Glycogenolysis, gluconeogenesis and the cori cycle

Question 1

How is glucose stored?

Answer 1

As glycogen

Question 2

Why is glucose stored as glycogen?

Answer 2

Reduces osmotic potential

Avoids glycosylation of proteins as occurs in diabetes

Question 3

Describe the structure of glycogen

Answer 3

Polymer of glucose joined at a1-4 except at branch points approx. every 10 units where it is joined a1-6

Question 4

How does the size of glycogen molecules vary throughout the day?

Answer 4

approx. 10nm between meals

> 40nm after feeding

Question 5

What form does glycogen take in cells?

Answer 5

Granules

Each granule consists of several glycogen molecules

Question 6

How does the ATP and citrate produced in the citric acid cycle effect glucose?

Answer 6

ATP and citrate inhibit glycolysis

Prevents breakdown of glucose and allows gluconeogenesis

Question 7

How much glycogen is there in liver and muscle

Answer 7

Liver = 70g

Muscle = 200g

Question 8

Why is UTP used in the synthesis of glycogen?

Answer 8

Glucose-1P is not powerful enough a glucose donor to form a gluc-gluc bond

Requires energy input from UTP

UTPG is powerful enough to glycosylate glycogen

Question 9

How does UTP interact with G-1P to provide energy?

Answer 9

G1P + UTP → UDPG + PPi

PPi + H2O → Pi + Pi

Question 10

What is glycogen metabolism controlled by?

Answer 10

Hormonal and neuronal stimulation

Question 11

What is the role of adrenaline in metabolism?

Answer 11

Stimulates glycogen metabolism via the second messenger model to increase glycogen phosphorylase

Question 12

What regulates glycogen breakdown?

Answer 12

Adrenaline via the second messenger model

5’AMP allosterically stimulates the less active phosphorylase b.
-ATP opposes this

In muscle Ca2+ also activates phosphorylase kinase
-Turns on phosphorylase

In the liver glucagon has more of an effect
-Released by pancreas α cells

Question 13

How is the signal to breakdown glycogen turned off?

Answer 13

cAMP is hydrolysed to 5’AMP by a specific phosphodiesterase

Protein phosphatases remove phosphates from proteins

Insulin acts through glycogen synthase kinase 3 (GSK3), which is inhibited, to turn on glycogen synthase

Question 14

Give 2 examples of where dephosphorylation occurs in glycogen formation

Answer 14

Glycogen phosphorylase is dephosphorylated

Glucose IN LIVER promotes the dephosphorylation of phosphorylase a

Question 15

What did Clark describe in 1962?

Answer 15

How to make an electrochemical sensor “more intelligent” by adding “enzyme transducers as membrane enclosed sandwiches”.

Question 16

How can glucose be monitored experimentally?

Clark, 1962

Answer 16

Glucose oxidase entrapped at a Clark oxygen electrode using dialysis membrane.

The decrease in measured oxygen concentration was proportional to glucose concentration.

Question 17

How is glucose monitored currently?

What sample size of blood is required for an accurate reading?

Answer 17

Glucose pens

<1 µL

Question 18

What are the 2 fates of lactate in the body?

Answer 18

Oxidation in the Citric acid cycle

Or conversion back to glucose (gluconeogenesis)

Question 19

Why is gluconeogenesis important?

Answer 19

The brain always requires glucose

Some organs in the body have little oxidative capacity e.g. RBCs and fast twitch muscle

Question 20

How many ways are there to synthesise glucose from pyruvate?

Answer 20

3

Question 21

Is PFK2 under hormonal or neuronal control?

Answer 21

Hormonal

Question 22

How does glucagon act in the liver?

Answer 22

Glucagon activates protein kinase A which phosphorylates the bifunctional enzyme so that PFK-2, Fru-2,6-bisPase


The resulting fall in [Fru-2,6-P2], a potent activator of PFK-1 and inhibitor of Fru-1,6-bisPase, favours gluconeogenesis over glycolysis

Question 23

How does glucagon act in cardiac muscle?

Answer 23

hormonal action of adrenaline causes the phosphorylation of PFK-2 on DIFFERENT residues INCREASING its rate, Fru-2,6-bisP increases and glycolysis increases

No substrate cycling possible because no Fru-1,6-bisPase

Question 24

How does glucagon act in skeletal muscle?

Answer 24

PFK-2 isoform is not phosphorylated, it just responds to changes in [Fru-6-P]. Fru-2,6-bisP reinforces effects of AMP

Question 25

Why Fru-2,6-bisP activator system work differently in muscle and liver?

Answer 25

In muscles:

There is no gluconeogenesis

There are different isoenzymes of the
bifunctional PFK-2/Fru-2,6-bisPase

Question 26

What is the Cori cycle?

Answer 26

The interplay between anaerobic glycolysis in muscle tissue and gluconeogenesis in liver tissue

Question 27

Describe the events of the cori cycle

Answer 27

Muscle uses glucose and forms lactate in explosive glycolysis

This lactate is converted back to glucose in the liver via gluconeogenesis as it still contains a large amount of potential energy

The glucose is transported back to the muscle where it is stored as glycogen for metabolism during explosive activity again.

Question 28

How does the brain receive sufficient energy during periods of starvation?

Answer 28

Ketone bodies

Proteins converted into glucose via amino acids and the krebs cycle (gluconeogenesis)

Question 29

What substrates are used in gluconeogenesis?

Answer 29

Lactate (via pyruvate)

Pyruvate

Oxaloacetate

Glycerol (via glycerol-P) (glycerol kinase only found in liver, not in adipose tissue)

Alanine (via pyruvate)

Question 30

How is gluconeogenesis related to type 2 diabetes?

Answer 30

Excess of lactate, alanine and glycerol produced by adipose tissue and skeletal muscle. These all serve as substrates for gluconeogenesis, with the energy required for ATP coming from β-oxidation of fatty acids.

Under normal circumstances gluconeogenesis is controlled by the expression of PEPCK which is negatively regulated by insulin. This is lost in type 2 diabetes, causing expression of PEPCK to rise and increased production of glucose adding to hyperglycaemia.

Question 31

What is the first line of treatment for type 2 diabetes?

Answer 31

Metformin - suppresses liver gluconeogenesis