18. Metabolic and endocrine control during special circumstances Flashcards
1
Q
Which fuel sources are normally available in the blood?
A
GLUCOSE
• Glucose is the preferred fuel source
• Little (~12g) free glucose available
• More glucose (~300g) stored as glycogen
FATTY ACIDS
• Can be used as fuel by most cells except red blood cells, brain and CNS
• Stored as triacylglycerol (fat) in adipose
• 10-15 kg fat in 70kg man (~2 months fuel supply)
2
Q
Which fuel sources are available on special circumstances?
A
AMINO ACIDS
KETONE BODIES
LACTATE
3
Q
Describe how amino acids can be made available as a fuel source on special circumstances?
A
- Some muscle protein (~6kg) can be broken down to provide amino acids for fuel
- Converted to glucose or ketone bodies
- ~2 weeks supply of energy
4
Q
Describe how ketone bodies can be made available as a fuel source on special circumstances?
A
- Mainly from fatty acids
- Used when glucose is critically short
- Brain can metabolise instead of glucose
5
Q
Describe how lactate can be made available as a fuel source on special circumstances?
A
- Product of anaerobic metabolism in muscle
- Liver can convert back to glucose (Cori cycle) or can be utilised as fuel source for TCA cycle in other tissues (e.g. heart)
6
Q
What are the 3 main energy stores?
A
glycogen, fat and muscle protein
7
Q
Describe the energy store glycogen
A
- Readily available source of glucose
- Made & stored in liver and muscle
- Made when glucose is in excess in blood
8
Q
Describe the energy store fat
A
- Made from glucose and dietary fats when in excess
- Stored as triacylglycerol in adipose tissue
Source of:
• Fatty acids
• Glycerol
9
Q
Describe the energy store Muscle protein
A
• Used in emergency • Amino acids can be: - Glucogenic (e.g. Ala & Val) - Ketogenic (Lys & Leu) - or both (e.g. Tyr & Phe) • Store ‘filled’ by normal growth and repair processes
10
Q
What are the key features in metabolic control(from feeding to starvation)?
A
1) Feeding
2) Glucose and fat available from gut (~2 hours)
3) Glucose and fats no longer being absorbed (~2-10 hours)
4) No food for ~8-10 hours - Glycogen stores depleted
5) Starvation
11
Q
What happens when glucose and fat are available?
A
- Immediate metabolism supported by glucose
- Speed up growth and repair processes
- Make glycogen as rapidly as possible
- Increase fat stores
12
Q
What happens when glucose and fat no longer being absorbed?
A
- Maintain blood glucose by drawing on glycogen stores
- Support other metabolic activity with fatty acids released from stores
- Preserve blood glucose for brain
13
Q
What happens when No food for ~8-10 hours and Glycogen stores depleted?
A
- Need to make more glucose for brain from amino acids, glycerol & lactate by gluconeogenesis
- Continue to support other metabolism with fatty acids
14
Q
Summarise what happens during starvation
A
- Fatty acid metabolism produces ketone bodies
* Brain becomes able to metabolise ketone bodies (reduces need for glucose)
15
Q
What do anabolic hormones promote in terms of fuel conserves?
A
Promote fuel storage
16
Q
What do catabolic hormones promote in terms of fuel conserves?
A
Promote release from stores & utilisation
17
Q
What are examples of anabolic hormones?
A
• (Growth Hormone)
increases protein synthesis
18
Q
What are examples of catabolic hormones?
A
• Glucagon • Adrenaline • Cortisol • Growth hormone (increases lipolysis & gluconeogenesis) • Thyroid hormones
19
Q
Which hormones are called anti-insulin hormones?
A
glucagon, adrenaline, growth hormone and cortisol - oppose the actions of insulin
20
Q
What processes does insulin stimulate?
A
- Glucose uptake in muscle and adipose (GLUT 4).
