalamus in GH regulation?
It integrates signals that are driving or suppressing expression of GH
What are the 2 nuclei of the hypothalamus involved in GH regulation?
How do they affect each other?
- paraventricular nucleus secretes somatostatin
- arcuate nucleus secretes GRH
They inhibit each other, leading to an episodic cyclic response
How will the paraventricular and arcuate nuclei influence GH production?
Somatostatin from the paraventricular nucleus suppresses anterior pituitary GH
GHR from the arcuate nucleus increases anterior pituitary GH
What factors will increase growth hormone secretion?
- low glucose
- amino acids
- TRH
- Ghrelin
- androgens/oestrogens
- sleep, exercise and stress
How does Thyroid hormone (T3) influence GH production?
It increases growth hormone production
What is the main result of growth hormone secretion?
It will increase metabolic activity and produce IGFs (insulin-like growth factors)
What is the role of IGFs?
They provide feedback inhibition and longer-term growth
How does growth hormone release change during the day?
There are lots of rapid pulses of release
More is released at night
What is the mechanism behind growth hormone secretion?
- GRH binds to the receptor
- This causes activation of adenylate cyclase
- adenylate cyclase activates protein kinase a
- this causes a enzymatic cascade leading to Ca2+ influx
- Growth hormone is released by exocytosis
What is the effect of somatostatin on growth hormone release?
It will inhibit adenylate cyclase
What are the 2 variants of growth hormone?
22 kDa form predominates
20 kDa form
What happens to growth factor after it is released into the circulation?
About 40% of the molecule binds to a carrier protein in the plasma
This protein is made by cleaving its receptor
What is the half-life of growth hormone?
How does binding to a carrier protein in the plasma affect this?
25 minutes
Binding to a carrier protein increases half-life as GH is protected from cleavage by proteases
What receptor does growth hormone bind to?
It acts via a tyrosine kinase associated receptor
This leads to protein phosphorylation
Why is growth hormone said to have “diabetogenic effects”?
It antagonises the effect of insulin to increase blood glucose concentration
How fast are the effects of growth hormone?
How are longer-term effects mediated?
Rapid effects in minutes to hours
Longer term effects on growth are mediated via insulin-like growth factor 1 (somatomedin)
How does growth hormone affect:
i. liver
ii. fat
iii. muscle
iv. insulin?
i. increased gluconeogenesis
ii. increased lipolysis
iii. decreased glucose uptake
iv. creates insulin-resistance
Why does growth hormone antagonise the effects of insulin receptors?
If muscles take up less glucose, this can be used for the RBCs and the brain
The muscles can use the fatty acids produced from lipolysis
When is somatomedin released?
What must be present?
It is released from many tissues in response to GH
It requires insulin to be present as well
What are the 2 IGFs (somatomedins)?
- IGF1 is the main active IGF that is stimulated by GH
2. IGF2 is not stimulated by GH
What is significant about IGF1 having a strong homology to insulin?
The receptors are similar and work in the same way
IGF1 will work okay on the insulin receptor and vice versa
What is the role of IGF1?
What happens if it is present in excess?
It enhances protein synthesis and growth
In excess, it can cause hypoglycaemia
Other than growth hormone, what other 3 factors affect growth?
- insulin - especially in utero
- steroids
- thyroid hormones
How do sex steroids and glucocorticoids affect growth?
Sex steroids accelerate growth but hasten maturity
(this is bc they increase rate of growth as well as fusion of the epiphyses)
Glucocorticoids slow growth
Why are thyroid hormones involved in growth?
They are essential for normal growth and response to GH
What are the 2 forms of thyroid hormones?
T3 - triiodothyronine
T4 - thyroxine
What is strange about the mechanism of action of thyroid hormones?
They are peptide hormones but have intracellular receptors
They will enter the nucleus to affect transcription
(they act like steroids)
How is T4 carried in the blood?
