S10.9&10-Metabolism & Fed And Fasting State

Front 1

How are changes in the metabolic pattern achieved?

Back 1

1. Variation in amount of available substrate
e.g. fatty acid use in starvation
2. allosteric effects on enzymes
e.g. AMP and PFK in muscle
3. Covalent modification of enzymes
e.g. phosphorylation of glycogen - phosphorylase and synthetase
4. Changes in enzyme synthesis
e.g. Glucokinase and dietary CHO
e.g. HMG CoA reductase inhibited by cholesterol

Front 2

Describe the main hormones controlling intermediary metabolism?

Back 2

Insulin = only hypoglycaemic hormone
Glucagon = hyperglycaemic

Other insulin counter-regulatory hormones:
adrenaline (adrenal medulla)
cortisol (adrenal cortex)
growth hormone (anterior pituitary)

Front 3

Describe the endocrine part of the pancreas?

Back 3

Islets o Langerhans
2% of total pancreatic mass
(adult pancreas contains ~1 million islets)

B cells (60-70%) secrete insulin
alpha cells (30-40%) secrete glucagon
gamma cells seccrete somatostatin

Front 4

What is insulin secretion stimulated by?

Back 4

1. Rise in blood glucose
2. Rise in [amino acids]
3. Gut hormones
Secretin and other GI horones released after food intake before blood glucose elevated
4. Glucagon
to provide fine tuning of blood glucose homeostasis

Front 5

What is insulin secretion inhibited by?

Back 5

adrenaline

Front 6

Describe the control of insulin secretion?

Back 6

Glucose and a.acids enter the pancreatic B cell
ATP blocks K+ channels
causing depolarisation and inhibiting hyperpolarisation
Ca2+ channels open
increased cellular [ca2+]
causes insulin release

Front 7

Describe the processing of pro insulin into insulin and C-peptide?

Back 7

Insulin prohormone --> C peptides + alpha and beta chain of insulin

Front 8

What is secretion of glucagon stimulated by?

Back 8

1. Low blood glucose
2. High [amino acid] in blood
-prevents hypoglycaemia after protein meal
3.Adrenaline
regardless of blood glucose

Front 9

Describe the metabolic effects of insulin?

Back 9

1. promotes fuel storage after a meal
2. promotes growth
3. promotes glycogen synthesis
4. stimulates fatty acid sythesis and storage from CHO when intake exceeds glycogen storage capacity
5. stimulates a.acid uptake and protein synthesis

Front 10

How are the metabolic effects of insulin mediated?

Back 10

Mediated by binding to tyrosine kinase receptor
Receptor autophosphorylates
Insulin receptor substrates phosphorylated
Causes phosphorylation of target enzymes and expression of Glut 4 receptors in the membrane

Front 11

Describe the action of insulin?

Back 11

Promotes appearance o GLUT4 in muscle and adipose tissue
Insulin effects vary in time - glucose transport and enzyme activation very rapid, synthesis of enzymes very slow

Front 12

Where in the body has GLUT receptors that are not insulin dependent?

Back 12

brain, liver, erythrocyte, pancreas
high [insulin] leads to down regulation of receptors

Front 13

Describe the action of glucagon?

Back 13

1. Mobilises fuel
2. Maintains blood glucose during fasting
3. Activates glycogenolysis (liver)
4. Activates gluconeogenisis (liver)
5. Activates uptake of amino acids --> for gluconeogenesis

6. activates FA release from adipose tissue
7. activates FA oxidation and ketone body formation in the liver

Front 14

Describe the action of adrenaline?

Back 14

Mobilises fuel during stress
-stimulates glycogenolysis (liver)
-stimulates fatty acid release from adipose tissue

Front 15

Describe the action of cortisol?

Back 15

provides for long term requirements, stimulating:
gluconeogenisis
a.a. mobilisation from muscle
FA release from adipose tissue

Front 16

Describe the fed (absorptive state)?

