Flashcards in Metabolism S11 - Calcium Metabolism and Adaptations of Metabolism Deck (60):
What are the major functions of calcium in the body?
Required for nerve transmission at NMJ
Helps maintain normal nerve and muscle function
Major constituent of bone
Assists in normal blood clotting
Important to normal kidney function
Lowers blood pressure
Regulates heart rhythm
Needed for some enzymes and hormone receptor binding
Helps regulate the passage of nutrients in and out of cells
In what forms does calcium appear in plasma?
What are the relative proportions of calcium in each form?
What is the total blood concentration of calcium?
What is the free Ca2+ concentration in plasma?
As a free ionised species (45%)
Bound or associated with anionic sites on serum proteins (especially albumin) (45%)
Complexed with low molecular weight organic anions (especially citrate or oxaloate) (10%)
Total concentration on blood is normally 2.2 - 2.7mM/L
Free plasma concentration of calcium ions between 1.0 - 1.3mM/L
What is the key role of Phosphate in the body?
Part of the ATP molecule therefore plays a critical role in cellular energy metabolism and the in/activation of enzymes
Why does plasma phosphate concentration fluctuate throughout the day?
Not strictly regulated
How are calcium and phosphate homeostasis linked?
What organs are involved in calcium and phosphate homeostasis?
Calcium and phosphate are both major components in hydroxyapatite crystals which constitute a major portion of the mineral in bone
They're regulated by the same hormones, primarily parathyroid hormone and calcitriol, to a lesser extent calcitonin.
These hormones act on the bone, kidney and GI tract to control plasma concentration of the two ions.
Hormones actions on each ion are opposed, what raises calcium concentration will lower phosphate concentration
What hormones are responsible for raising serum calcium levels?
Parathyroid hormone (PTH)
Calcitriol (Derived from Vit. D)
Describe the regulation of serum PTH levels
Make sure to fully describe the mechanism of action
Calcium inhibits parathyroid hormone (PTH) release via negative feedback
Parathyroid chief cells have unique G-protein calcium receptors on the cell surface
When increased Ca2+ binds to these receptors:
- It stimulates Phospholipase C (PLC)
- This inhibits adenylate cyclase
- Which leads to reduced Cyclic AMP and reduced PTH release
Reverse occurs when Ca2+ is low
What hormone is responsible for lowering serum calcium levels?
What is the suggested reason behind this?
To preserve the maternal skeleton during pregnancy ( i.e. lower serum calcium = lower osteoclast activity)
What are the two major types of vitamin D?
How are they acquired by the body and what is their action on the body?
Absorbed in gut
Produced in skin when exposed to UV light
No action on the body, they are prohormones
Where/how is calcitriol produced and what from?
What regulates its production?
What is its action on the body?
Produced in the kidney
Produced via hydroxylation of calciferol
Production regulated by PTH
Promotes Ca2+ absorption via binding to Ca2+ in the gut
Also stimulates Pi absorption from the gut
Stimulates reabsorption of Ca2+ from the kidney
Activates osteoclasts, hence increasing serum calcium levels
Where is Parathyroid hormone produced and what are its actions on the body?
Produced by chief cells in the parathyroid gland
Stimulates Conversion of calciferol to calcitriol
Stimulates Ca2+/Pi release from bone/osteoclast activity
Stimulates Ca2+ reabsorption in the kidney
Inhibits Pi reabsorption from the kidney
How does PTH affect kidney function?
What proportion of Ca2+ is reabsorbed in the kidney tubules?
What percentage of reabsorbed Ca2+ is reabsorbed in each major section of the kidney tubule?
Increases Ca2+ absorption from the Distal convoluted tubule
Inhibits Pi reabsorption
PCT - 66%
Loop of Henle - 24%
DCT/Collecting Duct - 10%
How is inorganic phosphate (Pi) removed from circulation?
Why is this necessary?
Inhibition of its reabsorption from the kidney proximal convoluted tubule
Prevents calcium phosphate stone formation
Where/how is calciferol produced and what from?
What is its action on the body?
Produced in the liver
Produced via hydroxylation of Vitamin D
No action on the body, it is a prohormone
What are the symptoms of Hypercalcaemia?
What is the most common cause?
How is it treated?
Moans, Groans, Stones.
May result in the formation of kidney stones (renal calculi), constipation, dehydration, kidney damage, tiredness and depression
Fluid administration to replace fluid lost in urine
Removal of (normally benign) tumour in the parathyroid gland
Describe the effects of Hypocalcaemia on the body
What is the cause of these effects?
Results in hyper-excitability in the nervous system, including the neuromuscular junction resulting in:
Paresthesia (tingling sensations)
Tetany (involuntary muscle contraction)
This is due to low amount of Ca2+ bound to NMJ membrane, allowing Na+ to depolarise it much more easily
What is parathyroid hormone related peptide (PTHrP)?
What is it secreted by?
