Glycolysis and Energy Stores

Question 1

Where is glycogen mainly stored?

Answer 1

In muscle and in the liver

Question 2

What are the 2 main energy stores in the body?

Answer 2

• Fats (triacylglycerols)
• Carbohydrate stores (glycogen)

Question 3

What happens to proteins in a state of starvation?

Answer 3

• The proteins are transaminated and deaminated to remove the amino acid groups.
• These amino groups are shuttled away to make urea in the liver.
• The urea is removed in the kidneys and you are left with a form of ketoacid.
• The carbon skeletons of these ketoacids are processed in the liver to make glucose.
• Ketoacids which come from proteins can be broken down by glycolysis or citric acid cycle but many are resynthesized to add to the glucose pool.

Question 4

What happens when the body is so hypoglycaemic that the brain starts to become affected?

Answer 4

• Most other tissues in the body stop using glucose once blood glucose drops below ~3mmol, because the brain has a high glucose requirement for function.
• The brain cannot use free fatty acids for energy because these cannot diffuse across the blood-brain barrier.
• Glucose is taken up across the blood-brain barrier.

Question 5

What is needed to use fats for energy?

Answer 5

• To use fats / derivatives of fats for energy you need lots of mitochondria.
• Mitochondria in neurons are found in the cell body. The long axons have very few mitochondria.
• So, glucose is required for making ATP in axons and axon terminals.

Question 6

What happens during hyperglycaemia?

Answer 6

• The kindey cannot retain glucose which is filtered in the kindey fluid, so the glucose is filtered out in the kidney.
• Once glucose concentration reaches ~10-11mmol in the blood, it saturates the reuptake mechanisms for glucose in the kidney and glucose appears in the urine.

Question 7

How are dietary carbohydrates used as a source of energy?

Answer 7

• They are broken down to glucose and added to the glucose pool, then used to make glycogen.
  
  • Glycogen is stored mainly in muscle and in the liver.
• Glycogen can be broken down by glycogenolysis to form more glucose in times of starvation to maintain the level of glucose in the glucose pool.
• Where there is a surplus of glucose it can be used to make fats.
  
  • This is lipogenesis.

Question 8

What happens during lipogenesis?

Answer 8

Lipogenesis turns glucose into free fatty acids which can be combined with glycerol to form triacylglycerols.

Question 9

What happens to dietary fats?

Answer 9

• These are broken down in the intestine to free fatty acids and glycerol.
• These can be recombined to form fat stores.
  
  • Fat synthesis mainly takes place in the adipose tissue.
• OR the fats and glycerols can be directly oxidised and metabolised in most tissues.

Question 10

Which nutrient pool is the most tightly controlled?

Answer 10

The glucose pool

Question 11

What happens post-prandially to the glucose?

Answer 11

• ~95+% of glucose absorbed after a meal travels to the liver in the hepatic portal system.
  
  • ~35% is metabolised in the liver
  • ~65% continues on, to be distributed to other tissues

Question 12

What are the 2 states of metabolism?

Answer 12

• Fed (absorptive) state
  
  • Shortly after a meal when new nutrients are available.
• Fasted (postabsorptive) state
  
  • Body needs to draw upon its fuel stores.

Question 13

Describe the fed (absorptive) state of metabolism.

Answer 13

• Anabolic
• Nutrient molecules are used to provide energy stores or to provide needs of growth and maintenance of cells and tissues.
• But, these needs mean tht some molecules are used immediately to provide energy.

Question 14

Describe the fasted (postabsorptive) state of metabolism.

Answer 14

• Catabolic
• The body calls on the energy stores and they become depleted.

Question 15

What are the key hormones involved in regulating metabolism?

How are their actions mediated?

Answer 15

• Insulin
• Glucagon
• Adrenaline and noradrenaline
• Actions mediated by activation of intracellular protein kinases and phosphorylation of key regulatory proteins on tyrosine, serine or threonine residues - covalent modifications alter enzyme acivites.

Question 16

What are the functions of the pancreas?

Answer 16

• Most of the pancreas has an exocrine function (digestive enzymes).
• Endocrine cells only make up about 2% of its mass.

Question 17

Describe the groups of cells within the pancreas.

Answer 17

• The pancreas has clusters of cells with a different structure to the other epithelial cells.
  
  • The centre of the clusters = mainly beta cells.
  • Beta cells secrete insulin and amylin.
• On the periphery are alpha cells.
  
  • Alpha cells secrete glucagon.
• Between the beta cell clusters and the alpha cells thee are D cells.

Question 18

Describe the interaction between glucose and beta cells.

Answer 18

Glucose can freely permeate the beta cells and the metabolic rate of the beta cells depends on the concentration of glucose in the cell.

Question 19

How is glucagon release regulated?

