Lecture 3 Regulation of glucose homeostasis 1

Question 1

How does the body achieve glucose homeostasis?

Answer 1

Regulation of glycolysis/gluconeogenesis.

Glycogen metabolism.

Question 2

What are 2 intracellular control mechanisms for the regulation of glucose homeostasis?

Answer 2

Allosteric regulation.

Covalent modification.

Question 3

What is the intercellular control mechanism for the regulation of glucose homeostasis?

Answer 3

Hormonal control (insulin, adrenaline, glucagon)

Question 4

What is the overall equation for glycolysis?

Answer 4

Glucose + 2NAD+ + 2ADP + 2Pi&raquo_space;»» 2Pyruvate + 2NADH + 2H+ + 2ATP

Question 5

When will glycolysis occur in regard to these concentrations? 
[ATP]
[ADP]
[AMP]
[NADH] to [NAD+] ratio.

Answer 5

Glycolysis occurs when the cell needs energy therefore it will occur when;
[ATP] is low
[ADP] is high (up to 5-fold)
[AMP] is relatively high (up to 20-fold)
[NADH] to [NAD+] ratio is low.

Question 6

What is the overall equation for gluconeogenesis?

Answer 6

2Pyruvate + 4ATP + 2GTP + 2NADH + 2H+ + 4H2O&raquo_space;»»> Glucose + 4ADP + 2GDP + 6Pi + 2NAD+

Question 7

When will gluconeogenesis occur in regard to these concentrations? 
[ATP]
[ADP]
[AMP]
[NADH] to [NAD+] ratio.

Answer 7

Gluconeogenesis occurs when the cell has a good supply of energy. Therefore it will occur when;
[ATP] is high
[ADP] is low
[AMP] is low
[NADH] to [NAD+] ratio is high

Question 8

3 of the glycolytic enzymes are exergonic. What implication does this have and what effect does it have on the idea that GNG is just the reverse of glycolysis?

Answer 8

Because they are exergonic they will be irreversible. This meas that in order for the same step to be reversed it will need a different enzyme or series of enzymes. This means that GNG is not just a reversal of glycolysis.

Question 9

What is meant by the ‘futile cycle’ with regards to GNG and glycolysis?

Answer 9

It means that without regulation, the processes could take place simultaneously. As there is an overall loss of ATP between the 2 cycles this would consume ATP without any work being done.

Question 10

What steps in glycolysis are the futile cycles?

Answer 10

Glucose to G-6-P by hexokinase
F-6-P to F-1,6-BP by PFK1
PEP to pyruvate by pyruvate kinase

Question 11

What enzymes in GNG are used to perform the reverse of the futile cycles?

Answer 11

G-6-P to glucose by G-6-Pase
F-1,6-P to F-6-P by F-1,6-BPase
Pyruvate to oxaloacetate by pyruvate carboxylase then to PEP by PEP carboxylase.

Question 12

How many isoenzymes does hexokinase have?

Answer 12

4

Question 13

Where are the different hexokinases found?

Answer 13

1 and 2 in the muscle

4 in the liver

Question 14

What is the Km of hexokinse IV relative to the othe hexokinases, what purpose does this serve?

Answer 14

HKIV is only expressed in the liver. Its high Km means that it is responsive to higher glucose concentrations. This means that glucose will only be broken down in the liver when there is an abundance of glucose. This allows the glucose to be preferentially broken down in other more critical tissues in times of low glucose concentrations.

Question 15

Is HKIV inhibited by its product, G-6-P? What effect does this have?

Answer 15

It is not inhibited by G-6-P, this allows it to continually produce G-6-P at high concentrations when there is an abundance of glucose.

Question 16

What happens to HKIV when glucose levels are low.

Answer 16

It is sequestered in the nucleus.

Question 17

What step is the ‘commitment step’ in glycolysis?

Answer 17

F-6-P to F-1,6-P by PFK1.

Question 18

What are the negative effectors of the second futile cycle?

Answer 18

ATP

Citrate

Question 19

What are the positive effectors of the second futile cycle?

Answer 19

AMP, ADP

F-2,6-BP

Question 20

How does the ratio of ATP to AMP allosterically regulate the effects of PFK1?

Answer 20

When ATP is high, it inhibits PFK1
When AMP is high it activates PFK1
Therefore in times of high energy glycolysis is inhibited and when there is low energy glycolysis is activated.

Question 21

What inhibits FBPase1?

Answer 21

AMP, therefore GNG will be inhibited under conditions of low energy.

Question 22

Apart from ATP, ADP, and AMP What else regulates PFK1, what effect does it have?

Answer 22

Citrate regulates PFK1 by inhibiting it. Citrate is produced in the CAC. High levels of it indicate that there is high energy and thus glycolysis is inhibited.

Question 23

What 2 hormones are the most vital in glucose homeostasis?

Answer 23

Insulin and Glucagon.

Question 24

What is the role of glucagon?

Answer 24

It indicates when blood glucose is low. It prompts the production or release of glucose. (Glycogenolysis/gluconeogenesis)
It stops the liver consuming for its own needs.

Question 25

What is the role of insulin?

Answer 25

It indicates when blood glucose is high. It signals to the liver to use glucose as a fuel.
Precursor for the synthesis of glycogen and TAGs.

Question 26

What is the role of F-2,6-BP?

Answer 26

It acts as a regulator. It is produced specifically to regulate glycolysis and gluconeogenesis.
It activates PFK1 and therefore glycolysis.
It inhibits FBPase1 therefore inhibiting gluconeogenesis.

Question 27

How does F-2,6-BP activate glycolysis?

Answer 27

It increases the affinity of PFK1 for F-6-P therefore making the reaction go forward more easily.

Question 28

How does F-2,6-BP inhibit GNG?

Answer 28

It reduces the affinity of FBPase1 for F-1,6-BP.

Question 29

How is F-2,6-BP pruduced?

Answer 29

It is produced from F-6-P by PFK2.

It is converted back by FBPase2.

Question 30

What effect does insulin and glucagon have on PFK2/FBPase2? How does this regulate glucose homeostasis?

Answer 30

Insulin responds to high blood sugar by activating the PFK2 part of the enzyme. This is done through dephosphorylation. Once PFK2 is active this creates more F-2,6-BP which goes onto increase the affinity of PFK1 for F-6-P which promotes glycolysis and inhibits GNG.

Glucagon responds to low blood glucose and activates the FBPase2 part of the enzyme by phosphorylating it. The FBPase2 lowers the level of F-2,6-BP. This inhibits glycolysis and stimulates GNG.

Question 31

What is the role of pyruvate kinase?

Answer 31

It catalyses the final step of glycolysis which is the 3rd futile cycle. The reaction is PEP to pyruvate by pyruvatte kinase.

Question 32

What inactivates PK in the liver only?

Answer 32

It is inactivated in the liver in response to signs of glucose depletion (glucagon). This allows glucose from the liver to be exported from the liver to the brain and other vital organs.

Question 33

What activates PK?

Answer 33

It is allosterically activated by F-1,6-BP.

Question 34

What inhibits PK?

Answer 34

It is allosterically inhibited by signs of abundant energy.
ATP
Acetyl-CoA and long-chain FAs
Alanine (enough amino acids)