Metabolism in the fed and starved states

Question 1

What is the feed-fast cycle?

Answer 1

• Human metabolism oscillates between the fed and fasting states
• The ‘switch’ that determines metabolic changes is the molar ratio of insulin to glucagon in the blood

Question 2

What is the fed state?

Answer 2

• FED state - during meals and for several hours afterwards
• Characterized by high insulin and low glucagon (a high insulin/glucagon ratio)

Question 3

What is the fasting state?

Answer 3

• FASTING state: 6-12 hr after a meal
• Characterized by low insulin and high glucagon (a low insulin/glucagon ratio)

Fasting that lasts in excess of 12 hr is ‘prolonged fasting’ or starvation

Question 4

What changes in metabolism occur from the absorptive to the post-absorptive state?

Answer 4

Question 5

What happens in metabolism in the fed state?

Answer 5

• Food intake stimulates insulin release and insulin inhibits glucagon secretion
• This affects metabolism in the liver, muscle and adipose tissue
• Glucose utilization in the brain remains unchanged

Question 6

What happens during metabolism in the fed state in the liver?

Answer 6

• High concentrations of nutrients lead to an increase in the insulin:glucagon ratio
• High blood glucose means it enters the liver and is converted to glycogen and TGs which are secreted as VLDL. Some enters TCA cycle.
• Glycerol from peripheral tissues is also converted to triacylglycerols
• Excess amino acids entering from the gut are converted to pyruvate and metabolised via the TCA cycle for energy or converted to triacylglycerols

Question 7

What happens during metabolism in the starved state in the muscle?

Answer 7

• Glucose enters the muscle via insulin-stimulated Glut 4 transport system - converted to glycogen or metabolised via glycolysis and TCA cycle
• Fatty acids enter muscle both from the diet via chylomicrons and from the liver via VLDL. These are oxidised via β-oxidation to acetyl CoA to produce ATP to support contraction
• Amino acids are incorporated into proteins

Question 8

What happens during metabolism during the fed state in the adipose tissue?

Answer 8

• Glucose enters adipose tissue by the insulin-dependent Glut 4 transport system - converted via glycolysis and PDH into acetyl CoA and then to fatty acids and triacylglycerol
• Fatty acids enter from VLDL and chylomicrons and are converted to triacylglycerol
• Glycerol released from TGs is returned to liver for re-use

Question 9

What is the effect of insulin on LPL and HSL?

Answer 9

LPL activity increased & HSL activity inhibited by insulin

Question 10

What happens to metabolsim during the fed state in the brain?

Answer 10

The brain takes up glucose via Glut 1 & 3 transporters and metabolises it oxidatively by glycolysis and the TCA cycle to produce ATP

Question 11

What happens to Metabolism in the early fasting state?

Answer 11

• During fasting, the liver switches from a glucose-utilizing to a glucose-producing organ
• Decrease in glycogen synthesis and increase in glycogenolysis
• Gluconeogenesis

Question 12

What happens during the early fasting state in the liver?

Answer 12

• As plasma glucose falls no longer enters liver as Glut 2 transporter has low affinity. Liver changes from a user to exporter of glucose
• Reduced insulin: glucagon ratio activates glycogenolysis and gluconeogenesis (from lactate and alanine) via cAMP production in response to glucagon
• Protein in liver and other tissues are broken down to amino acids to fuel gluconeogenesis.
• Fatty acids from lipolysis used to produce energy via b-oxidation.

Citrate and acetyl CoA produced from oxidation of fatty acids activate gluconeogenesis and inhibit glycolysis

Question 13

What happens during the early fasting state in the muscle?

Answer 13

• The fall in insulin reduces glucose entry. Glycogenolysis does not occur as there are no glucagon receptors in skeletal muscle to cause activation
• Muscle and other peripheral tissues switch to fatty acid oxidation as a source of energy which inhibits glycolysis and glucose utilisation
• Proteins are broken down to amino acids and the carbon skeletons can be used for energy or exported to the liver in the form of alanine

Question 14

What happens during the early fasting state in adipose tissue?