- Glycolysis
- Glycogen synthesis
- Protein synthesis
21
Q
What processes does insulin inhibit?
A
- Gluconeogenesis
- Glycogenolysis
- Lipolysis
- Ketogenesis
- Proteolysis
22
Q
What are the effects of feeding?
A
Increase in blood glucose stimulates pancreas to release
insulin.
• Increases glucose uptake and utilisation by muscle and adipose (GLUT 4)
• 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
23
Q
What are the effects of fasting?
A
1) Blood glucose falls & insulin secretion depressed.
• Reduces uptake of glucose by adipose and muscle.
2) Low blood glucose stimulates glucagon which stimulates:
• Glycogenolysis in the liver to maintain blood glucose for 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.
24
Q
What are the processes that occur in energy starvation?
A
• The initial response to starvation is merely a prolonged version of the normal fasting response
• Reduction of blood glucose stimulates release of cortisol from adrenal cortex & glucagon from pancreas.
• Stimulate gluconeogenesis & breakdown of protein & fat
• Reduction in insulin & anti-insulin effects of cortisol prevent most cells from using glucose & fatty acids are preferentially metabolised.
• Glycerol from fat provides important substrate for gluconeogenesis, reducing the need for breakdown of proteins.
• Liver starts to produce ketone bodies & brain starts to utilise these sparing glucose requirement from protein
• Kidneys begin to contribute to gluconeogenesis
• Once fat stores depleted system must revert to use of protein as fuel
• Death usually related to loss of muscle mass (respiratory muscle:infection)
infection).
25
What is the main cause of death in starvation?
Death results from a number of causes related
| to loss of muscle mass including serious respiratory infections due to loss of respiratory muscle.
26
Which system in the body needs a constant supply of glucose?
The central nervous system.
27
What is a mother's average net weight gain by the end of pregnancy?
8Kg
28
Why are there alterations to maternal metabolism and endocrine system during pregnancy?
• Accommodate increased demands of developing fetus
and placenta
• Growth of fetus requires lots of energy & raw materials
29
When does most fetal growth occur in the pregnancy?
last trimester
30
What are the 2 main phases of metabolic adaptations during pregnancy?
Anabolic phase (early pregnancy): Preparatory increase in maternal nutrient stores (especially adipose)
Catabolic phase (late pregnancy): Maternal metabolism adapts to meet an increasing demand by fetal-placental unit
31
Describe the anabolic phase of pregnancy.
* Increase in maternal fat stores
* Small increase in level of insulin sensitivity.
* Nutrients are stored to meet future demands of rapid fetal growth in late gestation and lactation after birth.
32
Describe the catabolic phase of pregnancy.
* Decreased insulin sensitivity (increased insulin resistance).
* Increase in insulin resistance results in an increase in maternal glucose and free fatty acid concentration
* Allows for greater substrate availability for fetal growth
33
How are most substances transported in placental transfer?
Simple diffusion down concentration gradients
| - some active transport (e,g amino acids)
34
how is glucose transferred in the placenta?
Glucose is principal fuel for fetus and Transfer facilitated by transporters (mainly GLUT 1
35
Why is the fetus called the agressive parasite
Because the Fetus controls maternal metabolism to ensure its own survival
36
What is the fetoplacental unit and what is it made up of?
Placenta, fetal adrenal glands and fetal liver,
| constitute a new endocrine entity, known as the fetoplacental unit
37
What hypothalamic like releasing hormones does the placenta release?
Corticotropin releasing hormone (CRH)
Gonadotropin releasing hormone (GnRH)
Thyrotropin releasing hormone (TRH)
Growth hormone releasing hormone (GHRH)
38
What pituitary like hormones does the placenta release?
ACTH (small amount compared to CRH)
Human chorionic gonadotropin (hCG)
Human chorionic thyrotropin (cCT)
Human placental lactogen (hPL)
39
What are the 2 important placental steroid hormones?
