Session 14 ILOs - Calcium metabolism and special circumstances for metabolic and endocrine control Flashcards
Explain the significance of maintaining serum calcium levels within set limits
Calcium plays a critical role in many cellular processes in the body: (7)
- Muscle contraction
- Hormone secretion
- Nerve conduction
- Exocytosis
- Blood clotting
- Activation and inactivation of many enzymes
- Ca2+ also serves as an intracellular second messenger
Therefore serum calcium is kept within a narrow range
There is significant consequences to serum calcium being outside the range:
Hypocalcaemia - hyper excitability in the nervous system leading to tetany, paralysis or convulsions
Hypercalcaemia - formation of renal calculi, constipation, dehydration, kidney damage, tiredness or depression (6)
Explain the benefits of exercise (6)
- Reduced adipose, increased muscle
- Improved glucose tolerance
- Improved insulin sensitivity
- Reduced blood triacylglycerol
- Reduced blood pressure
- Psychological effect
Explain the regulation of parathyroid hormone
Regulation of parathyroid hormone: (5)
- PTH is continually synthesised but there is little stored
- Chief cells degrade hormone as well as synthesis it
- Synthesis is regulated both at transcriptional and post transcriptional levels:
- Low serum calcium up-regulates gene transcription (prolongs survival of mRNA)
- High serum calcium down-regulates gene transcription
Explain the significance of renal function on calcium metabolism
- Kidneys are the site of activation of vitamin D (from 25(OH)D)
Kidney failure:
- 3 main effects:
1. Kidney failure results in decreased production of active Vitamin D, therefore there is increased calcium resaborption and more calcium is lost in the gut and therefore serum calcium can decrease
2. Levels of phosphate in the blood rise, because the kidneys are not excreting excess phosphate into the urine
3. PTH may be produced in large quantities, stimulated by low levels of calcium in the blood, which can cause bone reabsorption. Eventually the parathyroid glands work so hard that they cause persistently high calcium levels
Describe disorders of calcium metabolism and metabolic bone disease
Osteomalacia (adults):
- Normal structure but under mineralised bone
- Caused by a lack of Vitamin D in adulthood only
Rickets (osteomalacia in children):
- Normal structure but under mineralised bone
- Caused by a lack of Vitamin D in childhood
Osteoporosis:
- Normal mineralisation but structure is degraded (channels)
- Usually caused by changes to function of osteoblasts and osteoclasts, as a result of hormone changes
Describe the major metabolic fuels and their sources in the normal individual
2 main sources - normally:
- Glucose - the preferred fuel source
- Only small amount of free glucose available, more glucose stored as glycogen - Fatty acids - can be used by most cells except RBCs, brain and CNS
- A large store of fatty acids in the form of triacylglycerol in adipose
3 main sources - in special conditions:
- Amino acids - from broken down muscle protein, can be converted to glucose or ketone bodies (2 week supply)
- Ketone bodies - mainly from fatty acids, can be used by the brain instead of glucose
- Lactate - product of anaerobic metabolism in muscle, liver can convert back to glucose in the Cori cycle
Describe the metabolic responses to feeding and fasting and explain how they are controlled
Feeding and fasting affect the fuel source used, in order to provide the body with a continuous supply of glucose for the RBCs and brain/CNS
Timeline:
<2 hours - uses available glucose and fats from gut
2-10 hours - no longer absorption of glucose and fats, uses glycogen stones and may use fatty acid stores
8-10 hours - needs to undertake gluconeogensis and use of fatty acid stores
Effects of feeding:
- The absorption of glucose, amino acids and lipids increases their blood concentration
Stimulates pancreas to release insulin:
- Increases glucose uptake and utilisation by muscle and adipose tissue
- Promotes storage of glucose as glycogen in liver and muscle
- Promotes amino acid uptake and protein synthesis in liver and muscle
- Promotes lipogenesis and storage of fatty acids in adipose tissue
Effects of fasting:
- As the blood glucose concentration falls insulin secretion is depressed
- Reduces the uptake of glucose by adipose tissue and muscle
Falling blood glucose concentration also stimulates glucagon secretion i.e. decreased insulin/anti-insulin ratio:
- Glycogenolysis in the liver to maintain blood glucose for the brain and other glucose dependent tissues.
- Lipolysis in adipose tissue to provide fatty acids for use by tissues.