Answer 14

• Entry of glucose into adipose tissue via the Glut 4 transport system is reduced in response to the lowered insulin and metabolism of glucose via glycolysis is severely inhibited
• Mobilisation of TGs occurs in response to the reduced insulin:glucagon ratio and activation of the sympathetic NS by release of noradrenaline
• Some fatty acids are used directly within the tissue to produce energy - remainder are released into the bloodstream to support glucose-independent energy production in muscle and other tissues
• Glycerol cannot be metabolised and is recycled to the liver to support gluconeogenesis

Question 15

What happens during the early fasting state in the brain?

Answer 15

• Continues to take up glucose because of the high affinity of Glut1 and Glut3 transport system and independence from insulin
• Glucose continues to be metabolised despite the fact that no glucose is provided in the diet
• Brain cannot switch to fatty acids as a source of fuel as free fatty acids do not cross the blood brain barrier

Question 16

What happens to metabolism in the starved state?

Answer 16

• Chronic low-insulin, high glucagon state
• Accompanied by decrease in concentration of thyroid hormones – decreases metabolic rate
• Free fatty acids become the major energy source
• Production of ketone bodies as alternative fuel source

Question 17

What happens during the starved state in the liver?

Answer 17

• No glucose enters liver and glycogen stores are depleted within 24 hours
• Plasma glucose dependent on gluconeogenesis from lactate, glycerol & alanine from fat and protein breakdown. The kidney also becomes an important source of gluconeogenesis
• Urea synthesis stimulated to cope with increasing amino groups entering liver
• Glycogen synthesis and glycolysis are inhibited
• Fatty acids enter the liver and provide energy to support gluconeogenesis with excess acetyl CoA being converted to ketone bodies (acetoacetate and β-hydroxybutyrate). These are not used by the liver but released for oxidation by other tissues (e.g. muscle, brain)

Question 18

What happens during the starved state in the muscle?

Answer 18

• Little glucose entry with fall in insulin and switch to fatty acids as the fuel
• Ketone bodies are taken up by muscle and other peripheral tissues and used as a further source of fuel in heart and muscle conserving glucose
• Ketone bodies reduce proteolysis and decrease muscle wasting
• Fatty acid oxidation supplies the energy needed for muscle contraction.

Question 19

What is the glucose-fatty acid cycle?

Answer 19

The glucose-fatty acid cycle spares glucose during fatty acid oxidation

Question 20

How does the glucose-fatty acid cycle work?

Answer 20

• Mobilisation of fatty acids in response to glucagon or adrenaline increases fatty acid oxidation to acetyl CoA in peripheral tissues
• Excess acetyl CoA converted to citrate in TCA cycle which builds up in cytoplasm and inhibits PFK-1
• Build up of G-6-P inhibits hexokinase and prevents glucose phosphorylation
• Increase in glucose prevents further glucose entry and so conserves glucose

Question 21

What happens during the starved state in adipose tissue?

Answer 21

• Little glucose entry with fall in insulin secretion
• Body switches to using fatty acids from triacylglycerol to supply all the energetic needs of the major tissues
• Lipolysis is greatly activated because of the low insulin:glucagon ratio and blood levels of fatty acids rise 10-fold
• Glycerol exported to the liver to be converted into glucose

Question 22

What happens during the starved state in the brain?

Answer 22

• Although fatty acids cannot be used by brain, as the levels of ketone bodies rise in the plasma, these can cross the blood brain barrier and enter the brain as a source of energy sparing use of glucose
• Ketone bodies cannot completely replace the need for glucose and therefore brain continues to take up glucose and metabolise through glycolysis net glucose synthesis during starvation is essential

Question 23

When does ketone body production increase?

Answer 23

Ketone body concentration increases during fasting or starvation

Question 24

When can the CNS use ketone bodies?

