L18: Metabolic and Endocrine control during special circumstances Flashcards
What are the different fuel sources in the body?
Normally available
–>Glucose- preferred fuel, essential for cornea of eye, RBC, medulla of kidney, CNS and brian
–>Fatty acids –> most cell (except ones above)
Specialised conditions
–>Amino acids
–>Ketone bodies
–>Lactate
How much glucose is available in the body?
Preferred fuel
Little (12g) free glucose available
More glucose (300g) stored as glycogen
How many fatty acids are available in the body?
Stored as triacylglycerol (fat) in adipose
10-15kg fat in 70kg man –> last for 2 months
What releases amino acids? What do they get converted into for fuel?
Muscle protein (6kg) broken down to provide amino acids for fuel
Converted to glucose or ketone bodies
2 weeks supply of energy
What can ketones be used for?
Used in the brain in starvation BUT brain needs time to adapt to using them–> only provide 50% necessary fuel
Derived from fatty acids
When is lactate produced? What is it converted to?
Anaerobic metabolism in muscle
Converted to glucose in Cori cycle or utilised as fuel source in TCA cycle
What are the major energy stores?
Glycogen –> 400g
Fat –> 10-15kg
Muscle protein –> 6kg
What is glycogen?
Readily available source of glucose
Made and stored in the liver and muscle
Made when glucose is in excess in the blood
What is fat?
Made from glucose and dietary fats when in excess
Stored as TAGs
Source of FA and glycerol
What is muscle protein?
Used in emergency Amino acids can be --> glucogenic --> Ala, Val --> ketogenic --> Lys, Leu --> both --> Tyr, Phe Store 'filled' by normal growth and repair processes
Why do we need different stores of energy?
Food is consumed episodically–> intermittent use
Absorbed nutrient sometimes available in excess and sometimes unavailable –> feed/fasting cycle, starvation
Need long and short term energy stores
For the first two hours after feeding what supplies the fuel for the body to function? What is it used for?
Glucose and fat from the gut Immediate metabolism: --> speed up growth and repair processes --> Make glycogen as rapidly as possible --> Increase fat stores
What supplies fuel for the 2-10 hours since feeding? What is it used for?
Glycogen stores
Support metabolic activities by releasing FA from stores
Preserve blood glucose for brain
What provides fuel for 8-10 hours since feeding? What is it used for?
Glycogen stores depleted
Glucose made from amino acids, glycerol and lactate by gluconeogenesis
Support metabolism with fatty acids
What provides fuel for >10 hours since feeding?
FA produce ketone bodies
Brian becomes able to metabolise ketone bodies (reduce need for glucose)–> Glucose sparring effect
What controls the availability of fuel molecules in the blood?
Hormonal control
Insulin–> promotes storage (growth hormone increase protein synthesis so minor contribution)–> anabolic
Glucagon, Adrenaline, Cortisol, Growth hormone (increases lipolysis and gluconeogenesis) and thyroid hormone–> promote release stores and utilisation–> catabolic
What are anti-insulin hormones?
Hormones that work against insulin
Glucagon, Adrenaline, Cortisol, GH and thyroid hormone
Why is it important that the levels of glucose in the blood is maintained?
CNS, RBC and some other tissue require glucose to function–> cannot do oxidative phosphorylation
Metabolism proceeds at a constant rate
CNS- 140g/24hrs
Other tissue- 40g/24hrs
Rate of uptake of glucose is related to the concentration
Glucose maintained between 4.0-6.0mmol/L to ensure enough glucose uptaken
What is hypoglycaemia? What are the signs and symptoms?
Low blood glucose
Reduction <3 mmol/L
S and S: Trembling, weakness, tiredness, headache, sweating, sickness, tingling around the lips, palpitations, changes in mood, slurred speech, staggering walk–> confused with intoxication
Unconsciousness and death
What is hyperglycaemia? What happens?
High blood glucose
Elevated >7mmol/L
Nervous, cardiovascular and renal system affected
Glucose in urine–> filtered and cannot be recovered–> renal threshold exceeded
More water is lost in urine–> polyuria
Increased thrist–> polydipsia
Associated with abnormal metabolism
Increased glycation of plasma proteins–> lipoproteins
What does insulin promote?