PTHrP is a polypeptide hormone
Secreted by tumours, commonly in patients with breast/prostate cancers and occasionally with myeloma
What is the effect of Parathyroid hormone related peptide on the body?
Effects similar to PTH
Stimulates calcium release from bone
Stimulates calcium resorption from the kidney
Inhibits Phosphate reabsorption from the kidney
This leads to humeral hypercalcaemia of malignancy
However PTHrP does not stimulate calcitriol production
What are the pools of calcium present in the body and how much calcium is present in each?
Most calcium located in Bone, about 1Kg
Extracellular calcium pool is ~1g
Where in our diet does calcium come from and what is the ideal daily intake?
How does calcium absorption/excretion in the gut affect calcium levels?
800-1200mg calcium in diet per day, mainly from dairy
Intestines absorb approx. 500mg per day
Intestines remove ~325mg of calcium from the body per day
Net uptake of ~175mg per day
What is the renal throughput of calcium per day?
Why is amount of calcium excreted significant?
Kidneys filter about 10g per day
Urinary excretion should match intestinal absorption of calcium, so about 175mg of calcium eliminated per day
How much calcium is deposited and reabsorbed from the bones per day?
What is the typical weight gain in pregnancy?
What are the constituents of this extra weight?
Foetus, placenta, amniotic fluid - 5Kg
Maternal nutrient stores - 3Kg
What is rate of transfer of nutrients to the foetus dependant on?
Dependant on the mother:foetal concentration gradient
How is the environment in which the foetus develops controlled?
By maternal metabolism
What are the reasons behind maternal metabolism changes?
Foetus is supplied with a range of nutrients
Nutrients supplied at appropriate rate
This is achieved with minimal disturbance to maternal nutrient homeostasis
The foetus is buffered from major disturbances in maternal nutrient supply
What aspects of maternal nutrient metabolism are affected by pregnancy and how are these changes controlled?
Metabolism of all major nutrients is affected
Changes are long term adaptive responses that are hormonally controlled
How is maternal insulin level change during pregnancy and why?
Concentration in circulation increases
Promotes uptake and storage of nutrients, largely as fat in maternal adipose tissue
How do foetal-placental hormones affect maternal metabolism and why?
Largely oppose the action of insulin (anti-insulin)
This is to maintain the glucose concentration gradient to ensure it's in constant supply
What is the reason for maternal metabolic changes in the first half of pregnancy? (First 20 weeks)
Mostly related to preparatory increase in maternal nutrient stores (especially adipose tissue) in preparation for more rapid foetal growth, birth and lactation
What changes are made to maternal metabolism in the 2nd half of pregnancy and why?
Keeping circulation levels of nutrients in maternal plasma high
Reduce maternal utilisation of glucose by switching to using fatty acids
Delayed maternal disposal of nutrients after meals
Releasing fatty acids built up in the first half of pregnancy
This is required due to the increased demand for nutrients from the foetal-placental unit due to increased growth rate
How are the changes in maternal metabolism during the second half of pregnancy controlled?
Maternal insulin levels continue to increase
However foetal-placental anti-insulin production increases at an even faster rate
This leads to a fall in the insulin/anti-insulin ratio producing the required metabolic changes
Describe how maternal ketogenesis comes about
Mobilisation of maternal adipose to increase availability of fatty acids coupled with the fall in insulin/anti-insulin ratio leads to ketogenesis being switched on
What are ketone bodies produced in the maternal liver used for?
Fuel the developing foetal brain
How is the extra demand for insulin in the maternal body met?
Hyperplasia and hypertrophy of the beta cells
Increased rate of insulin synthesis by the beta cells
What is the result of maternal metabolic demand overwhelming the endocrine pancreas?
Pancreas fails to produce the required level of insulin
As a result there is loss of control of metabolism, blood glucose increases and gestational diabetes results
In a woman suffering gestational diabetes, what occurs after birth?
Increased metabolic demands are removed and hormone levels change
Endocrine pancreas can once again respond to insulin need adequately and diabetes disappears
However women who experience gestational diabetes are more likely to develop diabetes later in life
Why are metabolic changes necessary when exercising?
Metabolic response ensures that:
Increased energy demands of skeletal and cardiac muscle are met by mobilisation of energy stores
There are minimal disturbances to homeostasis by keeping rate of mobilisation and utilisation equal
Glucose supply to the brain is maintained
End products of metabolism are removed as quickly as possible
What does the extent of metabolic response to exercise depend on?
Type of exercise
Intensity and duration of exercise
Physical condition and nutritional status of the individual
What is the major difference between high and low intensity exercise in terms of O2 supply?
O2 supply is inadequate for aerobic metabolism during high intensity exercise so muscle works in anaerobic conditions
O2 supply is adequate to maintain aerobic metabolism in muscles in low intensity exercise.
How is energy for muscle contraction supplied?
Give an equation showing the release of energy
How is the source of energy maintained?
