Metabolism in the fasting state

Question 1

What must the blood glucose be maintained between ?

Answer 1

Between 3mM-8mM (normal 4.5-5mM)

Question 2

The insulin:glucagon ratio is key to ?

Answer 2

Regulating blood glucose levels

Question 3

What is the well-fed state characterised by ?

Answer 3

Insulin secretion and a lipogenic liver

Question 4

When does the post-absorptive state occur? and what happens to the I:G ratio?

Answer 4

Post-absorptive state about 12 hours after a meal: I:G ratio falls about threefold down to 0.15

Question 5

Explain the early fasting state in the Liver ?

Answer 5

• As plasma glucose falls it no longer enters liver: Glut2 is low affinity transporter
• Liver changes from a user to exporter of glucose
• Reduced I:G ratio activates
  glycogenolysis and gluconeogenesis in response to glucagon (via cAMP)
• Glycogen and fat synthesis and glycolysis are simultaneously inhibited
• Proteins are broken down to amino acids to fuel gluconeogenesis. Amino groups are returned to the liver and detoxified by conversion to urea
• Fatty acids from lipolysis enter the liver and produce energy via beta oxidation. Citrate and acetyl CoA produced from oxidation of fatty acids activate gluconeogenesis and inhibit glycolysis

Question 6

Explain the early fasting state in the adipose tissue ?

Answer 6

• Entry of glucose into adipose tissue via Glut 4 is reduced in response to lowered insulin, and metabolism of glucose via
  glycolysis is severely inhibited
• Mobilisation of TAGS occurs in response to the reduced I:G ratio
• Some fatty acids used to directly to produce energy
• The remainder are released into the bloodstream to support glucose-independent energy production in muscle and other peripheral tissues
• Glycerol cannot be metabolised and is recycled to the liver to support gluconeogenesis

Question 7

Explain the early fasting state in the muscle ?

Answer 7

• Fall in insulin reduces glucose entry. No glycogen breakdown as there are no glucagon receptors in skeletal muscle to cause activation
• Muscle and peripheral tissues switch to fatty acid oxidation for 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 8

What do highly active muscles do ?

Answer 8

• Respire anaerobically and produce lactate

Question 9

Where does the lactate travel to in the Cori Cycle ?

Answer 9

• Travels in the bloodstream to the liver where it is converted to glucose via glucogeogenesis
• The glucose can then be re-exported back to the muscle and used for energy

Question 10

Explain the early fasting state in the brain ?

Answer 10

• Continues to take up glucose because of the high affinity of the 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 11

Explain two days onwards without food in metabolism in the late fasting state ?

Answer 11

I:G ratio very low, now down to 0.05

Question 12

Explain the late fasting state in the liver ?

Answer 12

• No glucose enters liver and glycogen stores are depleted within 24 hours
• Plasma glucose is dependent on gluconeogenesis from fat and protein breakdown. The kidney also becomes an important source of gluconeogenesis
• Urea synthesis stimulated to cope with more amino groups entering
• 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 beta-hydroxybutyrate). These are not used by the liver but released for oxidation by other tissues (muscle, brain).

Question 13

Explain the late fasting state in the adipose tissue ?

Answer 13

• 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 I:G ratio and blood levels of fatty acids rise 10 fold
• Glycerol exported to the liver to be converted into glucose

Question 14

Explain the late fasting state in the muscle ?

Answer 14

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

Question 15

Explain the late fasting state in the brain ?

Answer 15

• 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

Question 16

In terms of adipose tissue, what is critical for survival ?

Answer 16

The amount of fat-containing adipose tissue is critical to survival

Question 17

What happens once the fat supplies are exhausted ?

Answer 17

Then the body has no choice but to undergo massive protein breakdown, leading to excessive muscle wasting and organ shrinkage

Question 18

What is the ultimate cause of death in starvation ?

Answer 18

Absent other factors (e.g. dehydration, exposure,

illness) is often heart failure as the cardiac muscle breaks down

Question 19

Explain where the glucose comes from during starvation?

Answer 19

• 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: protein and fat breakdown provides amino acids and glycerol as substrates

Question 20

Mobilisation of fatty acids in response to glucagon or adrenaline increases ?

Answer 20

• Fatty acid oxidation in peripheral tissues to acetyl CoA (inhibits PDH)
• Excess acetyl CoA converted to citrate in TCA cycle which builds up in cytoplasm and inhibits PFK-1
• Build up of G-6P inhibits hexokinase and prevents glucose phosphorylation
• Increase in glucose prevents further glucose entry and so conserves glucose