It is tightly bound to carrier proteins
These are thyroid binding globulin and transthyretin
How does being bound to proteins affect the activity and half-life of T4?
It has a low free concentration in the circulation
It is also very stable and the half-life is prolonged
Half life = 8 days
What is the half-life of T3?
Why is it different to T4?
1 day
T3 is less bound to protein and less stable
It is the active form that enters cells to produce effects
What will stimulate production and release of thyroid hormones?
Thyrotropin from the anterior pituitary gland
this is TSH
What are the roles of thyroid hormones?
- increase metabolic rate
- increase heat generation
- essential for normal growth and development
What is the structure of the thyroid gland like?
It is anchored to thyroid cartilage and moves on swallowing
It contains follicles which contain thyroglobulin
What are C cells?
Clear cells
They secrete calcitonin, which is involved in calcium handling
What is the role of TSH on the basolateral membrane of the thyroid follicular cell?
It increases the activity of the Na/I cotransporter (NIS)
This enhances the uptake of iodine by the follicular cell so that the ratio of follicular cell iodine:plasma iodine increases
What happens to iodide after it has entered the follicular cell?
What happens at the same time?
It is transported into the follicular lumen
The follicular cell also secretes thyroglobulin
What happens during iodination?
What stimulates this process?
TSH stimulates iodination of thyroglobulin in the follicular lumen
What happens after iodination is completed?
CONJUGATION
TSH stimulates the conjugation of iodinated tyrosines to form T4 and T3 linked to thyroglobulin
What happens after conjugation is completed?
TSH stimulates endocytosis of iodinated thyroglobulin into the follicular cells
What happens after endocytosis is completed?
PROTEOLYSIS
TSH stimulates the proteolysis of the iodinated thyroglobulin, forming T3 and T4
What happens after proteolysis is completed?
TSH stimulates secretion of T4 and T3 into the circulation
What other type of thyroid hormone is produced?
rT3 which is inactive
What is meant by TSH having a trophic effect on cells?
The thyroid gland becomes enlarged (hyperplasia) if TSH levels are high
What are the 2 enzymes that will deiodiniate T4 into T3?
Where are they found?
- Type I
found in liver, kidney and thyroid
- Type II
found in pituitary, CNS and placenta
What is the role of the Type III enzyme?
It cleaves T4 to rT3
What will inhibit Type I and Type II?
Type I is inhibited by stress and caloric restriction
Type II is constitutive (active all the time)
What happens to T3 once it has entered a cell?
It migrates to the nucleus, where it binds to the thyroid hormone receptor
This then binds to the response element of the relevant gene to activate or suppress transcription
How does T3 affect the Na+/K+ pump and the beta adrenergic receptors?
- increases activity of Na+/K+ pump
2. activates beta-adrenergic receptors which increases sympathetic stimulation
How does thyroid hormone acutely increase metabolic rate and heat production?
- increases metabolic rate via “futile cycles” that do not actually achieve anything
- mitochondrial decoupling only generates heat, and no ATP is produced
How does thyroid hormone affect activities in the liver?
Increases gluconeogenesis (glucose production)
Increases glycogenolysis (glycogen breakdown)
What is an example of a futile cycle involving fats?
Thyroid hormone causes both lipolysis and lipogenesis
Lipolysis provides free glycerol for gluconeogenesis
What is an example of a futile cycle involving proteins?
What is the overall effect of this?
Thyroid hormone increases proteolysis, but also protein synthesis
Proteolysis provides amino acids for gluconeogenesis
Net effect is muscle wasting
How does thyroid hormone affect the Na+/K+ pump?
it causes a sodium leak
this increases Na+/K+ ATPase activity which wastes energy
Why is there usually no hyperglycaemia under the action of thyroid hormones?
Insulin control is normal
Thyroid hormones enhance the insulin response as everything is just running a bit faster than normal, and more heat is generated
What organ depends on thyroid hormone for development?
What does deficiency in infancy lead to?
