Metabolism in the fed and starved states

Question 1

What is the ‘switch’ that determines metabolic changes?

Answer 1

The molar ratio of insulin to glucagon in the blood

Question 2

Define what is meant by the fed state

Answer 2

During meals and for several hours afterwards

Characterized by high insulin and low glucagon (a high insulin/glucagon ratio)

Question 3

Define what is meant by the fasting state

Answer 3

6-12 hr after a meal
Fasting that lasts in excess of 12 hr is ‘prolonged fasting’ or starvation
Characterized by low insulin and high glucagon (a low insulin/glucagon ratio)

Question 4

How does food intake affect insulin and glucagon?

Answer 4

Food intake stimulates insulin release; this inhibits glucagon secretion

Question 5

What occurs in the absorptive phase?

Answer 5

Molecules of storage are built up

Question 6

What occurs in the post-absorptive phase?

Answer 6

Storage compounds are broken down

Question 7

In the fed state what happens to glucose utilisation in the brain?

Answer 7

Remains unchanged

Question 8

Describe metabolism in the fed state in the liver

Answer 8

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

Question 9

Describe metabolism in the fed state in the muscles

Answer 9

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 energy to support contraction
Amino acids are incorporated into proteins

Question 10

Describe metabolism in the fed state in the adipose tissue

Answer 10

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 TAGs is returned to liver for re-use

Question 11

Describe metabolism in the fed state in the brain

Answer 11

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

Question 12

Describe metabolism in the early fasting state

Answer 12

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

Question 13

What occurs in the liver during the early fasting state?

Answer 13

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 enter the liver and produce energy via b-oxidation.
Citrate and acetyl CoA produced from oxidation of fatty acids activate
gluconeogenesis and inhibit glycolysis

Question 14

What happens in the adipose tissue during the early fasting state?

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 TAGS occurs in response to the reduced insulin:glucagon ratio and activation of the sympathetic NS by release of noradrenaline
Some of the 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 peripheral tissues
Glycerol cannot be metabolised and is recycled to the liver to support gluconeogenesis

Question 15

What occurs in the early fasting phase in the muscle?

Answer 15

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 16

What occurs in the early fasting phase in the brain?

Answer 16

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 17

Define metabolism in the late fasting state

Answer 17

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

Question 18

Describe what happens during the late fasting state in the liver

Answer 18

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 (muscle, brain)

Question 19

Describe what happens in the late fasting state in adipose tissues

Answer 19

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 20

Describe the late fasting state in the muscle

Answer 20

Little glucose entry with fall in insulin and switch to fatty acids as the fuel
Fatty acid oxidation 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 in heart and muscle conserving glucose
Protein breakdown (proteolysis) stimulated by noradrenaline and cortisol supply carbon skeletons for net glucose synthesis in the form of alanine
Ketone bodies reduce proteolysis and decrease muscle wasting

Question 21

What is the purpose of the glucose-fatty acid cycle?

Answer 21

Spares glucose during fatty acid oxidation

Question 22

Describe the glucose fatty acid cycle

Answer 22

Mobilisation of fatty acids in response to glucagon or adrenaline increases fatty acid oxidation in peripheral tissues to acetyl CoA

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 23

Describe what happens in the brain during the late fasting state

Answer 23

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 so net glucose synthesis during starvation is essential

Question 24

State the metabolic utilization of glucose in (a) Fed state, (b) Fasted state and (c) Starved state

Answer 24

(a) Glucose provided by diet
(b) Most glucose provided by the breakdown of
liver glycogen, increasing amounts by
gluconeogenesis
(c) Most glucose comes from gluconeogenesis, the
breakdown of protein and fats provide amino acids and
glycerol as substrates

Question 25

What is hormonal control mediated by?

Answer 25

Changes in phosphorylation

Question 26

How are enzymes involved in glycogenolysis and glycogen synthesis controlled?

Answer 26

Allosteric control

Hormonal control

Question 27

List the hormones involved in the hormonal control of glycogenolysis and gluconeogenesis

Answer 27

Glucagon
Adrenaline
Cortisol
Insulin

Question 28

When are glucagon and epinephrine (adrenaline) released?

Answer 28

The hormones glucagon and epinephrine (adrenaline) are released in response to low blood glucose, thus releasing glucose from glycogen in the liver to increase blood glucose
Epinephrine is also part of the “fight or flight” response; levels rise greatly during exercise when metabolic demands of muscle are high and glycogen breakdown is required to support muscle contraction
Prepares the muscle for strenuous activity

Question 29

How is glycogen metabolism controlled by adrenaline?

Answer 29

Adrenaline stimulates glycogenolysis in muscle via b-adrenergic receptors and cAMP formation, but in liver uses a1-adrenergic receptors and Ca2+ and diacylglycerol as second messengers

Question 30

Describe the regulation of glycogen metabolism

Answer 30

Occurs via both allosteric and covalent modification (phosphorylation) of the enzymes

During exercise glycogen breakdown is stimulated to provide energy for muscle contraction while glycogen synthesis is inhibited

Epinephrine (Adrenaline) stimulates breakdown and inhibits synthesis in skeletal muscle to prepare the body for physical work

In liver glycogen breakdown is stimulated by epinephrine and glucagon, whereas glycogen synthesis is inhibited in order to elevate blood glucose.

Insulin stimulates glycogen synthesis in response to feeding and a high blood glucose, whereas it simultaneously switches off glycogen breakdown in both liver and muscle.