Back 16

2-4hours after a meal
-Increase in blood glucose, a. acids and TAG as:
CHO-->glucose
Fat-->Chylomicrons as TAG
Proteins-->a.acids

-Synthesis/storage of glycogen TAG and protein as:
Glucose--> Glycogen (in liver and muscle)
FA+Glycerol+glucose-->Tryglyceride (in adipose)
a. acids --> proteins (tissues) --> TCA --> ATP +CO2

Front 17

Describe carbohydrate metabolism by the liver?

Back 17

1. Liver = Gluconeogenesis at all times but FED STATE (high ins/glucagon ratio)
2. In fed glycolysis activated through activation of GLUCOKINASE
3. high Km for glucose so no competition with brain while glycolysis is low
4. Glycogen synthesis is activated
as glycogen sythase is activated and phosphorylase inhibited
5. gluconeogenisis inhibited

Front 18

Describe Liver Fat Metabolism?

Back 18

Fatty acid and TAG synthesis activated

Acetyl CoA carboxylase activated (rate limiting step)
Malonyl CoA inhibits carnitine transferase
Thus newly synthesised FA does not enter the mitochondrion for oxidation but is esterified to TAG

Front 19

Describe metabolism in the fed state in the brain and erythrocyte?

Back 19

->rely on glycolysis
a. acids can't pass BBB and RBC has no mitochndrion

glyc transport to brain and erythrocyte = independent of insulin (GLUT 1)
This allows us use of glc. at higher and lower [insulin]

Front 20

Describe metabolism in the fed state in the muscle?

Back 20

Glucose transport in muscle increased
GLUT4 transporters increase in number
Glycogen synthetase activated and phosphorylase inhibited
a. acid uptake activated adn protein sythesis increased

Front 21

Describe metabolism in the fed state in Adipose Tissue

Back 21

Lipoprotein Lipase is activated by insulin
Allows entry of FA for esterification
and storage of TAG

Glucose transport is increased through GLUT4
It is needed or prod. of glycerol phosphate and esterification of TAG
Hormone sensitive lipase in apidocyte is inhibited so TAG is not degraded

Front 22

Describe the fasting (post absorptive state)?

Back 22

Blood [glucose] peak ~ 1hr after eating
Return to normal two hours after meal
Blood glucose removed for oxidation/storage
[insulin] decreases and [glucagon] increase

Front 23

Explain how the liver and adipose tissue respond to the early stages of fasting?

Back 23

-Liver maintains blood [glucose] @ 4mM
-Apdipose tissue provides greatest source of energy as TAGs
-Hormone sensitive lipase activated by adrenaline and glucagon
-FA transported to liver bound to albumin

Front 24

Describe glucose production in the liver?

Back 24

1. First supplier of blood [glucose] is glycogen
2. Gluconeogenesis follow from lactate (erythrocytes and muscles), glycerol (from adipose tissue) and amino acids (from muscle)
3. After 24hr fasting all blood glucose comes from gluconeogenesis

Front 25

Are fatty acids a gluconeogenic precursor or not and explain why?

Back 25

No.
As fatty acids can make Acetyl CoA
but this can not be converted to glucose as can not be converted back to pyruvate as reaction catalysed by pyruvate dehydrogenase is irreversible

Front 26

What is pyruvate dehydrogenase inhibited/activated by and what does this ensure?

Back 26

inhibited by glucagon
activated by insulin
ensures that fasting gluconeogenic substrates are channeled into glucose production and not acetyl CoA formation as glucose is needed as fuel for brain etc

Front 27

Describe what happens in the liver in the FED state?

Back 27

glycolytic enzymes activated
pyruvate dehydrogenase activated
excess acetyl CoA is channeled into FA synthesis by activation of acetyl CoA carboxylase

Front 28

Describe what happens in the fasting state in the liver?

Back 28

FA can be used as fuel by liver, muscle, adipose tissue
Thus draining of gluconeogenic substrates to acetyl CoA is inhibited
and conversion to glucose is favoured

Front 29

Describe ketone body formation?