Translocation of GLUT4 channel–> glucose uptake in muscle and adipose
Glycolysis
Glycogen synthesis
Protein synthesis
What does insulin inhibit?
Gluconeogenesis Glycogenolysis Lipolysis Ketogenesis Proteolysis
What is the feeding/fasting cycle?
Regular metabolic changes that occur during feeding and fasting
What effects does feeding having on metabolism?
Increased glucose–> pancreas–> insulin
- ↑ glucose uptake and utilisation by muscle and adipose (GLUT4)
- Promotes storage of glucose as glycogen in liver and muscle
- Promotes amino acid uptake and protein synthesis in the liver and muscle
- Promotes lipogenesis and storgae of fatty acids as TAG in adipose tissue
What effect does fasting have on metabolism?
Low blood glucose—> Increase glucagon secretion and inhibit insulin secretion
—> Increase glycogenolysis—> increase glucose for brain and other dependent tissues
—> Lipolysis—> provide fatty acids for other tissues
—> Gluconeogenesis—> maintain supplies of glucose to the brain
What is meant by starvation?
Inadequate intake of energy in a previously well nourished individual
How does the body respond to starvation?
- Initially blood glucose maintained by glucagon—> breakdown of hepatic glycogen
- Reduced blood glucose—> Pituitary releases ACTH—> cortisol increases
- Simulates gluconeogenesis and breakdown of protein and fat to increase gluconeogenic substrates available
- Lipolysis increases—> FA increase to 2mmol/L
- Decrease in insulin and increase in anti-insulin effects prevents cells using glucose—> FA metabolised
- Glycerol from FA —> gluconeogenesis (less need for protein breakdown)
- Liver produces ketone bodies—> brain utilises—> reduces need of protein breakdown for gluconeogenesis
- Kidneys contribute to gluconeogenesis
- Once fat stores are depleted—> protein breakdown
What is re-feeding syndrome?
After starvation
Introduction of food must be gradual
Reduction in urea sythesis leads to down regulation of the enzymes involved
Sudden increase in protein or AA—> ammonia toxicity
What metabolic and endocrine changes occur to the mother during pregnancy?
1st half— anabolic metabolism
2nd half catabolic metabolism
Change in sensitivity to hormones
Why does metabolism and endocrine functions in the mother change?
Accommodate the demands of the foetus and placenta
Support growth
Ensure foetus is supplied with the correct nutrients at the correct stage of development
What is the typical net gain in weight by the end of pregnancy?
8kg Foetus 3.5kg Placenta 0.6kg Amniotic fluid 0.8kg Maternal fuel stores 3kg
What controls the maternal metabolism during pregnancy?
Hormones
Maternal insulin
Foetal-placental unit—> oestrogen, progesterone and placental lactogen
What are the two main metabolic phases during pregnancy?
Anabolic phase—> early pregnancy
—> Increased maternal fat stores
—> Small increase in level of insulin sensitivity
—> Store nutrients for later
Catabolic phase—> late pregnancy
—> Decrease in insulin sensitivity (insulin resistance)
—> Increase in maternal glucose and free FA concentration (prevent storage)
—> Greater substrate availability for fetal growth
How are nutrients transferred from the mother to the baby?
Placental transfer
Simple diffusion down conc gradient
Glucose—> principle fuel—> facilitated by GLUT1
What is meant by the ‘aggressive parasite’?
Fetus controls maternal metabolism to ensure its own survival
Fetoplacental unit (placenta, fetal adrenal gland and fetal liver) new endocrine entity
Produce proteins that control the maternal hypothalamic pituitary axis
CRH—> ACTH
GnRH—> hCG (human chorionic gonadotropin)
TRH—> cCT (human chorionic thyrotropin)
GHRH—> hPL (human placental lactogen)
Placental hormones—> Oestriol and progesterone
What are the changes in the first half of pregnancy?
