Physiology - Endocrine Flashcards
How are thyroid hormones regulated
- TRH secreted by the hypothalamus and acts on the anterior pituitary to release TSH
- TSH acts on the thyroid gland by increasing expression of the NIS symporter (2 Na+ with I-)
- T3 and T4 both released into the blood, most of which is bound to proteins but some in free form
- free T3 and T4 provide negative feedback on the hypothalamus and anterior pituitary
- inhibitors of thyroid secretion: free T3/T4, stress, warmth, dopamine, somatostatin
- stimulators of thyroid secretion: TSH, cold
Thyroid hormone effects
- heart = positive chronotropic and inotropic, increased number and affinity of beta receptors
- adipose tissue = breakdown of fats
- muscle tissue = breakdown of protein
- bone = promotes normal bone growth
- nervous system = promotes normal brain development, increases reflexes, increases CNS activity
- gut = increased rate of carbohydrate absorption, raises blood glucose
- lipoprotein = lowers circulating cholesterol
- calorigenic = increases oxygen consumption of almost all metabolically active tissues
Describe the steps in the synthesis of thyroid hormones
- Iodide uptake: absorption through GIT, then uptake by thyroid follicular cells via Na-Iodide symporter (NIS) (secondary active transport),
- Transportation of iodide into colloid by pendrin (Cl-/I- exchanger)
- Iodide oxidation: via thyroid peroxidase (TPO), iodide (I-) is oxidised to iodine (I2)
- Secretion of thyroglobulin Tg into the colloid
- Iodination of Tg: Iodine is then attached to tyrosine residues on Tg, forming monoiodotyrosine (MIT) and diiodotyrosine (DIT)
- Coupling of MIT and DIT: form thyroxine (T4) and triiodothyroxine (T3)
- endocytosis from colloid into thyroid cell and then release into blood
What is the mechanism of action of T3/T4
- T3 is more active, but more of T4 is made
- thyroid hormone exerts its effects by entering cells and binding to the intracellular thyroid receptor
- hormone-receptor complex binds to DNA and alters gene expression
What factors determine plasma glucose level
- overall balance between glucose entering and leaving the bloodstream
1) dietary intake
2) cellular uptake
3) hepatic production versus storage
4) renal filtration (freely filtered but reabsorbed up to Tmax)
5) hormonal effects
Explain how blood glucose is maintained during fasting
- fasting: liver glycogen is broken down to glucose, released into bloodstream
- prolonged fasting: glycogen is depleted, increased gluconeogenesis from glycerol and amino acids in the liver
What are the physiological effects of glucagon
acts on G proteins, increases blood glucose levels
- breaks down glycogen in the liver (not muscle)
- gluconeogenesis
- breaks down triglycerides to glycerol and 3 fatty acids
- ketogenic
- positive inotropic effect on the heart
- stimulates insulin and GH secretion
What stimulates/inhibits glucagon release?
stimulators:
hypoglycaemia, amino acids, CCK, gastrin, cortisol, exercise, infection, stress, beta stimulators, ACH
inhibitors:
glucose, somatostatin, secretin, FFA, insulin, alpha stimulators, GABA, ketones
What happens to glucose homeostasis in the absence of insulin (physiological effects of insulin deficiency)?
Plasma hyperglycaemia due to:
- decreased peripheral uptake of glucose into muscle and fat
- reduced uptake of glucose by the liver
- increased glucose output by the liver and lack of glycogen synthesis
Result:
- intracellular glucose deficiency
- protein/fat catabolism
- ketosis
- secondary osmotic diuresis, dehydration
How does exercise affect glucose levels
increased entry of glucose into skeletal muscle due to increase in GLUT 4 transporters in muscle cell membranes
Describe the biosynthesis of insulin
insulin is a polypeptide made in beta cells of pancreas, formed of 2 chains of amino acids linked by disulfide bond
initially made as preproinsulin in the rER, then signal peptide is cleaved in the golgi, making proinsulin
c-peptide is then cleaved, making insulin (both insulin and c-peptide are released)
What metabolic effects does insulin have on the liver
decreased gluconeogenesis
increased glycogen synthesis
increased lipid synthesis
increased protein synthesis
What are the principle actions of insulin
based on tissue:
- skeletal muscle = increased glucose uptake, increased glycogen synthesis, increased protein synthesis
- adipose tissue = increased glucose uptake, increased lipogenesis, decreased lipolysis
- liver = decreased gluconeogenesis, increased glycogen synthesis, increased lipogenesis
based on time:
- rapid (seconds) = increased transport of glucose, amino acids and K+ into insulin sensitive cells
- intermediate (minutes) = stimulation of protein synthesis, activation of glycolytic enzymes and glycogen synthase
- delayed (hours) = lipogenesis
Describe the structure of the insulin receptor
tyrosine kinase receptor
tetramer made up of 2 alpha and 2 beta glycoprotein subunits bound by disulfide bonds
alpha is extracellular and binds insulin
beta is transmembrane
What happens when insulin binds to its receptor
- insulin binds to the extracellular alpha subunit of the insulin receptor (tyrosine kinase receptor)
- this causes autophosphorylation on tyrosine residues, causing phosphorylation on cytoplasmic proteins
- insulin receptors then aggregate in patches and are taken up by endocytosis and enter a lysosome
What happens to insulin secretion when a person is injected with 50ml of 50% dextrose?
- G uptate by beta cells via GLUT-2
- G metabolism: glycolysis into pyruvate, generating ATP
- Closure of ATP-sensitive K (KATP) channels: increase in intracellular K+
- Membrane depolarisation, opening of voltage-gated calcium channels (VGCC) -> influx of Ca2+ into beta cells
- Exocytosis of insulin into the blood via calcium-mediated vesicle docking and fusion
Name the endogenous catecholamines and where are they produced
adrenal medulla
adrenaline
noradrenaline
dopamine
(also intrinsic cardiac adrenergic cells - adrenaline, sympathetic nervous system cells - dopamine, ventral tegmental area in midbrain - dopamine)
What are the physiological effects of adrenaline and noradrenaline
act on 2 receptor types = alpha and beta
(adrenaline: beta > alpha, noradrenaline: alpha > beta)
cvs effects:
vasoconstriction and dilation, increased heart rate and strength
-alpha 1 = constriction of blood vessels
-alpha 2 = central vasodilation, peripheral vasoconstriction
-beta 1 = positive cardiac inotropy and chronotropy
-beta 2 = dilation of skeletal muscle and liver blood vessels
metabolic effects:
increased metabolic rate, mobilises free fatty acids, glycogenolysis
-alpha receptors = decreased insulin secretion
-beta receptors = increased insulin secretion