Back 29

FA oxidation in hepatocytes leads to high [acetyl CoA]
Exceeds capacity of TCA cycle
Thus --> ketone body formation
ACETOACETATE and B-HYDROXYBUTYRATE released -> bloodstream

Front 30

Where are ketone bodies used?

Back 30

most tissues oxidise mix of FA and KD
Erythrocyte oxidise FA only
Brain uses FA and small amount of KD

Front 31

What happens in prolonged fasting?

Back 31

If early pattern were to continue body protein would be severely depleted
Only about 1/3 of body protein can be lost without severe or fatal consequences

Front 32

How does urea excretion in the fed and fasting state change?

Back 32

Glucose - Urea excretion small
Fasting - 12 hours Greatest
Starvation 3 Days - Less
Starvation 5-6 weeks - Least

Front 33

Describe the changes that occur in the body in continued starvation?

Back 33

1. more ketone bodies are recovered from the kidny
2. Muscle uses less KB and more FA
3. [FA] plateaus and [KB] rise (as FA used up)
4. brain can thereore use more KB and less glucose
5. need for gluconeogenesis is reduced, thus muscle breakdown for protein is reduced
6. urea production decrease

Front 34

Describe the action of ketone bodies?

Back 34

Act on pancreas to stimulate insulin release
Limiting muscle proteolysis
& Limits adipose tissue Lipolysis
So muscle tissue is conserved

Front 35

How long does it take you to starve to death?

Back 35

40 days

Front 36

What causes death due to starvation?

Back 36

fuel exhaustion
loss of function due to loss of protein
impairment of immune system
often due to infection

Front 37

How much of the UK population does diabetes mellitus affect and how much of all endocrine disorders does it consist of?

Back 37

affects 2-3% of UK popn
90% of all endocrine disorders

Front 38

What are the effects of diabetes mellitus?

Back 38

blindness
amputations
premature death

Front 39

How much of the healthcare budget?

Back 39

5-10%

Front 40

Describe the different types of diabetes mellitus?

Back 40

Type 1: Insulin dependent diabetes mellitus (IDDM)
Type 2: Non-insulin dependent diabetes mellitus (NIDDM)

Front 41

How many diabetics are IDD?

Back 41

10-20%

Front 42

Describe Diabetes Type 1?

Back 42

Autoimmune destruction of B cells
early onset
(polyuria, polydipsia, polyphagia, fatigue, weight loss, muscle wasting, weakness)
hallmarks = hyperglycaemia and ketoacidosis
Treatment = insulin

Front 43

Describe Diabetes Type 2

Back 43

Insulin resistance
Later onset
Association with diet and lifestyle

Hyperglycaemia but no ketoacidosis
Treatment: diet & oral hypoglycaemic agents

Front 44

How does the metabolic pattern of uncontrolled diabetes mellitus relate to that of starvation and why?

Back 44

Resemble starvation but more exaggerated as:
in starvation insulin is low
in diabetes type 1 insulin is absent
Glucagon acts unapposed
KB produced in starvation stimulates insulin release - limits muscle breakdown, release of FA from apidocytes and uncontrolled production of KB
This DOES NOT HAPPEN IN DIABETES

Front 45

What are the chronic complications o diabetes mellitus?

Back 45

1. Microangiopathy
thickening of basement membrane in walls of small blood vessel
2. Retinopathy
blindness is 25x more likely
3. Nephropathy
Renal failure is 17x more likely
4. Neuropathy
postural hypotension, impotence, foot ulcers

Front 46

What is the treatment of type 1 diabetes?

Back 46

exogenous injection of insulin

Front 47

What is the treatment of type 2 diabetes?

Back 47

weight reduction, dietary modification, oral hypoglycaemic agents
biguanides increase number of GLUT 4
Sulphonylureas act on B cell to improve insulin secretion

Front 48

What is metabolic syndrome?

Back 48

High fasting glucose/insulin resistance/diabetes type 2/ impaired GT
Plus 2 of:
Hypertension
Dyslipidaemia (high TAG/low HDL)
Central obesity
Microabuminuria