4. Energy storage (glycogen)

Question 1

Describe the major energy stores in a healthy 70kg man. How is this different in an obese 135kg man?

Answer 1

70kg man

1) triaglycerols: 15kg
2) muscle protein: 6kg
3) glycogen: 0.4kg

135kg man

1) triaglycerols: 80kg
2) muscle protein: 6kg
3) glycogen: 0.4kg
i. e. extra weight stored solely as TAGs!

Question 2

Why are stable blood glucose levels essential?

Answer 2

Glucose = preferred fuel

1. Some tissues have absolute requirement for glucose as energy source: erythrocytes, neutrophils, innermost cells of kidney medulla and lens of eye
2. Essential for normal brain function.

Question 3

What is the normal stable serum [glucose]?

Answer 3

~5mM

Question 4

What are the consequences of different levels of hypoglycaemia?

Answer 4

Blood glucose

2. 8mmol/L - confusion
3. 7mmol/L - weakness, nausea
4. 1mmol/L - muscle cramps
5. 6mmol/L - brain damage, death

Question 5

How is excess glucose stored?

Answer 5

as glycogen

Question 6

How is a continuous supply of glucose provided to cells despite intermittent availability from diet?

Answer 6

1. Storage of glucose as glycogen when it is available following a meal and releasing it between meals via GLYCOGENOLYSIS.
2. If depletion of stored glycogen (8-12hrs after meal), glucose synthesis via GLUCOGENESIS (using lactate, glycerol or amino acids).

Question 7

What are the 2 main stores of glycogen? What is each store used for?

Answer 7

Glycogen stored as granules in:

• muscle (specific glucose store for muscle activity)
• liver (to replenish plasma glucose levels)

Question 8

Describe the structure of glycogen.

Answer 8

• Branching polymer of glucose residue chains originating from a dimer of the glycogenin protein (acts as primer at core of glycogen structure).
• Glucose residues linked by alpha-1-4 glycosidic bonds.
• Branch points formed by alpha-1-6 glycosidic bonds every 8-10 residues.

Question 9

What are the benefits and disadvantages of glycogen as an energy store?

Answer 9

Benefits:

i) branched structure provides many sites for enzyme activity for addition/removal of glucose residues - rapid synthesis and degradation.
ii) large size reduces osmotic effect in storage tissue.

Disadvantages:

i) highly polar molecule that attracts much water - limit to amount that can be stored
ii) no specialised storage tissue

Question 10

Which body tissue stores the most glycogen?

Answer 10

1. muscle (300g)

2. liver (100g)

Question 11

In which form is glucose added to glycogen? How is glucose converted to this stage?

Answer 11

As UDP-glucose - reactions require energy (ATP and UTP)

1) glucose + ATP –> glucose-6-P + ADP
(hexokinase or glucokinase in liver)

2) glucose-6-P glucose-1-P
(phosphoglucomutase)

3) glucose-1-P + UTP + H2O –> UDP-glucose + PPi
(G1P uridyltransferase)

Question 12

How is UDP-glucose added to glycogen?

Answer 12

glycogen(n residues) + UDP-glucose –> glycogen(n + 1residues) + UDP

Via enzymes:

• glycogen synthase (for alpha-1-4 glycosidic bonds)
• branching enzyme (for alpha-1-6 glycosidic bonds)

Question 13

Why is UDP-glucose an important intermediate?

Answer 13

Highly activated form of glucose, important intermediate in synthesis of many sugar-containing molecules (e.g. lactose and glycogen) and in interconversion of glucose and galactose.

Question 14

When is glycogenolysis stimulated?

Answer 14

• exercise (in skeletal muscle)

- fasting or stress response (in liver) - released in blood for use by other tissues

Question 15

How is glucose-1-P and free glucose released from glycogen?

Answer 15

glycogen (n residues) + Pi –> glucose-1-P + glycogen(n-1)

Catalysed by glycogen phosphorylase: phosphorolysis rather than hydrolysis of alpha1-4 bonds releases G1P rather than free glucose.

De-branching enzyme catalyses alpha1-6 bonds: releases free glucose.

Question 16

Why can liver glycogen be used to produce glucose for use throughout the body but nor muscle glycogen?

Answer 16

1. Glucose-1-P glucose-6-P by phosphoglucomutase.
2. • In muscle cells (don’t contain glucose-6-phosphatase): glucose-6-P enters glycolysis - provides energy for exercising muscle but can only be used here.