First 20 weeks
Preparatory increase in maternal nutrient stores (adipose tissue)
Preparation for:
- Rapid growth rate of fetus
- Birth
- Subsequent lactation
↑ insulin –> ↑ insulin/anti-insulin ratio
Promotes anabolic state–> increase storage
What are the changes in the second half of pregnancy?
Adapts to meet increasing demands
Concentration of nutrient in maternal circulation kept high by:
- Reduce maternal use of glucose–> FA used instead
- Delay maternal disposal of nutrients after meals
- Release FA from stores built up during 1st half of pregnancy
Maternal insulin levels ↑ BUT the anti-insulin levels ↑ even faster so insulin/ anti-insulin ratio falls
Why do the changes that occur during the second half of pregnancy happen?
Rapid increase in the growth of the fetus and the placenta
What are anti-insulin hormones in pregnancy?
Hormones that exert an anti-insulin effect on maternal metabolism
Corticotropin releasing hormone –> ↑ by 1000 fold
maternal anterior pituitary becomes desensitised resulting in more modest increase in ACTH and cortisol
Human placental lactogen
Progesterone
What is the effect of the anti-insulin hormones?
Transient hyperglycaemia after meals–> ↑ insulin resistance
Overall pregnancy blood glucose becomes 10% lower since insulin levels are 1.65 % higher in fasting and 3% higher in postprandial state
Hypoglycaemia can occur between meals and at night because continuous fetal draw of glucose
What is the role of increased insulin sensitivity in pregnancy?
Increased appetite–> more glucose ingested
Oestrogen and progesterone increase sensitivity of maternal pancreatic β cells to blood glucose
–> β cell hyperplasia and hypertrophy
Increased insulin synthesis and secretion
If β cells do not respond normally–> blood glucose seriously elevated –> gestational diabetes
What is maternal ketogenesis?
Decrease in insulin/anti-insulin ratio and increased availability of FA from mobilisation of maternal adipose –> ketone body production in maternal liver–> fuel for developing fetal brain
What is gestational diabetes?
Pancreatic β cells do not produce enough insulin
Blood glucose levels rise–> gestational diabetes
After birth, decreased metabolic demand and normalisation of hormones –> pancreas can respond adequately and diabetes disappears
However more likely to develop type 2 diabetes in life
What is thought to be the cause of gestational diabetes?
- Autoantibodies similar to those characteristic of type 1 DM
- Genetic susceptibility similar to maturity onset diabetes
- β-cell dysfunction in setting of obesity and chronic insulin resistance
What are the clinical implications of gestational diabetes?
Affects 3-10% pregnancies
Increased incidence of miscarriage
Incidence of congenital malformation 4x higher
Fetal macrosomia–> large body
–> increased amount around shoulder and chest–> shoulder dystocia
Associated with hypertensive disorders of pregnancy such as Gestational hypertension and Preeclampsia
Risk of complications reduced if diagnosed and managed
What is preeclampsia?
High blood pressure
Protein in urine
What are the risk factors for gestational diabetes?
Age >25yrs
–> insulin resistance increases with age (fat:lean mass ratio increases)
BMI >25kg/m2
Race/ethnicity–> Asian, Black and Hispanic ethnic groups more common
Personal or family history of diabetes
Family history of macrosomia
What is the management of gestational diabetes?
Initial dietary modification including calorific reduction in obese patients
Insulin injection if persistant hyperglycaemia is present : (7.5-8.0 mmol/L postprandial or >5.5-6 mmol/L)
Regular ultrasound scans to access fetal growth and well being
What is the body’s metabolic response to exercise need to ensure?
Increased energy demands of skeletal and cardiac muscle–> mobilisation of energy stores
Minimal disturbances of metabolic homeostasis by keeping rate of mobilsation equal to rate of utilisation
Glucose supply to brain maintained
End products of metabolism are removed as quickly as possible
What systems need to adapt to ensure the change from rest to exercise is maintained?
Musculo-skeletal system
Cardiovascular system
Respiratory system
Temperature regulation
Why does the body need to changes its metabolism in response to exercise?
