MEH Session 11 Flashcards
Which fuel molecules are normally available in the blood?
Glucose
Fatty acids
Which fuel molecules are only available under special conditions?
Amino acids
Ketone bodies
Lactate
What is the difference between muscle and liver glycogen use?
Muscle glycogen - used to release glucose in muscle during exercise
Liver glycogen - used to release glucose into the bloodstream when blood glucose concentration is low
What determines the availability of fuel molecules in the blood?
Hormones
Changing activity of enzymes in metabolic pathways:
- intracellular signals
- metabolites
- signals from hormone action
Why is using amino acids as a fuel not ideal?
Amino acid metabolism can form ammonia.
Ammonia is toxic
How much glucose do we have in our bodies and for how long would this last?
3-6mmol/L g plasma glucose = 12g
Supports CNS for approximately 2 hours
Which cells can use fatty acids as their fuel?
Most cells except those with an absolute requirement for glucose
Which intermediate in the keys cycle can be used for fatty acid synthesis?
Citrate
Which intermediates of the krebs cycle can be used for amino acid synthesis?
Alpha-ketoglutarate
Succinate
Fumarole
Oxaloacetate
Which intermediate of the krebs cycle can be used in both the synthesis of haem and amino acids?
Succinate
Which intermediate of th e krebs cycle can be used for glucose synthesis?
Oxaloacetate
What are the symptoms of hypoglycaemia?
CNS function impaired Confusion Slurred speech Staggering Loss of consciousness Death
What happens to insulin concentration after you eat?
Increases in concentration
What are the effects of increased insulin concentration after feeding?
- 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 as triacylglycerols in adipose tissue
How does hormone concentration change when you are fasting?
As blood glucose concentration falls, insulin secretion is depressed. The falling of blood glucose concentration stimulates glucagon secretion (insulin/anti-insulin hormone ratio decreases)
What are the effects of increased glucagon when fasting?
-glycogenolysis in the liver to maintain blood glucose for the brain and other glucose dependent tissues
(Activates glycogen phosphorylase)
- lipolysis in adipose tissue to provide fatty acids for use by tissues (hormone sensitive lipase)
- gluconeogenesis to maintain supplies of glucose for the brain (PEPCK and fructose, 1,6 bisphosphatase)
When do changes associated with starvation begin?
10 hours
After feeding, for how long is glucose and fat available from the gut?
2 hours
After how long is glucose and fats no longer being absorbed?
2-10 hours after feeding
How does metabolism change 2-10 hours after feeding?
Maintain blood glucose by drawing on glycogen stores
Support other metabolic activity with fatty acids released from stores
Preserve blood glucose for the brain
How long after feeding are glycogen stores depleted?
8-10 hours
How does metabolism change 8-10 hours after feeding?
- need to make more glucose for brain from amino acids, glycerol and lactate
- continue to support other metabolism with fatty acids
What are the metabolic changes that occur after 10 hours after feeding?
Gluconeogenesis - breakdown of protein and fat
Glycerol from fat provides important substrate for reducing the need for breakdown of proteins
Ketone bodies - liver starts to produce ketone bodies and brain utilises these sparing glucose requirement
Kidneys begin to contribute to gluconeogenesis
Which hormones are released in response to starvation?
Cortisol from adrenal cortex
Glucagon from pancreas
What does the metabolic response to exercise ensure?
Increased energy demands met by mobilisation of energy stores
Minimal disturbances to metabolic homeostasis by keeping rate of mobilisation equal to equal to rate of utilisation
Glucose supply to brain is maintained
End products of metabolism are removed as quickly as possible
What does the magnitude and nature of the response to exercise depend on?
Type of exercise
Intensity and duration of exercise
Physical condition and nutritional state of individual
How long can creatine phosphate give you energy for during a 100m sprint?
Approximately 5 seconds
If you continue intensive exercise for up to 2 minutes, how can it be sustained?
Breakdown of muscle glycogen
What is the cori cycle?
Liver recycles lactate produced by anaerobic metabolism
Does anaerobic respiration usually occur with an hour of low intensity exercise?