Answer 19

• The main regulator of glucagon release is insulin.
• Before insulin can get into the general circulation it has to pass the alpha cells.
• Alha cells have insulin receptors - the insulin binds to these alpha cell receptors and this inhibits the secretion of glucagon.
• So, alpha cells don’t respond directly to alpha cells, but rather via insulin.

Question 20

What controls insulin secretion?

Answer 20

β cells are stimulated to secrete insulin by elevated blood glucose, and by the parasympathetic nervous system.

Question 21

What is the effect of insulin on metabolism?

Answer 21

• Drives the fed state.
• ​Stimulates storage of fuels and anabolism.
  
  1. Stimulates glycogen synthesis in liver and muscle.
  2. Stimulates uptake of glucose into muscle and adipose tissue.
  3. Stimulates glycolysis and hence fatty acid synthesis in the liver.
  4. Stimulates formation of triglycerides in fat tissue.
  5. Stimulates protein synthesis in muscle.

Question 22

What is the effect of glucagon on metabolism.

Answer 22

• α cells of the pancreas are stimulated to secrete glucagon when blood glucose falls during the fasting state.
• The main target is the liver where it:
  
  • Stimulates the release of glucose from glycogen.
  • Stimulates gluconeogenesis but inhibits glucose incorporation into glycogen.

Question 23

What determines whether metabolism is in the fed or fasting state?

Answer 23

• It is the balance between circulating levels of insulin and glucagon that determine whether metabolism is in the fed or fasting state.
• In the fed state, insulin dominates:
  
  • ​Increased glucose oxidation
  • Increased glycogen synthesis
  • Increased fat synthesis
  • Increased protein synthesis
• In the fasting state, glucagon dominates:
  
  • ​Increased glycogenolysis
  • Increased gluconeogenesis
  • Increased ketogenesis

Question 24

What hormonal regulation occurs when blood glucose falls?

Answer 24

• Adrenaline and noradrenaline (amines) are secreted by the adrenal medulla and neurones of the synmpathetic nervous system when blood glucose falls.
• Like glucagon they drive breakdown of glycogen and triglycerides.
• Unlike glucagon, their glycogenolytic action is mainly on muscle (producing glucose-6-P) rather than on the liver.
• The amines lower glucose uptale by muscle, so that fatty acids released by adipose tissue are used as fuel.
• The amines also increase glucagon secretion and inhibit insulin secretion.

Question 25

What happens to the glucose which is stored in muscle?

Answer 25

• Muscle cannot release glucose in the blood, only the liver can because the enzyme that converts the glucose-6-phosphate to glucose is absent in muscle.
• Once glucose is in a muscle it can only be used by that muscle - it is locked in.

Question 26

What is the normal blood glucose range, and what constitutes hyper- and hypo-glycaemia?

Answer 26

• Blood glucose normally ranges between 80mg/100ml before a meal to about 120mg/100ml after a meal.
  
  • Normal blood gucose = 4-8mmol/L
• Hypoglycaemia = <3mmol/L
• Hyperglycaemia = >11mmol/L

Question 27

What regulates blood glucose levels?

Answer 27

• The liver is key to regulation of blood glucose within sch narrow limits.
• It can buffer changes because it can take up and release large amounts of glucose.
• Because secretion of insulin and glucagon are themselves controlled by blood glucose, and because they have opposite actions on the enzymes that promote glycogen synthesis and breakdown, their relative concentrations are key to keeping blood glucose within their narrow limits.

Question 28

What is the approximate total store of energy in the body and how long would these last in starvation?

Answer 28

• Total stores = ~162000kcal
• Therefore, fuel stores are sufficient for about 1-3 months of starvation, depending on level of physical activity.

Question 29

What results from the breakdown of fatty acids for use as energy?

Answer 29

• Under conditions when other fuels are not available, breakdown of fatty acids leads to the formation of chemicals known as ketone bodies.
• These ketone bodies are mainly:
  
  • Acetoacetate
  • 3-hydroxybutyrate
  • Acetone

Question 30

Why are ketone bodies made when the body uses fat to produce energy?

Answer 30

• Ketone bodies are made because acetyl-CoA formed in the breakdown of fatty acids cannot enter the cirtic acid cycle since oxaloacetate becomes depleted because the liver converts it to pyruvate to produce glucose (gluconeogenesis).
• Acetly-CoA, therefore, is converted to ketone bodies.
• Ketone bodies smell fruity, so they can often be smelled on the breath of people who have been fasting for some time.

Question 31

What are ketone bodies?

Answer 31

• Metabolic products that are produced in excess during excessive breakdown of fatty acids.
• Acetoacetate, acetone and β-hydroxybutyrate are collectively known as ketone bodies (acetone bodies).

Question 32

Describe the structure of the various ketone bodies.

