L7 - The Liver and Gluconeogenesis

Question 1

Glucose the Almighty Fuel Source!

Answer 1

Glucose is the preferred fuel source of all tissues.

Some tissues have a continuous dependence on glucose - brain and RBCs. RBCs lack mito and brain has BBB so can’t use FAs as fuel.

Question 2

Blood Glucose concentrations:

(Average amongst men! and Physiological range)

Consequences of less than 2.5mM and more than 6.2mM:

Answer 2

Average: 4.5-5.0mM
Physiological Range: 3.9-6.2mM

If < 2.5mM, this can lead to coma and death.
If > 6.2mM, dehydration is seen –> wasting of body tissue and death. (Get breakdown of proteins instead of glucose).

Question 3

Explain why glucose is an important metabolic fuel i.e. the role of glucose:

Answer 3

1) It can be oxidised to provide energy
Glucose –> Pyruvate 2 ATP
Glucose –> CO2 and H2O 31 ATP

2) It is a source of NADPH via pentose phosphate pathway
NADPH is needed for FA and steroid synthesis and drug metabolism. It is also needed to maintain RBC membrane integrity as a lack of this leads to haemolytic anaemia.

3) It is a source of pentose sugars - synthesis of nucleotides and DNA
4) It is a source of carbon for other sugars and glycoconjugates e.g. galactose, glucuronic acid and mannose.

Question 4

Advantages of glucose as a metabolic fuel:

Answer 4

1) Water soluble - doesn’t need a carrier
2) Pass through BBB
3) Can be oxidised anaerobically to produce ATP

Question 5

Disadvantages of glucose as a metabolic fuel:

Answer 5

1) Osmotically Active
2) Low yield of ATP
3) High concentrations can lead to tissue damage and accumulation of toxic by products (sorbitol - cataracts)

Question 6

Role of Glucose in Skeletal Muscles: i.e. glucose pathways in muscles

Answer 6

Glycolysis: - provides energy for contraction (aerobic and anaerobic)

Glycogen synthesis and degradation: - breaks down glycogen to glucose to provide energy for muscle contraction (SELFISH ORGAN)

Question 7

Role of Glucose in Heart/Brain: i.e. glucose pathways in heart/brain

Answer 7

Glycolysis/TCA/OXPHOS: - produces energy (in fed and unfed state)

Question 8

Role of Glucose in Adipose Tissue: i.e. glucose pathways in adipose

Answer 8

Glycolysis: glucose –> glyceraldehyde-3-phosphate –> glycerol-3-phosphate –> glycerol
Glycerol is used to re-esterify FAs to produce TAG (stored) - FED state

Question 9

Role of Glucose in RBC: i.e. glucose pathways in RBC

Answer 9

Glycolysis: glucose –> pyruvate –> lactate
This produces energy in FED and UNFED state.

Pentose Phosphate pathway: Synthesises NADPH to maintain integrity

Question 10

Role of Glucose in Liver: i.e. glucose pathways in Liver

Answer 10

Glycolysis: Glucose –> Acetyl CoA –> FA synthesis

Glycogen synthesis and breakdown: Glucose storage for other tissues.

Gluconeogenesis: Provide glucose for other tissues

Pentose phosphate pathway: Synthesise NADPH and pentoses (FA synthesis).

LIVER ONLY DOES GLYCOLYSIS TO PRODUCE FAs FOR ADIPOSE STORAGE - When you have excess glucose and glycogen, TAG storage occurs. It doesn’t do glycolysis for energy.

Question 11

Blood glucose, insulin and glucagon levels in OGTT:

Answer 11

Give glucose –> BGLs increase but return to fasting levels after 2hrs. Insulin levels follow a similar pattern (less changes in concentration - μM rather than mM).

Glucagon tends to be fairly constant - doesn’t follow the above pattern.

Question 12

Sources of glucose:

Where do the sources of glucose come from in starvation?

Answer 12

1) Dietary Sources
2) Liver Glycogen
3) Gluconeogenesis

In starvation, glycogen stores are initially used (lasts for 24hrs). Gluconeogenesis still occurs due to RBCs producing lactate so still get small amounts of glucose from this.

Question 13

What is gluconeogenesis and when does it occur?

Which substances can be used for this process?

Answer 13

Gluconeogenesis occurs in the fasting state (in carb deprivation), where non-carbohydrates are used to synthesise glucose in liver.

E.g. Lactate, glucogenic a.a, other monosaccharides, Glycerol, NOT FATTY ACIDS (as pyruvate –> acetyl CoA is irreversible)!

Question 14

Why is gluconeogenesis not a reversal of glycolysis?