No
How is glucose uptake adapted in exercising muscle?
Usually muscle takes up blood glucose via GLUT4 transporter (insulin promotes translocation to plasma membrane) and GLUT1 (constitutively active)
Exercising muscle also has insulin independent process of glucose uptake (increase in AMP stimulates AMPK resulting in a signalling cascade which increases GLUT4 translocation)
How long could fatty acids theoretically provide energy for in low intensity exercise?
48 hours
Can fatty acids be used as a fuel in anaerobic conditions?
No
What are the limitations of using fatty acid as a fuel?
Can only be used in aerobic conditions
Slow release from adipose tissue
Limiting carrying capacity in blood
Capacity limited by uptake across mitochondrial membrane (carnitine shuttle)
Low rate of ATP production (but high capacity for sustained production)
Which fuel stores are used in a 100m sprint?
Creatine phosphate
Glucose
Muscle glycogen
Describe the metabolic processes that occur during a 100m sprint.
Anaerobic respiration - lactate production and build up in H+
Which fuel stores are used in a 1500m race?
Initial start - creatine phosphate, anaerobic muscle glycogen
Long middle phase - aerobic muscle glycogen
Final finishing sprint - anaerobic muscle glycogen
Which fuel molecules are used when running a marathon?
Muscle glycogen - depleted within a few minutes
Liver glycogen - glucose from liver glycogen peaks at 1 hour and then declines steadily
Fatty acids - rises steadily from 20-30 minutes
Describe the hormonal response to running a marathon.
Insulin falls slowly (inhibition of secretion by adrenaline)
Glucagon rises
Adrenaline and growth hormone rise rapidly
Cortisol rises slowly
What are the effects of increases glucagon when running a marathon?
-glycogenolysis in the liver to maintain blood glucose for the brain and other glucose dependent tissues
(Activates glycogen phosphorylase)
- lipolysis in adipose tissue to provide fatty acids for use by tissues (hormone sensitive lipase)
- gluconeogenesis to maintain supplies of glucose for the brain (PEPCK and fructose, 1,6 bisphosphatase)
What are the effects of increases adrenaline and growth hormone when running a marathon?
- adrenaline stimulates glycogenolysis and lipolysis
- growth hormone mobilises fatty acids (lipolysis)
What are the effects of increased cortisol when running a marathon?
Gluconeogenesis
Lipolysis
What are the benefits of exercise?
- body composition changes (decreased adipose and increased muscle)
- glucose tolerance improves (increased muscle glycogenesis)
- insulin sensitivity of tissues increases
- blood triglycerides decrease (decreases VLDL LDL, increases HDL)
- blood pressure falls
Give five cellular functions of calcium.
Neuromuscular excitability Coagulation - it is factor IV Synaptic transmission Second messenger for hormones and growth factors Regulation of gene transcription Bone formation
What is EDTA and what is it used for?
Calcium chelator - used to prevent blood from clotting when taking blood samples for a full blood count
Why do you have to give intravenous calcium to patients who have received >5 units of blood?
Citrate is a calcium chelation which is put into bags of blood obtained from donors to prevent the blood from clotting.
Therefore, the recipient will be hypocalcaemic if they are transfused with large quantities of blood.
What is normal plasma calcium concentration?
2.2-2.6mmol/L
What is normal biologically active free ionised plasma concentration of Ca2+?
1.0-1.3mmol/L
Give 5 cellular roles of phospate.
- part of ATP (energy carrier)
- activation and deactivation of enzymes
- part of membrane phospholipids
- part of DNA/RNA
- bone formation
Is plasma phosphate concentration well regulated?
No - levels fluctuate throughout the day, particularly after meals
Why are calcium homeostasis and phosphate homeostasis intimately linked?
Calcium and phosphate are the principal components of hydroxyapatite crystals which constitute the major mineral component of bone
They are regulated by the same hormones: PTH, calcitriol, calcitonin
How is the control of plasma Ca2+ different from the control of plasma Na+ and K+?
