Metabolism S11 - Calcium Metabolism and Adaptations of Metabolism Flashcards Preview

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Flashcards in Metabolism S11 - Calcium Metabolism and Adaptations of Metabolism Deck (60):
1

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

2

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

3

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

4

Why does plasma phosphate concentration fluctuate throughout the day?

Not strictly regulated

5

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

6

What hormones are responsible for raising serum calcium levels?

Parathyroid hormone (PTH)
Calcitriol (Derived from Vit. D)

7

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

8

What hormone is responsible for lowering serum calcium levels?

What is the suggested reason behind this?

Cacitonin

To preserve the maternal skeleton during pregnancy ( i.e. lower serum calcium = lower osteoclast activity)

9

What are the two major types of vitamin D?

How are they acquired by the body and what is their action on the body?

Vitamin D2
Absorbed in gut

Vitamin D3
Produced in skin when exposed to UV light

No action on the body, they are prohormones

10

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

11

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

12

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

99% reabsorbed

PCT - 66%
Loop of Henle - 24%
DCT/Collecting Duct - 10%

13

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

14

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

15

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

Primary hyperparathyroidism

Fluid administration to replace fluid lost in urine

Removal of (normally benign) tumour in the parathyroid gland

16

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)

Paralysis

Convulsions

This is due to low amount of Ca2+ bound to NMJ membrane, allowing Na+ to depolarise it much more easily

17

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

18

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

19

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

20

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

21

What is the renal throughput of calcium per day?

Why is amount of calcium excreted significant?

Kidneys filter about 10g per day

98% reabsorbed

Urinary excretion should match intestinal absorption of calcium, so about 175mg of calcium eliminated per day

22

How much calcium is deposited and reabsorbed from the bones per day?

280mg deposited

280mg reabsorbed

Steady state

23

What is the typical weight gain in pregnancy?

What are the constituents of this extra weight?

8Kg

Foetus, placenta, amniotic fluid - 5Kg

Maternal nutrient stores - 3Kg

24

What is rate of transfer of nutrients to the foetus dependant on?

Dependant on the mother:foetal concentration gradient

25

How is the environment in which the foetus develops controlled?

By maternal metabolism

26

What are the reasons behind maternal metabolism changes?

Ensures that:

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

27

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

28

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

29

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

30

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

31

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

32

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

33

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

34

What are ketone bodies produced in the maternal liver used for?

Fuel the developing foetal brain

35

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

36

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

37

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

38

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

39

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

40

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.

41

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

42

How is ATP regenerated from ADP initially in muscle?

From creatine phosphate

Creatine~P + ADP ---> Creatine + ATP

43

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)

44

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

45

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.

46

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

47

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)

48

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

49

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

50

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)

51

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

52

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)

53

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

54

How is ATP generated during medium duration/intensity exercise?

60% aerobically
40% anaerobically

55

Does H+ present a major problem to muscle engaged in medium duration/intensity exercise?

Explain

No

H+ can be buffered, preventing rapid muscle fatigue

56

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

Finishing burst:
Relies on anaerobic metabolism of glycogen and produces lactate

57

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

58

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:
Noradrenaline

59

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.

60

Explain the benefits of exercise

Body composition change:
Increased muscle, decreased adipose

Glucose tolerance improves:
Increased muscle glycogenesis and increased glucose transport protein expression in cell membranes

Insulin sensitivity of tissues increases:
Increased skeletal vascularisation?

Blood TAG levels decrease:
Decresed VLDL, LDL, increased HDL

Blood pressure falls:
Vascularisation?

Psychological effects:
Feeling of 'well-being'