Meet acute oxygen and fuel demands of cardiac and skeletal muscle during exercise
Removal of end products of metabolism
What determines the size of the response in exercise?
Type of exercise (muscles used)
Intensity and duration of exercise
Physical condition and nutritional state of individual
How does the energy requirements vary between resting metabolic rate, 100m sprint, 1500m sprint and marathon?
Resting–> 4kJ per minute
100m sprint–> 200kJ per minute, 30kJ total
1500m race–> 140kJ per minute, 500kJ total
Marathon 42km–> 80kJ per minute, 10,000kJ total
Where does the energy for exercise come from? What happens during exercise?
Hydrolysis of ATP ATP--> ADP + Pi + energy ATP stores are limited--> 5mmol/kg Last 2 seconds during a sprint Never falls below 20% due to regeneration Rapidly synthesised at a rate to meet demand Muslce ATP turnover -Resting 0.06 mmol/sec/kg -Marathon 1.2 mmol/sec/kg -100m sprint 3mmol/sec/kg
What uses the ATP during exercise?
70% myosin ATPase
Rest on ionic gradients across the cell membrane (Na+, K+ and Ca2+)
How is ATP regenerated during exercise?
Creatine phosphate
–> Creatine-P + ADP –> ATP and creatine
–> Immediately available–> drive contraction
Glycolysis
Oxidative phosphorylation
What are the energy stores used to provide substrate for these pathways?
Muscle glycogen
Blood glucose
Fatty acids
What does muscle glycogen uses allow?
Intensive anaerobic exercise sustained for 2 mins
Low intensity aerobic exercise susatined for 60 mins –> complete oxidation
What is the metabolic pathway for the use of muscle glycogen?
1) Muscle glycogen–> glycogenolysis by glycogen phosphorylase (↑ adrenaline (phosphorylation) and ↑ AMP (allosteric regulator)
2) Glucose-6-P
3) Glycolysis –> phosphofructokinase (key regulator)–> Stimulated by ↑AMP and inhibited by ↑ATP
4) Pyruvate–> TCA cycle in aerobic conditions
5) Lactate–> end product anaerobic conditions
What are the advantages of using muscle glycogen over free glucose?
Availability not affected by blood supply
No need for membrane transport into muscle cell
Produce G-6-P without using ATP
Mobilisation rapid–> highly branched structure
How is glucose used in exercise?
Liver control plasma glucose
Exercise increases glycogenolysis and gluconeogenesis
Liver recycles lactate produced by anaerobic metabolism (Cori cycle)–> glucose
Muscles glucose uptake via GLUT4 transporter–> insulin promotes translocation and GLUT 1–> constitutively active
Exercising muscle–> insulin independent pathway–> ↑AMP stimulates AMPK –> signalling cascade increase GLUT 4 translocation
Rate of glucose metabolism insufficient to meet full demands in exercising muscles
Blood glucose maintained for brian
What limits anaerobic metabolism of glycogen or glucose?
Lactate and H+ build up
Accumulation of H+ so dramatic–> exceeds buffering capacity–> impaired function and fatigue
H+ inhibits glycolysis
Interferes with actin/myosin interaction
Causes sarcoplasmic reticulum to bind calcium –> inhibits contraction
What do fatty acids allow?
Major store in adipose (some in muscle)
Enough to provide energy for low intensity exercise for 48hrs
What factors limit the use of fatty acids for execise?
- Requires aerobic conditions
- Slow release from adipose tissue
- Limit carrying capacity in blood
- Capacity is limited by uptake across mitochondrial membrane (carnitine shuttle)
- Require more O2 per mole of ATP produced
- Low rate of ATP production but sustained
What is the metabolic response to short duration high intensity exercise (100m sprint)?
10seconds
Metabolic response rapid
Anaerobic production of ATP
-Muscle ATP and C-P used initially (5 secs)
-Muscle glycogen is rapidly mobilised to provide glucose 6-P (5 secs)
-Glycolysis anaerobic conditions
Produces lactate (lactic acid) subsequent build up of H+ –> fatigue
What is the metabolic response to medium duration medium intensity exercise (1500m race)?