- the extent of Ca2+ absorption from the GI tract is hormonally controlled and depends on Ca2+ status of the body (K+ and Na+ homeostasis is primarily maintained by regulating urinary excretion)
- bone serves as a large Ca2+ store that can be drawn upon to maintain free plasma Ca2+ levels (similar stores not available for Na+ and K+)
Which three hormones are involved in the regulation of serum calcium and phosphate?
Parathyroid hormone (PTH)
Calcitriol
Calcitonin
Which target organs do the hormones that are involved in calcium regulation act on?
Bone
Kidneys
GI tract
Do the hormones that are involved in calcium regulation have the same effect on calcium and phosphate?
No - actions are typically opposed in that a particular hormone may elevate the level of one ion while lowering the other
Where is most calcium located in the body?
Bone - 1kg
Remodelling of the bone requires the coordinated activity of which cells?
Osteoclasts - demineralise bone (release acids that dissolve calcium phosphate and enzymes that break down organic matrix)
Osteoblasts - lay down new bone (osteocytes = retired osteoblasts imprisoned in bone they have laid down around themselves)
Is the structural function or the metabolic function of the skeleton more important?
Metabolic function
Serum calcium concentration is more important than structural support so calcium from hydroxyapatite crystals in bone is released to buffer plasma levels at the cost of structural stability
What is the total amount of calcium in the extracellular pool?
1g
What is the typical dietary intake of calcium per day?
800-1200mg
What is the net intestinal uptake of calcium per day?
Intestines absorb approximately half of the dietary calcium = 500mg/day
Intestines excrete 325mg/day
Net intestinal uptake = 175mg/day
How much calcium is reabsorbed form the kidney tubules into the blood?
98%
How much calcium is excreted by the kidneys into the urine per day?
175mg/day
In a person, renal excretion is the same as net absorption by the GI tract
How does calcium exist in plasma?
- free ionised species
- associated with anionic sites on serum proteins (especially albumin)
- complexed with low molecular weight organic anions (citrate and oxalate)
Which form of plasma calcium is the most important with regard to regulating the secretion of PTH and is involved in most of the biological actions of calcium?
Free ionised species
In laboratory tests, the concentration of which forms of plasma calcium are measured?
Although it is the free ionised calcium in plasma that is physiologically active, common lab tests measure total calcium which includes that which is bound to albumin and other proteins.
Levels are corrected depending on the level of albumin to determine if free calcium is in the correct range or not.
Which hormones involved in calcium regulation increase plasma calcium concentrations?
Parathyroid hormone (PTH)
Calcitriol
What is the main difference between the actions of PTH and calcitriol?
Short term regulation -PTH
Long term regulation -calcitriol
Where is parathyroid synthesised?
Chief cells of parathyroid gland
What cells are found in the parathyroid gland?
Chief cells - synthesise and release PTH
Oxyphil cells - don’t know what these do
How is parathyroid hormone synthesised and released?
Straight chain polypeptide hormone
Pre-pro hormone (115AA long), cleaved to 84AA
No serum binding protein
What regulates the synthesis and release of PTH?
Synthesis is regulated at both transcriptional and post-translational levels. There is a calcium receptor located on the cell surface membrane of chief cells.
Low serum calcium
- gene transcription up-regulated
- prolonged survival of mRNA
- more PTH released
High serum calcium
- gene transcription down-regulated
- cleavage of PTH in chief cells activated
- less PTH released
How long is the half life of parathyroid hormone?
4mins - released PTH is cleaved and inactivated in the liver
Is parathyroid hormone stored?
No - Continually synthesised but little store
Chief cells degrade hormone as well as synthesise it
Cleavage of PTH in chief cells is accelerated by high serum calcium levels
What are the effects of parathyroid hormone on plasma calcium and phosphate levels?
Increase plasma calcium
Decrease plasma phosphate
How does PTH affect bone?
PTH induces osteoblasts cells to synthesise and secrete cytokines on their cell surface
Cytokines stimulate differentiation and activity in osteoclasts and protect them from apoptosis
Increases number and activity of osteoclasts
PTH decreases osteoblasts activity exposing bony surface to osteoclasts
These cells release acids that dissolve calcium and phosphate and enzymes that break down organic matrix releasing it into extracellular fluid
What are the effects of parathyroid hormone on the kidneys?