• In liver: glucose-6-P + H2O –> glucose + Pi by glucose-6-phosphatase.
  Glucose released into bloodstream for use by all body tissues.

Question 17

Which enzymes are regulated to control glycogen metabolism?

Answer 17

enzymes catalysing irreversible reactions:

• glycogen synthase (glycogenesis)
• glycogen phosphorylase (glycolysis)

Question 18

Which 2 main mechanisms allow regulation of glycogen synthase and glycogen phosphorylase to control glycogen metabolism?

Answer 18

1. allosteric control (AMP activates muscle phosphorylase)
2. covalent modification (reversible phosphorylation) in response to changes in hormone levels - synthase is inhibited by phosphorylation, phosphorylase is activated by phosphorylation

Question 19

Which hormones regulation glycogen metabolism?

Answer 19

1. glucagon (and adrenaline) = hormone of starvation
   - phosphorylate/inhibit glycogen synthase
   - phosphorylate/activate glycogen phosphorylase
2. insulin = hormone of plenty
   - de-phosphorylate/activate glycogen synthase
   - de-phosphorylate/inhibit glycogen phosphorylase

Question 20

How is the regulation of muscle and liver glycogen metabolism different?

Answer 20

• glucagon has no effect on muscle glycogen stores (as can’t be released into blood anyway)
• AMP = allosteric activator (low energy signal) of muscle glycogen phosphorylase but not in liver

Question 21

What are glycogen storage diseases and what are their major features?

Answer 21

• Inherited disorders involving deficiency in enzymes of glycogen metabolism.
• 11 types, relatively rare, severity depends on enzymes/tissues affected.
• Major features:
  1. increased or decreased amounts of glycogen which can cause
  i) tissue damage if excessive storage
  ii) fasting hypoglycaemia (low blood glucose)
  iii) poor exercise tolerance
  2. glycogen structure may be abnormal
  3. usually liver and/or muscle are affected

Question 22

Give 2 examples of glycogen storage diseases and a clinical feature of each.

Answer 22

1. von Gierke’s disease
   - glucose-6-phosphatase deficiency
   - hepatomegaly as can’t release glycogen as glucose
2. McArdle disease
   - muscle glycogen phosphorylase deficiency
   - rapid exhaustion

Question 23

Where does gluconeogenesis occur?

Answer 23

liver and to lesser extent in kidney cortex

Question 24

Name the possible substrates for glucogenogenesis.

Answer 24

• pyruvate, lactate (converted to pyruvate) and glycerol (converted to DHAP)
• essential and non-essential glucogenic amino acids whose metabolism involves pyruvate or intermediates of the TCA cycle

Question 25

Why can acetyl-CoA not be converted to glucose?

Answer 25

reaction catalysed by pyruvate is irreversible

Question 26

Which 3 key enzymes are used in gluconeogenesis to bypass irreversible reactions of the corresponding glycolysis steps?

Answer 26

1. PEPCK (converts oxaloacetate (converted from pyruvate by pyruvate carboxylase) to phosphoenolpyruvate)
2. Fructose 1,6-bisphosphatase (converts fructose 1,6-bis phosphate to fructose 6-phosphate)
3. Glucose-6-phosphatase (converts glucose-6-phosphate to glucose)

Question 27

Which enzymatic reactions link the TCA cycle to gluconeogensis?

Answer 27

1. pyruvate to oxaloacetate by pyruvate carboxylase (requires ATP)
2. oxaloacetate to phosphoenolpyruvate by PEPCK (requires GTP)

enables products of amino acid catabolism that are intermediates of the TCA cycle to be used for glucose synthesis

Question 28

Which situations promote gluconeogenesis and how is this regulated?

Answer 28

2 key enzymes (fructose 1,6-bisphosphatase and PEPCK) regulated by hormones (glucagon/cortisol and insulin) in response to:

• starvation/fasting
• prolonged exercise
• stress

Question 29

What are the effects of glucagon (and cortisol) and insulin on gluconeogenesis?

Answer 29

1. Glucagon/cortisol stimulates gluconeogenesis
   - increases amount of PEPCK
   - increases amount and activity of fructose 1,6-bisphosphatase
2. Insulin inhibits gluconeogenesis
   - decreases amount of PEPCK
   - decreases amount and activity of fructose 1,6-bisphosphatase

Question 30

What is the impact of diabetes on gluconeogenesis?

Answer 30

Diabetes = absence of adequate insulin levels… increases rate of gluconeogenesis… hyperglycaemia.