Progesterone, oestriol
40
What is the metabolic change in the first half pregnancy in preparation for?
Changes to maternal metabolism during first 20 weeks of pregnancy related to a preparatory increase in maternal nutrient stores (mainly adipose tissue).
In preparation for:
• Rapid growth rate of fetus
• Birth
• Subsequent lactation
41
Why is increase in insulin during early pregnancy important?
Increasing levels of insulin (↑ insulin/anti-insulin ratio) promote an anabolic state in mother that results in increased nutrient storage
42
What Maternal metabolic changes occur during second half of pregnancy?
* Maternal metabolism adapts to meet increasing demands
* Concentration of nutrients in the maternal circulation kept relatively high
* Maternal insulin levels continue to increase but the production of anti-insulin hormones by the fetal-placental unit increases at an even faster rate and the insulin/anti-insulin ratio therefore falls
43
How are concentration of nutrients in the maternal circulation kept relatively high?
• Reducing maternal utilisation of glucose by switching tissues to use of fatty acids.
• Delaying maternal disposal of nutrients after meals.
• Releasing fatty acids from stores built up during 1st half
of pregnancy
44
What happens to insulin levels in the catabolic phase in late pregnancy?
Maternal insulin levels continue to increase but the production of anti-insulin hormones by the fetal-placental unit increases at an even faster rate and the insulin/anti-insulin ratio therefore falls
45
What are the 3 examples of hormones that are released by the placenta and exert an anti-insulin effect on maternal metabolism
* Corticotropin releasing hormone
* Human placental lactogen
* Progesterone
46
Despite large increase in (placental) CRH in maternal blood, why is the increase of ACTH and cortisol modest?
Maternal Anterior Pituitary becomes desensitised
47
Why is there transient hyperglycaemia after meals during late pregnancy ?
transient hyperglycaemia after meals because of increased insulin resistance
48
What is the overall effect on glucose levels during late pregnancy?
~10% lower
| - since insulin levels are ~1.65 x higher in fasting state and ~ 3 x higher in postprandial state
49
During which parts of the day might a pregnant woman be hypoglycaemic?
can occur between meals and at night because
| of the continuous fetal draw of gluco
50
How is insulin production increased during pregnancy?
Oestrogens and progesterone increase sensitivity of maternal pancreatic β-cells to blood glucose
• β-cell Hyperplasia (more cells)
• β-cell Hypertrophy (bigger cells)
51
What can result if there is no increased production of insulin during pregnancy?
If β-cells do not respond normally, blood glucose may become seriously elevated & Gestational diabetes may develop
- increased apetite during pregnancy
52
What is gestational diabetes?
Disease in which pancreatic β-cells do not produce sufficient insulin to meet increased requirement in late pregnancy
53
What are the 3 known causes of gestational diabetes?
1) Autoantibodies similar to those characteristic
of Type I DM
2) Genetic susceptibility similar to maturity
onset diabetes
3) β-cell dysfunction in setting of obesity and
chronic insulin resistance (i.e. "evolving" type II DM) (most common)
54
What are the clinical implication of gestational diabetes?
* Increased incidence of miscarriage
* Incidence of congenital malformation 4x higher
* Fetal macrosomia - Means “large body” (Disproportionate amount of adipose around shoulders and chest could lead to shoulder dystocia)
* Associated with hypertensive disorders of pregnancy such as Gestational hypertension and Preeclampsia
55
What is macrosomia, dystocia and preeclampsia?
Macrosomia: Large body
Dystocia: shoulder gets stuck during birth
preeclampsia: high BP, protein in urine
56
Which women are more likely to develop gestational diabetes?
High insulin resistance before pregnancy and many women who developed gestational diabetes go on to develop Type II diabetes later in life
57
What are the risk factors for gestational diabetes?
* Maternal age >25 years
* Body mass index >25 kg/m2
* Race/Ethnicity - More common in Asian, Black and Hispanic ethnic groups
* Personal or family history of Diabetes
* Family history of macrosomia
58
What is the management of gestational diabetes?