Affects tubular cells within kidney
- PTH increases Ca2+ reabsorption in ascending limb and distal convoluted tubule
- PTH decreases phosphate reabsorption so it is removed from circulation
- also has an an effect on magnesium reabsorption
(Prevents calcium stone formation)
If parathyroid hormone causes bone resorption, why is the overall effect of parathyroid hormone to increase plasma calcium and decrease plasma phosphate?
There is a net loss of phosphate as more is lost from urine than is gained from bones
What are the effects of parathyroid hormone on the GI tract?
PTH promotes the formation of calcitriol (the active form of vitamin D)
Calcitriol increases the rate of Ca2+ and phosphate absorption from food in the GI tract into the blood
When Ca2+ is not limited, how much Ca2+ is absorbed from the GI tract and how?
30%
Paracellular uptake
What is vitamin D?
Lipid soluble vitamin
Collective term for a group of prohormones:
-vitamin D2 (ergocalciferol)
-vitamin D3 (cholecalciferol)
How is vitamin D obtained?
Food - cheese, butter, margarine, fortified milk, fish, fortified cereals
Sun exposure
Supplements
How is dietary vitamin D activated?
It is biologically inert and must undergo a hydroxylation reaction in both the liver and kidney to be activated
How is inversion of dietary vitamin D to its active form controlled?
Pro-vitamin bound to carrier is small enough to be filtered by the glomerulus and enter the proximal convoluted tubule where conversion to its active form takes place via the second hydroxylation reaction.
This is under negative feedback. It is inhibited by:
- high plasma calcium
- low PTH
How is vitamin D3 transported in the blood?
Calcitriol
What is the half life of 25-hydroxyvitamin D?
2 weeks
This is formed by hydroxylation of dietary vitamin D by the liver
What is the half life of calcitriol?
0.25 days
Is PTH or calcitriol more important for the minute to minute regulation of Ca2+?
PTH
Effects of calcitriol are too slow
What are the actions of calcitriol?
GI - increases intestinal absorption of dietary calcium by increasing number of Ca2+ transporters in microvilli
Kidneys - increases renal absorption of Ca2+
Bone - increases bone resorption
What produces parathyroid related peptide (PTHrP)?
Tumours-commonly breast or prostate cancer, squamous tumours of the lung/head/neck
Occasionally in patients with myeloma
What can secretion of PTHrP lead to?
Hypercalcaemia
A patient is found to have unexplained hypercalcaemia with normal PTH, calcitriol (and calcitonin) levels.
Which hormone would you measure in the blood?
PTHrP
What are the actions of PTHrP?
Shares many actions with PTH as it binds to PTH receptors. Leads to:
- increased calcium release from bone
- reduced renal calcium excretion
- reduced renal phosphate reabsorption
How do the actions of PTHrP and PTH differ?
PTHrP does not increase renal C-1 hydroxylase activity so does not increase calcitriol concentration, unlike parathyroid hormone
What are the normal physiological roles of PTHrp?
Tooth eruption - secreted by enamel epithelium to stimulate local bone resorption
Mammary gland development
Lactation
Placental transfer of calcium
Where is calcitonin released from?
Thyroid gland - C cells (parafollicular cells)
What is the function of calcitonin?
In animals, lowers serum calcium levels
In humans, lacks pathology associated with hypo or hyper calcaemia suggesting that it has little function
In pregnancy, this hormone may preserve the maternal skeleton
If the thyroid gland is removed or destroyed, how the lack of calcitonin affect calcium homeostasis?
None
How is release of PTH controlled?
Negative feedback.
Stimulated by:
-low plasma Ca2+
Inhibited by:
-high plasma Ca2+
How is release of calcitriol controlled?
PTH
Stimulated by:
-high PTH
How is the release of calcitonin controlled?
Negative feedback
Stimulated by:
-high plasma Ca2+
Inhibited by
-low plasma Ca2+
Calcium reabsorption in the kidneys is controlled by…
PTH
Calcitriol
Directly by plasma concentration of Ca2+ - same calcium sensing receptor found on chief cells is found in thick ascending limb
Serum calcium > 3mmol/L
Serum phosphate is low
Serum PTH is high
Diagnosis?