- Gluconeogenesis to maintain supplies of glucose for the brain
If fasting exceeds 10hr, starvation begins
- Fatty acid metabolism produces ketone bodies (glucose sparing, brain is able to use ketone bodies)
Describe the metabolic responses to starvation and explain how they are controlled
Prolonged starvation:
- Reduced blood glucose causes cortisol and glucagon release
- These hormones cause gluconeogenesis, plus breakdown of protein and fat
- Cortisol prevents most cells from using glucose and they use fatty acids instead
- Glycerol can be used for gluconeogenesis (stops proteins from having to be broken down)
- Liver produces ketone bodies for the brain
- Kidneys can contribute to gluconeogenesis
- If fat stores become depleted, then proteins can be used for fuel
= death usually results from loss of muscle mass (lung muscle, leading to infections)
Beware of referring syndrome!!
Describe the metabolic and hormonal response to pregnancy
Pregnancy is split into 2 metabolic phases:
Phase 1 - anabolic phase
- Preparatory phase
- Increases in maternal fat stores
- Small increase in level of insulin sensitivity (insulin has more of an effect to increase storage)
- Nutrients are stored to meet the future demands of rapid fatal growth
Phase 2 - metabolic phase
- Decreased insulin sensitivity (insulin has less of an effect to prevent storage)
- Increased insulin resistance results increased maternal glucose and free fatty acids (more substrates available for foetal growth)
Most substances transfers by simple diffusion across the placenta - glucose is the principal fuel for the foetus and is facilitated by GLUT1
The foetus secretes a wide range of proteins that control the maternal hypothalamic pituitary axis
Explain the hormonal basis of gestational diabetes
Increased appetite in pregnancy results in increased glucose ingestion, if the beta cells do not respond with insulin secretion, then gestational diabetes can occur
- Oestrogen and progesterone increase the sensitivity of the maternal beta cells to glucose
- You then get more beta cells and bigger beta cells
- This results in increased insulin secretion to lower blood glucose
= IF beta cells do not respond normally, then gestational diabetes can occur
3 known underlying causes:
- Autoantibodies, similar to T1DM
- Genertic susceptibility
- B cell dysfunction in setting of obesity and chronic insulin resistance (i.e pre-diabetes waiting to happen!) - a starting point in terms of insulin resistance before pregnancy is crucial
Describe the metabolic and hormonal responses to various types of exercise
Metabolic response needs to adapt in order to ensure:
- Increased energy requirements are met
- Minimal disruption to metabolic homeostasis
- Glucose supply to the brain is maintained
- Waste produces are removed promptly
Response depends on the type of exercise (muscles used), duration and intensity and the physical condition of the individual
Initial burst - muscle creatine phosphate (~ 5 seconds)
Additional intensive exercise (anaerobic) - muscle glycogen breakdown (~2 minutes, up to 60 mins if aerobic)
Longer additional exercise (MUST be aerobic) - fatty acid breakdown but is slow release and can only be used in aerobic conditions (~48 hours of low intensity)
Hormonal changes:
- Insulin levels fall slowly (inhibited by adrenaline)
- Glucagon levels rise (energy release)
- Adrenaline and growth hormone rise (energy release)
- Cortisol rises slowly (energy release)
Explain the regulation of vitamin D ??????
Regulation of Vitamin D:
- Vitamin D3 (cholecalciferol) is made from the reaction between cholesterol in the skin and sunlight. It can be taken as a supplement also
- In the liver, cholecalciferol is hydroxylated to form calciferol
- In the kidney, calcitriol is produced from
- Production of active vitamin D in completed in 3 steps, through the skin, the liver then the kidneys
25-hydroxylation (liver) : 25-hydroxycholecalciferol
1-hydroxylation (kidney) : 1, 25-hydroxycholecaliferol
- Elevated serum calcium prevents C-1 hydroxylation
- Elevated PTH stimulates C-1 hydroxylation to form calcitriol
Describe the hormonal regulation of serum calcium
3 main hormones:
1) Parathyroid hormone
2) Calcitriol/Active Vitamin D
3) Calcitonin
Increase serum calcium:
- Parathyroid hormone (PTH) = short term
- Works quickly, within 1-2 hours
- Increases bone resorption and release of Ca2+ into circulation
- Increases Ca2+ reabsorption in kidney (decreases loss of calcium to urine) and excretion of phosphate
- Stimulates hydroxylation of 25-hydroxyvitamin D3 to make active Vitamin D (calcitriol) - Calcitriol (also called 1,25(OH)2D) = long term
- Increases intestinal absorption of dietary Ca2+ and renal reabsorption of Ca2+
- Increases bone resorption
Decrease serum calcium:
- Calcitonin
- Calcitonin counteracts the effects of PTH
- Increase bone building
- Reduces calcitriol absorption
- Increases loss in the urine