* Initial dietary modification including calorific reduction in obese patients
* Insulin injection if persistent hyperglycaemia is present: (7.5-8 mM postprandial or >5.5-6 mM fasting)
* Regular ultrasound scans to assess fetal growth & well being
59
Which systems does the change from rest to exercise involve?
```
The switch from rest to exercise involves rapid adaptations in a range of systems:
• Musculo-skeletal system
• Cardiovascular system
• Respiratory system
• Temperature regulation
```
60
During exercise, what does the metabolic response need to ensure?
• Increased energy demands of skeletal and cardiac muscle are met by mobilisation of energy stores.
• Minimal disturbances to metabolic homeostasis by keeping rate of mobilisation equal to rate of utilisation.
• Glucose supply to brain is maintained.
• End products of metabolism are removed as quickly as
possible.
61
What does the magnitude and nature of metabolic response to exercise depends on?
* Type of exercise (muscles used)
* Intensity and duration of exercise
* Physical condition and nutritional state of individual
62
How much ATP store is there in muscle, how long would this last in a sprint and thus what needs to occur?
* ATP “stores” in muscle are limited (~5 mmol/kg)
* In theory enough to last ~2 seconds during a sprint
* ATP must therefore be rapidly resynthesised at a rate that meets the metabolic demands placed upon cell
* Depending on rate of ATP hydrolysis, cell will employ different metabolic strategies to match re-synthesis rate with hydrolysis rate
63
What effect does decrease in the insulin/anti-insulin ratio during the second half of pregnancy have on
maternal ketogenesis?
The increased availability of fatty acids to the liver resulting from the mobilisation of maternal adipose tissue, coupled with the fall in the insulin/anti-insulin ratio switches on the production of ketone bodies by the maternal liver. These are used as a fuel by the developing foetal brain.
64
What accounts for most of ATP usage?
Myosin ATPase accounts for ~70% of the ATP usage. Remainder comes from other cellular processes such as maintaining ionic gradients across cell membrane (Na+, K+, Ca2+)
65
Where does the energy to replenish ATP come from?
* Muscle creatine phosphate stores (~17mmol/kg muscle) can rapidly replenish ATP to provide immediate energy
* Still only enough for ~5 seconds worth of energy during a 100m sprint
66
Beyond initial burst of energy, further ATP must be supplied, how?
* Glycolysis (Inefficient (2 ATP net per glucose)
* Oxidative phosphorylation (requires oxygen)
• Must therefore draw on energy stores to provide substrate for these pathways
67
After creatine phsophate is used for exercise what store is then used for energy production?
Muscle glycogen stores
- instensive exercise (anaeorobic): 2 minutes
- low intensity (aerobic): 60 minutes
68
How is muscle glycogen utilised in exercise?
It is converted to glucose - 6 - P which can then enter glycolysis and be converted to pyruvate which under anaerobic conditions forms lactate or enter TCA cycle
in aerobic conditions
69
What is the process that converts muscel glycogen to glucose -6-P called? What is the name of the enzyme needed?
- Glycogenolysis
| - Muscle Glycogen phosphorylase
70
What increases muscles glycogen phosphorylase activity?
```
By adrenaline (phosphorylation)
By AMP (allosteric modulator)
```
71
What stimulates and inhibits phosphofructokinase which is a key regulator in glycolysis?
Stimulated by high AMP
| Inhibited by high ATP
72
Which is the principal organ for regulating blood glucose?
liver
73
Describe the change in hepatic blood glucose during exercise
* Exercise results in an increase in hepatic blood glucose production through glycogenolysis and gluconeogenesis
* Liver also recycles lactate produced by anaerobic metabolism (Cori cycle).