Answer 24

[KB] plasma of 4mM or above is sufficient to allow use by the CNS

Occurs after approx. 3 days of starvation

Question 25

Label each line

Answer 25

Question 26

How is glucose utilised in each metabolic state?

Answer 26

• Fed state: glucose provided by diet
• Fasted state: most glucose provided by the breakdown of liver glycogen, increasing amounts by gluconeogenesis
• Starved state: most glucose comes from gluconeogenesis, the breakdown of protein and fats provide amino acids and glycerol as substrates

Question 27

How is glycogenolysis / glycogen synthesis hormonally controlled?

Answer 27

• Enzymes involved in glycogenolysis / glycogen synthesis are also subject to hormonal control by glucagon, adrenaline, cortisol and insulin
• Hormonal control is mediated by changes in phosphorylation

Question 28

Answer 28

Question 29

Which hormones are involved in Hormonal regulation of glycogen mobilisation (covalent modification)?

Answer 29

• Insulin released in response to increases in blood glucose promoting glucose oxidation, glycogen synthesis and TG synthesis
• Glucagon and adrenaline (epinephrine) released in response to low blood glucose, thus releasing glucose from glycogen in the liver to increase blood glucose
• Adrenaline is also part of the “fight or flight” response; levels rise greatly during exercise when glycogen breakdown is required to support muscle contraction

Question 30

Label the enzyme and whether it is active or inactive

Answer 30

Question 31

How does reciprocal regulation of phosphorylase and glycogen synthase by phosphorylation work?

Answer 31

• Glucagon (liver) and adrenaline (muscle) activate glycogen breakdown and inhibit synthesis by activating cAMP PK with ultimate phosphorylation of phosphorylase and glycogen synthase
• Mimicked by increasing Ca2+ during contraction
• Insulin activates protein phosphatase to reverse these effects

Question 32

How does Reciprocal regulation of phosphorylase and glycogen synthase by glucagon and adrenalin work?

Answer 32

• Glucagon and adrenaline increase cAMP production and activate cAMP PK.
• cAMP PK phosphorylates glycogen synthase switching it OFF.
• Does not phosphorylate phosphorylase but another kinase, phosphorylase kinase leading to activation.
• Phosphorylase kinase can also phosphorylate glycogen synthase ensuring it is inactive

Question 33

How does Reciprocal regulation of phosphorylase and glycogen synthase work?

Answer 33

• Phosphorylase kinase exists in an a and b form. The phosphorylated form is the active a form.
• Phosphorylase kinase phosphorylates phosphorylase switching it ON, allowing glycogen degradation at the same time that it inhibits glycogen synthesis.
• Phosphorylase kinase can also be activated allosterically by Ca2+ ions linking muscle contraction with glycogen breakdown ensuring adequate ATP

Question 34

How does Reciprocal regulation of phosphorylase and glycogen synthase work?

Answer 34

• Phosphorylase kinase exists in an a and b form. The phosphorylated form is the active a form.
• Phosphorylase kinase phosphorylates phosphorylase switching it ON, allowing glycogen degradation at the same time that it inhibits glycogen synthesis.
• Phosphorylase kinase can also be activated allosterically by Ca2+ ions linking muscle contraction with glycogen breakdown ensuring adequate ATP

Question 35

How does Regulation of phosphorylase and glycogen synthase by insulin work?

Answer 35

• Insulin activates protein phosphatase -1 which removes the phosphates from phosphorylase, glycogen synthase and phosphorylase kinase
• This switches OFF glycogen breakdown and switches ON glycogen synthesis

Question 36

What is the effect of hormones on glycogenesis?

Answer 36

Glucagon stimulates glycogenolysis: In liver - 2nd messenger is cAMP

Adrenaline stimulates glycogenolysis:

• in muscle & liver via b-adrenergic receptors – 2nd messenger is cAMP
• in liver via a1-adrenergic receptors – second messenger is Ca2+

Insulin stimulates glycogen synthesis in both tissues