Answer 14

This is not a reversal of glycolysis as glycolysis has three irreversible reactions which have to be bypassed. These reactions are catalysed by:

1) Glucokinase/Hexokinase
2) PFK
3) Pyruvate Kinase

Question 15

Bypassing of irreversible steps in gluconeogenesis:

Answer 15

1) Glucose-6-phosphate –> Glucose
This is done by removing Pi using Glucose-6-phosphatase.

2) Fructose-1,6-Bisphosphate –> Fructose-6-phosphate
This is done by removing Pi using Fructose-1,6-bisphosphatase.

3) Pyruvate –> Oxaloacetate –> PEP
This involves pyruvate carboxylase and PEP carboxykinase (PEPCK).
The former involves ATP hydrolysis (to ADP + Pi) and the latter is GTP hydrolysis (no Pi produced; only GDP).

Question 16

Regulation of Gluconeogenesis:

Answer 16

1) Depends on substrate availability: If have high levels of a.a and glycerol, this induces gluconeogenesis.

2) Regulating enzyme activity
- PEPCK, G-6-Pase and F-1,6-Pase are inhibited by insulin
- Pyruvate carboxylase is stimulated by acetyl CoA (product of β oxidation)

Question 17

Cori Cycle and Glucose-alanine Cycle

Answer 17

These involve cycling of nutrients between liver and muscles.

Lactate is produced due to anaerobic metabolism. This enters bloodstream and goes to liver where it is converted back to glucose and given back to muscle (to be converted back to lactate again) - CORI CYCLE.

Alanine from muscle can undergo transamination in liver and becomes pyruvate. This is then converted back to glucose and then given to muscles again - GLUCOSE-ALANINE CYCLE.

Question 18

Hormonal Control of BGLs and why is it necessary:

Answer 18

Insulin, glucagon, adrenaline and to some extent cortisol and glucose, can regulate BGLs by regulating the activity of liver, muscle and adipose.

Physiological BGLs have to be maintained to maintain brain function.

Question 19

Structure of Pancreas:

Answer 19

98% - exocrine (secretes digestive enzymes in duct)
2% - endocrine

α cells - glucagon
β cells - insulin

Question 20

Insulin Vs. Glucagon:

Answer 20

Insulin - anabolic hormone. Reduces BGLs by increasing its storage.

Glucagon - catabolic hormone. Increases BGLs by promoting breakdown of glycogen.

Question 21

Metabolic Effects of Insulin:

In Liver:

In Muscle:

Answer 21

IN LIVER:

• Stimulates glycogen synthesis by activating glycogen synthase
• increases a.a. uptake and protein synthesis
• stimulates FA synthesis and storage via lipoprotein lipase
• inhibits gluconeogenesis

IN MUSCLE:

• Increases glucose uptake by increasing GLUT4 uptake
• Increases glycogen synthesis
• Increases a.a. uptake and protein synthesis

Question 22

Metabolic Effects of Glucagon:

Answer 22

• Stimulates glycogen breakdown
• stimulates gluconeogenesis
• increases β-oxidation and increases TAG breakdown via hormone sensitive lipase (increases plasma FFA)
• increases ketone body formation (increases plasma ketone bodies)
• increases uptake of a.a in liver and does gluconeogensis (reduces plasma a.a)

Question 23

Ketone Bodies:

What happens if levels are too high?
Functions of ketone bodies:

Answer 23

If too high, it leads to ketoacidosis.

Ketone bodies can act on β-cells to cause insulin secretion.
This can also be used as fuel by brain in starvation.

Question 24

Liver in Fed and Fasted State:

Answer 24

FED:

• glucose is converted to glycogen
• excess glucose undergoes glycolysis to produce pyruvate –> acetyl CoA –> FA synthesis –> TAG (taken to adipose via VLDL)

FASTED:

• Glycogen is broken down to glucose –> released into bloodstream
• gluconeogenesis occurs (uses a.a, lactate, glycerol)
• β-oxidation causes FA –> acetyl CoA (stimulates pyruvate carboxylase)

Question 25

Muscles in Fed state and in aerobic exercise:

Answer 25

FED:
- Glucose is converted to glycogen

AEROBIC EXERCISE:
- Glycogen is converted to G-6-P and used as fuel (enters glycolysis –> TCA –> OXPHOS –> ATP synthesis)

Question 26

Brain in Fed and Fasted State:

Answer 26

FED AND FASTED:

Glucose enters glycolysis –> TCA –> OXPHOS –> ATP synthesis

Question 27

RBCs in Fed and Fasted State:

Answer 27

FED AND FASTED:
Glucose enters glycolysis – ATP synthesis –> Pyruvate –> Lactate.

Lactate enters blood and is converted back to glucose in liver via gluconeogenesis.