74
Describe the Cori Cycle
Glucose is converted to lactate in muscles which is transported to the liver, where it is converted back to glucose which is then transported to muscle
75
Which GLUT does the muscle use for glucose uptake?
GLUT4 and GLUT1 (constitutively active)
76
What is the insulin independent process of glucose uptake into muscle?
Increase in AMP stimulates AMPK (AMP activated protein kinase) resulting in signalling cascade which increases GLUT4 translocation
77
How much store of triacylglycerol do we have and how long could this provide energy for?
15 Kg Theoretically could provide enough energy for ~48 hours of low intensity exercise
78
In what condition can fatty acid be used as fuel?
Only in aerobic conditions
79
What is the carrying capacity of fatty acids in blood limited by?
By uptake across mitochondrial membrane (carnitine shuttle)
80
What is the energy supply in a 100 meter sprint?
• Short, high intensity exercise (anaerobic)
• Once high energy phosphate stores used
(~5 sec) must create ATP anaerobically
• Produces lactate (lactic acid) with subsequent build up in H+ produces fatigue
• Cannot deliver extra glucose to muscle cells fast enough
• Need muscle store of glycogen
• Helps to spare blood glucose for brain
81
What is the energy supply in a 1500m middle distance?
* Medium intensity
* Can deliver some extra oxygen to muscles
* However, still ~40% anaerobic metabolism
* Aerobic metabolism can use fatty acids as well as glucose
Three phases to race:
• Initial start uses creatine phosphate and anaerobic glycogen metabolism.
• Long middle phase in which ATP is produced aerobically from muscle glycogen (relies on adequate supply of O2 to muscles).
• Final finishing sprint relies again on the anaerobic metabolism of glycogen and produces lactate.
82
What is the energy supply in a marathon?
• Low intensity, long duration (95% aerobic)
Use of:
• Muscle glycogen
• Liver glycogen
• Fatty acids
* Muscle glycogen depleted in a few minutes. Glucose from liver glycogen peaks at ~1 hour then declines steadily
* Utilisation of fatty acids rises steadily from 20-30 minutes
83
How is insulin levels affected over prolonged exercise?
Insulin levels fall slowly (inhibition of secretion by adrenaline)
84
How is glucagon levels affected over prolonged exercise?
Glucagon levels rise:
• Stimulates glycogenolysis (activates glycogen phosphorylase)
• Stimulates gluconeogenesis (PEPCK & fructose 1,6 bisphosphatase)
• Stimulate lipolysis (Hormone sensitive lipase)
85
How are adrenaline and GH levels affected over prolonged exercise?
rise rapidly
• Adrenaline stimulates glycogenolysis & lipolysis
• Growth hormone stimulates lipolysis & gluconeogenesis
86
How is cortisol levels affected over prolonged exercise?
Cortisol rises slowly
| • Stimulates lipolysis & gluconeogenesis
87
What are the benefits of exercise?
* Body composition changes (adipose ↓, muscle ↑)*
* Glucose tolerance improves (muscle glycogenesis ↑)*
* Insulin sensitivity of tissues increases *
* Blood triglycerides decrease (VLDL & LDL ↓, HDL ↑) *
* Blood pressure falls. *
* Psychological effects Feeling of "well-being"
* Especially important for diabetics
88
What are the causes of fatigue?
* Depletion of muscle glycogen.
* Accumulation of H+ in muscle.
* Dehydration (reduces capacity for sweating, reduces heat loss, increases body temp).
89
What are the Whole body responses to prolonged exercise?
• Increased fuel consumption by muscles, need to be supplied with fuels. *
• Increased ATP production and utilisation by muscles (~20% efficiency).
• Increased heat production, heat must be dissipated - sweating.
• Increased delivery of O2 to muscles - vasodilation of arterioles. *
• Increased removal of CO2, H+ and lactate from muscles.
• Increased cardiac output - beats faster, larger stroke volume.*
• Redistribution of blood flow away from gut and kidneys to muscles.