The brain depends on thyroid hormone for development and growth
deficiency leads to cretinism and dwarfism
What is cretinism?
A marked impairment of brain function
What does deficiency of thyroid hormone cause in later childhood?
Severe impairment of growth
Catch-up growth is possible if the thyroid hormone is replaced
What is a goitre and what is it caused by?
It is a lump in the neck
It is caused by low thyroid hormone leves, as this means more TSH is produced
This causes the thyroid gland to enlarge
What usually causes a goitre?
it is common in areas with low environmental iodine
How does autoimmunity affect the thyroid gland?
It can cause both hyperthyroidism or hypothyroidism
How can autoimmunity cause hyperthyroidism?
What condition is this?
Antibodies against the TSH receptor may activate it, driving excess TH production and cause hyperthyroidism
This is Graves disease
What are the symptoms of Graves disease?
- weight loss
- tremor
- sweating
- tachycardia
- dislike of hot weather
Why do people with Graves disease have double vision?
Graves disease is a consequence of excess tissue growth
Exophthalmos develops - eyeballs project out of the front of the face
What is pretibial myxoedema in Graves disease?
Excess hypertrophy of tissue down the front of the shins
What is the difference between pretibial myxoedema and myxoedema?
Myxoedema is thickening of the tissue, which occurs in hypothyroidism
How can autoimmunity cause hypothyroidism?
What condition is this?
Antibodies that destroy TSH receptors or other thyroid targets cause hypothyroidism
This is Hashimoto’s thyroiditis
What are the symptoms of Hashimoto’s thyroiditis?
- weight gain
- hypothermia
- tiredness
- constipation
- skin thickening and oedema
- bradycardia
- dislike of cold weather
What is secondary anovulation in Hashimoto’s thyroiditis?
Ovulation terminates - it is amenorrhea
What is the main glucocorticoid in humans?
Cortisol
What causes the hypothalamus to release CRH?
It will integrate stress factors and diurnal rhythm to release CRH
What is the action of CRH?
It induces ACTH release from the anterior pituitary gland
What is the role of ACTH?
It stimulates adrenal cortex hypertrophy and cortisol production
What is the effect of iatrogenic steroids on cortisol production?
They will feedback into the pituitary and the hypothalamus to suppress ACTH (and glucocorticoid) production
They cause adrenal atrophy
What happens if someone takes steroids for too long?
The body is not in a position to replace the steroids after they have stopped being taken
This is due to atrophy
What are the key drivers for glucocorticoid production?
Physical, emotional and biochemical stress
What is the mechanism of action of glucocorticoids?
How rapid is their effect?
They act via a nuclear receptor to induce gene transcription
They take hours/days to exert an effect
What is the main effect of glucocorticoids?
They inhibit insulin responses and enhance SNS responses
This targets glucose to the brain, whilst other tissues use fatty acids
How do glucocorticoids affect the liver?
They promote gluconeogenesis and glucose release
How do glucocorticoids affect fat and muscle?
In fat, they stimulate lipolysis
This gives glycerol for gluconeogenesis andfree fatty acids for energy
In muscle they stimulate protein breakdown to release amino acids for gluconeogenesis
What type of effect do glucocorticoids have and why?
Diabetogenic effect
They act against insulin to increase glucose availability
What are the main 2 beneficial chronic effects of glucocorticoids?
- immunosuppression
2. reduction in inflammation and cytokine production
How do glucocorticoids affect the CNS and blood cell production?
- they have complex CNS effects ranging from euphoria (smaller doses) to psychosis (increased doses)
- they stimulate haematopoiesis and GI tract mucosa
How do glucocorticoids affect the skin and fat distribution?
They cause truncal obesity - fat is distributed from peripheral to central
They cause skin thinning, muscle wasting and osteoporosis
What does excess glucocorticoids cause?
Cushing’s disease
What does adrenocortical insufficiency cause?
Addison’s disease
This leads to a high ACTH which gives a slate grey pigmentation