Supplied by hydrolysis of ATP
ATP + H2O ---> ADP + Pi + Energy
ATP concentration doesn't fall by more than 20% as it is regenerated from ADP
How is ATP regenerated from ADP initially in muscle?
From creatine phosphate
Creatine~P + ADP ---> Creatine + ATP
After creatine phosphate stores are depleted by muscle, how is ATP regenerated by muscle?
ADP is coupled to the oxidation of fuel molecules (substrate level phosphorylation)
How long do glycogen stores last during aerobic and anaerobic exercise and what does this difference reflect?
Under low intensity aerobic conditions, can provide muscles with energy for ~60mins
Under high intensity anaerobic conditions can supply muscle with energy for ~2mins
This difference reflects the Different amounts of ATP produced in aerobic vs anaerobic conditions
Aerobic = 32 moles of ATP for every mole of glucose as glycogen
Anaerobic = 3 moles of ATP for every mole of glucose as glycogen
Why is using muscle glycogen advantageous during exercise and why is liver glycogen not used?
Using muscle glycogen advantageous because:
Availability not affected by blood supply
No need for membrane transport of glycogen into muscle cells
Produces G-6-P without using ATP
Mobilisation can be extremely rapid
- Highly branched glycogen structure allows for many sites of enzyme attack
- Glycogen phosphorylase activity can be changed rapidly by a mixture of covalent modification (phosphorylation ) and allosteric activation (ADP and Ca2+)
Liver glycogen not used because this store is used to prevent hypoglycaemia and associated CNS impairment.
How is continuous anaerobic metabolism in muscles limited?
Build up of Lactate and H+
Accumulation of H+ is dramatic (2mol of H+/mole of glucose)
This exceeds the buffering capacity of the muscle cells and impairs their function producing fatigue
What are the mechanisms of H+ impairment of muscle cells?
Inhibition of glycolysis by H+
H+ interferes with the actin-myosin interaction
H+ causes sarcoplasmic reticulum to bind calcium (inhibiting contraction)
How are triacylglycerol stores utilised during exercise?
Provide muscles with fatty acids
Oxidation of which could supply muscle for ~48 hours of low intensity exercise
What factors might limit the muscle's utilisation of fatty acids during exercise?
Rate of fatty acid release from adipose (rate of lipolysis)
Limited blood transport capacity for fatty acids (requires albumin)
Rate of FA uptake into cells and mitochondria
FA oxidation requires more O2 per mole of ATP produced than glucose
FAs can only be oxidised in aerobic conditions
Where does the metabolic response to short duration, high intensity exercise occur and how is it controlled?
Metabolic response limited to the muscles (no other metabolic changes outside the muscles)
Controlled by the nervous system (noradrenaline) and the endocrine system (adrenaline)
Describe the metabolic response to short duration, high intensity exercise in the first 5 seconds of exercise
Muscle ATP and Creatine phosphate used initially
Muscle glycogen is rapidly metabolised to G-6-P
How is G-6-P produced during short duration, high intensity exercise used to provide energy for the muscle?
What is produced?
G-6-P metabolised via substrate level phosphorylation to produce ATP from ADP
Glycolysis carried out anaerobically due to inadequate oxygen supply
Dramatic increase in rate of anaerobic glycolysis (1000x increase) produces lactate and H+ (max rate ~20mM of H+ per second)
How does rapid increase in rate of H+ production in muscle engaged in short duration, high intensity exercise affects muscle function
Build up of H+ produces fatigue
How is ATP generated during medium duration/intensity exercise?
Does H+ present a major problem to muscle engaged in medium duration/intensity exercise?
H+ can be buffered, preventing rapid muscle fatigue
Describe the 3 phases of metabolic response to medium duration/intensity exercise
Initial sprint phase:
Uses ATP, Creatine phosphate and anaerobic glycogen metabolism
Long middle phase:
ATP is produced aerobically from muscle glycogen, this relies on adequate O2 supply
Relies on anaerobic metabolism of glycogen and produces lactate
What are the major features of the metabolic response to long duration, low intensity exercise?
Carbohydrate stores are insufficient to complete the exercise
The muscle works aerobically
Muscle cells can use all type of fuel molecules
Origin and type of fuel changes as exercise progresses
Metabolic changes are more gradual and involve several tissues
Describe the control of metabolic changes during long duration, low intensity exercise
Control of these changes is largely hormonal:
Insulin, adrenaline growth hormone, glucagon and cortisol
With some input from the nervous system:
Describe the utilisation of different fuel types during long duration, low intensity exercise
Initially muscle glycogen is used, this would last ~60 minutes if it was the sole energy source.
Increased utilisation of circulation glucose by the muscles. This requires the promotion of gluconeogenesis (25%) and liver glycogen release (75%) to keep blood glucose concentration constant.
There are limited substrates for gluconeogenesis and eventually blood glucose will fall.
Due to aerobic conditions, fatty acids are also utilised by muscle cells, this utilisation increases with time.