• Changes in breathing - increases in rate and depth.
* Can be affected by training
90
What are the cardiovascular changes due to training?
* More 2,3- bisphosphoglycerate in blood (lowers affinity of haemoglobin for O2).
* Heart beats slower for same cardiac output
91
What are the skeletal muscle changes due to training?
* Glucose transport proteins in cell membrane (GLUT 4).
* Storage of glycogen.
* Potential for oxidative metabolism especially fatty acids - more mitochondria and more oxidative enzymes in mitochondria.
* Number and size of muscle fibres.
* Vascularisation (capillary density) of muscles - improves O2 supply.
* Myoglobin content of muscle (ability to store O2 in muscle)
92
Summarise the changes brought to the metabolic response by endrocrine system?
The major changes are:
• Insulin levels fall progressively as a result of inhibition of insulin secretion by adrenaline and noradrenaline.
• Adrenaline, noradrenaline and growth hormone levels increase rapidly.
• Glucagon and cortisol levels increase gradually.
The net effect of these changes is a progressive fall in the insulin/antiinsulin ratio:
• Increases glycogenolysis in liver.
• Increases gluconeogenesis in liver (uses lactate and glycerol).
• Increases lipolysis in adipose tissue.
• No effect on ketogenesis in liver (insulin still present).
93
Describe the Metabolic response to short-duration high intensity exercise (100m sprint)
* Muscle ATP and C~P are used initially (~5sec).
* Muscle glycogen is rapidly mobilised to provide glucose 6-P (~5sec).
* Glucose 6-P is metabolised via glycolysis to provide ATP from ADP by substrate level phosphorylation.
* Glycolysis is carried out under anaerobic conditions as oxygen supply to muscle is inadequate for aerobic metabolism.
* Dramatic increase in rate of anaerobic glycolysis (↑ 1,000 times) produces lactate and H+ (at maximum rate ~20 mmol of H+ are produced every sec).
* Build-up of H+ produces fatigue.
94
Describe the Metabolic response to long duration low intensity exercise e.g. marathon running
• The major fuel used during the initial phase of a marathon is muscle glycogen and if this was the sole source of energy it would last ~60min when metabolised aerobically.
• As the marathon proceeds there is increased utilisation of circulating blood glucose by muscles. The blood glucose concentration stays relatively constant however, as the glucose removed by muscles is replaced by glucose released from the liver. This glucose comes from the liver’s limited glycogen stores
(~75%) and from gluconeogenesis (~25%).
• There are limited substrates available for liver gluconeogenesis and eventually the blood glucose level may fall - exhaustion!
• Because of the aerobic conditions that the muscle cells are working under they able to use fatty acids as a source of energy and this utilisation increases with time.
95
What are the advantages of using muscle glycogen over circulating glucose
* Availability not affected by blood supply.
* No need for membrane transport into muscle cells.
* Produces G-6-P without using ATP (glycogen phosphorylase uses Pi).
* Mobilisation can be very rapid - highly branched structure allows many sites for enzyme attack and glycogen phosphorylase activity can be changed rapidly by a mixture of covalent modification (phosphorylation) and allosteric activation (ADP and Ca++).
96
Why can't anaerobic metabolism continue as the sole source of ATP generation?
build-up of lactate and H+
97
Give the mechanisms by which H+ impairs muscle function
* Inhibition of glycolysis by H+
* H+ interferes with actin/myosin interaction.
* H+ causes sarcoplasmic reticulum to bind calcium (inhibits contraction).
98
What factors limit the use of fatty acids by muscle?
• Rate of fatty acid release from adipose tissue (rate of lipolysis).
• Limited capacity of the blood to transport fatty acids (requires binding to albumin).
• Rate of fatty uptake into muscle cells and into muscle
mitochondria.
• Fatty acid oxidation requires more oxygen/mole of ATP produced than glucose.
• Fatty acids can only be metabolised under aerobic conditions