3.5 mins
Endurance as well as speed
ATP–> mixture of aerobic (60%) and anaerobic (40%) metabolism of glycogen
Eliminate large amounts of CO2, buffer H+ ions by muscle
Three phases:
- Initial–> Creatine phosphate and anaerobic glycogen metabolism
-Long middle phase–> ATP produced aerobically from mucles glycogen
- Final finishing–> anaerobic metabolism of glycogen and produces lactate
What is the metabolic response to long duration low intensity exercise (marathon running)?
Elite 125-135 mins
Carbohydrate store insufficient need to oxidise fatty acids
Metabolic changes are more gradual
95% aerobic
Muscle glycogen –> initial–> would last 60 mins–> carbohydrate rich diets to increase glycogen stores (best eating after exercise–> converted to glycogen not lipids)
Liver glycogen–> releases glucose–> 75% from stores, 25% from gluconeogenesis
Fatty acids–> utilisation increases with time 20-30mins rises
What controls the metabolic response in prolonged exercise?
Endocrine–> Hormonal control
Insulin levels fall slowly–> inhibition of secretion by adrenaline
Glucagon levels rise
Adrenaline and growth hormone rise rapidly
Cortisol rises slowly
How does the changes in hormone levels in prolonged exercise have an effect?
- Increase glycogenolysis in liver–> glycogen phosphorylase (G, A, GH)
- Increase gluconeogenesis in liver (lactate and glycerol)–> PEPCK and fructose 1,6 bisphosphate (G, A, GH and C)
- Increase lipolysis in adipose tissue–> Hormone sensitive lipase (G, A, GH and C)
What is fatigue? What causes it?
Inability to maintain a given power output affecting the intensity and/or duration of exercise
Caused by:
- Depletion in muscle glycogen
- Accumulation of H+ in muslce
- Dehydration (reduces capacity for sweating, reduces heat loss, increases body temperature)
How does the whole body respond to exercise?
- Increase fuel consumption by muscles
- Increased ATP production and utilisation by muscle
- Increased heat production–> sweating
- Increased O2 delivery to muscle –> vasodilation
- Increased removal of CO2, H+ and lactate
- Increased CO–> beats faster, larger stroke volume
- Redistribution of blood flow away from gut and kidney to muscles
- Changes in breathing–> increase rate and depth
How does the body respond to training?
Adaptation largely affect musculoskeletal and cardiovascular systems
CVD
–> More 2,3-bisphosphoglycerate in blood (lower affinity of Hb for O2)
–> Heart beats slower for same CO
SM–> increased:
–> Glucose transport proteins on cell membrane (GLUT4)
–> Storage of glycogen
–> Potential for oxidative metabolism especially FA –> More mitochondria and more oxidative enzymes
–> Number and size of muscle fibres
–> Vascularisation (capillary density) of muscles–> improves O2 supply
–> Myoglobin content of muscles (ability to store O2 in muscles)
What are the benefits of exercise?
Body composition changes ↓ adipose, ↑ muscle
Glucose tolerance improves
Insulin sensitivity of tissues↑
Blood triglycerides decreases (VLDL and LDL↓ and HDL↑)
Blood Pressure falls
Psychological effects–> well being
How does the muscle fibres vary between a sprinter and a marathon runner?
Physical properties and metabolic properties vary Two major fibre types --> Type I (red) and Type II (white) Long distance >70% type I Sprinters >70% type II
What are the major differences between type I and type II muscles fibres?
Speed of contraction: Slow (TI), Fast (TII)
Speed of fatigue: Slow (TI), Fast (TII)
Capillary supply: Good (TI), Moderate/Poor (TII)
Mitochondria: Many (TI), Few (TII)
Oxidative capacity: High (TI), Moderate/Low (TII)
Glycolytic capacity: Low (TI), High/Moderate (TII)
FA oxidation: High (TI), Low (TII)
Myoglobin content: High (TI), Low (TII)
Type of exercise: Low intensity, high endurance (TI), high intensity, low endurance (TII)