Answer 32

1. Acetone
2. Acetoacetate
3. β-hydroxybutyric acid

• Only acetone and acetoacetate are true ketones.
• β-hydroxybutyric acid does not possess a keto (C=O) group.
• Ketone bodies are water-soluble and energy yielding.
• Normal concentration of ketone bodies in the blood = ~3mg/100ml

Question 33

What happens to the ketone body concentration during starvation and during ketoacidosis?

Answer 33

• Starvation for ~3 days can cause ketone body concentration to increase to 3-5mmol.
• During ketoacidosis, ketone body concentration can increase to 15-20mmol.
  
  • At this point the urine is pure ketone bodies and is saturated.

Question 34

What happens to the concentration of glucose, fatty acids and ketone bodies during prolonged starvation?

Answer 34

• Carbohydrate stores only last a day or less, depending on level of activity, so blood glucose will fall.
• Because the brain is completely dependent on glucose, metabolism must adjust itself to maintain glucose at an adequate level.
• Triglycerides have a limited ability to be converted to glucose.

Question 35

What happens during the first days of starvation?

Answer 35

• Proteins potentially can yield glucose (gluconeogenesis), but these need to be preserved as much as possible.
• Muscle shifts from its use of glucose as a fuel to using fatty acids released from adipose tissue (so sparing glucose for the brain).
• The liver uses fats mobilised from adipose tissue and pyruvate, lactate and alanine (from breakdown of protein) from muscle to make as much glucose as possible for export into the blood (for the brain).

Question 36

What happens during the later stages of starvation?

Answer 36

• After about 3 days large amounts of ketone bodies begin to be formed by the liver (as a consequence of breaking down fatty acids and limitations in the activity of the TCA cycle).
• The brain has gained an ability to use ketone bodies to meet some of its fuel requirements.
• The ability of the brain to use ketone bodies gradually increases over weeks of starvation, so the need for glucose is lowered.
• Because the body uses less glucose, the need for amino acids to fuel gluconeogenesis is also reduces so there is a reduction in the rate at which the muscle is broken down.
• This is extremely important for survival.

Question 37

What happens to the glucose requirement of the brain during the later stage of prolonged starvation?

Answer 37

• Over the first few days of fasting the brain becomes more tolerant of lowered blood glucose and gains the ability to use ketone bodies to meet some of its fuel requirements.
• The ability of the brain to use ketone bodies gradually increases over weeks of starvation, the the need for glucose is lowered.

Question 38

Compare the glucose tolerance following ingestion of glucose of a normal patient to one who has diabetes mellitus.

Answer 38

• The deficiency in insulin or insensitivity of tissues to insulin means that glucose cannot be taken up by cells and so remains in the blood.
• In untreated people with diabetes, blood glucose is always elevated.
• When they ingest glucose, the rise in blood glucose level is higher and longer than in a non-diabetic individual.

Question 39

Describe the metabolism of a diabetes patient.

Answer 39

• The situation is aggravated because blood glucagon levels are higher than normal.
• Because tissues are not influenced by insulin, metabolism is largely similar to that seen during prolonged fasting.
• Despite high blood glucose levels (which cannot be used - famine amid plenty):
  
  • Glycolysis is slowed.
  • Gluconeogenesis (new glucose) is stimulated (using amino acids produced by protein breakdown).
  • Fatty acids (from adipose tissue) are broken down and used to form ketone bodies.
  • Newly formed glucose and ketone bodies pass into the blood.

Question 40

Describe why untreated diabetes is associated with excessive urination.

Answer 40

1. In the glomeruli of the kidney glucose leaves the blood and passes into the urine along with ions and other relatively small molecules.
2. Normally transporters in the proximal convoluted tubule reabsorb all the glucose and return it to the blood.
3. In diabetes, if the blood glucose rises beyond a certain level, the amount that passes into the kidney tubules is so great that the transporters cannot remove it all.
4. This glucose adds to the osmotic strength of the urine.
5. This makes it harder for the kidney to reabsorb water from the urine.
6. The result is that the urine volume is greatly increased
   
   • It also explains why the urine of a diabetic contains glucose.
7. In severe cases, acidic ketone bodies also appear in the urine (ketoacidosis) adding slightly to the osmotic strength.
   
   • It also explains why the urine of a diabetic contains ketones.

Question 41

Describe the tissue damage associated with long-term high blood glucose.

Answer 41

• In long-term high blood glucose, tissues can be damaged:
  
  • Blood vessels (polyneuropathy)
  • Eyes (retinal blood vessels)
  • Kidneys (urine infection; scarring and swelling in glomeruli leading to appearance of protein in the urine)
  • Cardiovascular diseases (largely a result of narrowing blood vessels)
• Ketone bodies cause acidosis, which cannot be fully counteracted.
  
  • As a result, an individual with uncontrolled diabetes can go into a coma as a result of low blood pH coupled with dehydration.