Primary hyperparathyroidism
Serum calcium is normal
Serum phosphate is normal
Serum alkaline phosphatase is high
Serum PTH is high
Diagnosis?
Secondary hyperparathyroidism
Serum calcium > 3mmol/L
Serum phosphate is normal
Serum alkaline phosphatase is very high
Serum PTH is low
Diagnosis?
Malignant hypercalcaemia
How does increased plasma calcium affect nerve membrane depolarisation?
Raises threshold
Makes resting membrane potential more negative
What is hypocalcaemia?
<2.1mmol/L
What are the symptoms of Hypocalcaemia?
Hyper-excitability in the nervous system including the neuromuscular junction
- parasthesia
- tetany
- carpopedal spasm
- paralysis
- convulsions
- epilepsy
Why can Hypocalcaemia kill?
Laryngeal tetany
What is Chvostek’s sign?
When you apply pressure to a nerve on the face, you can see the mouth twitching.
This is a sign of hypocalcaemia
What causes hypocalcaemia?
Most commonly,
Thyroidectomy - inadvertent removal/ischaemia of parathyroid glands. Symptoms can start within 6 hours
What is hypercalcaemia?
Plasma calcium > 2.6mmol/L
What are the symptoms of hypercalcaemia?
Leads to suppression of neuronal activity
- lethargy
- depression
- constipation
- renal canliculi - kidney stones
- frequent ruination
- nausea
- cardiac arrhythmia
- polyuria - exacerbates the hypercalcaemia
Where is alkaline phosphatase found?
Enzyme present on osteoblasts, liver bile canaliculi and in plasma
What is alkaline phosphatase a marker of?
Bone turnover - increased osteoblast activity (hypercalcaemia)
Liver bile canaliculi damage (alcoholic liver disease)
What are the causes of hypercalcaemia?
-malignant osteolytic bone metastases - most common (breast, lung, renal, thyroid)
Produce factors that activate osteoclasts
-haemotological malignancies eg. Myeloma
Produce factors that activate osteoclasts
-squamous tumours of head, lung and neck
Produce parathyroid hormone-related peptide that acts at PTH receptors
Where are the common sites for malignant osteolytic bone metastases?
Vertebrae, pelvis, proximal parts of the femur, ribs, proximal parts of the humerus, skull
These are well vascularised because erythropoiesis occurs here
How is hypercalcaemia treated?
Rehydration
In patient with malignant hypercalcaemia and coma, this is not necessarily a terminal event. After rehydration many go home.
What causes primary hyperthyroidism?
Primary abnormality of the parathyroid: one of the 4 parathyroid glands develops an adenoma and secretes excessive parathyroid hormone
What are the symptoms of primary hyperparathyroidism?
Moans - tired, exhausted, depressed
Groans - constipation, peptic ulcers, pancreatitis
Stones - kidney stones. Polyuria due to impaired sodium and water reabsorption
Bones - bone and muscle aches
What is the cause of secondary hyperparathyroidism?
Vitamin D deficiency due to:
Diet/environment
Chronic renal failure (not converting vitamin D to calcitriol)
What are the symptoms of secondary hyperparathyroidism?
Bone pain
Osteomalacia - vitamin D deficiency
Renal osteodystrophy - chronic renal failure
What is the difference between osteomalacia and osteoporosis?
Osteoporosis:
- decreased bone density
- normal ratio of mineral to matrix
- degeneration of already constructed bone
- brittle bones prone to fracture
Osteomalacia:
- ratio of mineral to matrix is decreased
- abnormality that affects bone building in children (rickets) or bone mineralisation in adults
- leads to soft bones that are prone to bending
Bone bending is seen in….
Osteomalacia
Brittle bones that are prone to fracture is seen in…
Osteoporosis
Osteomalacia in children is called…
Rickets
Risk factors for osteoporosis are…
Postmenopausal women Low body mass index Long term oral steroid use Heavy drinking Smoking Prolonged inactivity - bed rest
