Glycogenolysis, gluconeogenesis and the cori cycle Flashcards
How is glucose stored?
As glycogen
Why is glucose stored as glycogen?
Reduces osmotic potential
Avoids glycosylation of proteins as occurs in diabetes
Describe the structure of glycogen
Polymer of glucose joined at a1-4 except at branch points approx. every 10 units where it is joined a1-6
How does the size of glycogen molecules vary throughout the day?
approx. 10nm between meals
> 40nm after feeding
What form does glycogen take in cells?
Granules
Each granule consists of several glycogen molecules
How does the ATP and citrate produced in the citric acid cycle effect glucose?
ATP and citrate inhibit glycolysis
Prevents breakdown of glucose and allows gluconeogenesis
How much glycogen is there in liver and muscle
Liver = 70g
Muscle = 200g
Why is UTP used in the synthesis of glycogen?
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
How does UTP interact with G-1P to provide energy?
G1P + UTP → UDPG + PPi
PPi + H2O → Pi + Pi
What is glycogen metabolism controlled by?
Hormonal and neuronal stimulation
What is the role of adrenaline in metabolism?
Stimulates glycogen metabolism via the second messenger model to increase glycogen phosphorylase
What regulates glycogen breakdown?
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
How is the signal to breakdown glycogen turned off?
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
Give 2 examples of where dephosphorylation occurs in glycogen formation
Glycogen phosphorylase is dephosphorylated
Glucose IN LIVER promotes the dephosphorylation of phosphorylase a
What did Clark describe in 1962?
How to make an electrochemical sensor “more intelligent” by adding “enzyme transducers as membrane enclosed sandwiches”.
How can glucose be monitored experimentally?
Clark, 1962
Glucose oxidase entrapped at a Clark oxygen electrode using dialysis membrane.
The decrease in measured oxygen concentration was proportional to glucose concentration.
How is glucose monitored currently?
What sample size of blood is required for an accurate reading?
Glucose pens
<1 µL
What are the 2 fates of lactate in the body?
Oxidation in the Citric acid cycle
Or conversion back to glucose (gluconeogenesis)
Why is gluconeogenesis important?
The brain always requires glucose
Some organs in the body have little oxidative capacity e.g. RBCs and fast twitch muscle
How many ways are there to synthesise glucose from pyruvate?
3
Is PFK2 under hormonal or neuronal control?
Hormonal
How does glucagon act in the liver?
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
How does glucagon act in cardiac muscle?
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
How does glucagon act in skeletal muscle?
PFK-2 isoform is not phosphorylated, it just responds to changes in [Fru-6-P]. Fru-2,6-bisP reinforces effects of AMP
Why Fru-2,6-bisP activator system work differently in muscle and liver?
In muscles:
There is no gluconeogenesis
There are different isoenzymes of the
bifunctional PFK-2/Fru-2,6-bisPase
What is the Cori cycle?
The interplay between anaerobic glycolysis in muscle tissue and gluconeogenesis in liver tissue
Describe the events of the cori cycle
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.
How does the brain receive sufficient energy during periods of starvation?
Ketone bodies
Proteins converted into glucose via amino acids and the krebs cycle (gluconeogenesis)
What substrates are used in gluconeogenesis?
Lactate (via pyruvate)
Pyruvate
Oxaloacetate
Glycerol (via glycerol-P) (glycerol kinase only found in liver, not in adipose tissue)
Alanine (via pyruvate)
How is gluconeogenesis related to type 2 diabetes?
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.
What is the first line of treatment for type 2 diabetes?
Metformin - suppresses liver gluconeogenesis
