W6 Integration + regulation of metabolism

Question 1

Brain

Answer 1

Uses 100-120g glucose daily

No absoloute environment

Over half the energy consumed is used for Na+-K+ transport to maintain membrane potential and the synthesis of neurotransmitters

Lacks energy stores

Glucose is transported by GLUT3 which has a low Km – saturated under most conditions

Danger point when plasma glucose drops to below 2.2mM

Normally fatty acids are used not for energy but for membrane biosynthesis

Brain is approx. 2% of body mass but takes 20% of the cardiac output

Question 2

Cardiac muscle

Answer 2

Is exclusively aerobic with little or no glycogen stores (unlike SM)

Fatty acids are the main source of energy followed by lactate and ketone bodies

Lactate → pyruvate → acetyl CoA

Question 3

Adipose tissue

Answer 3

Reservoir metabolic energy in the form of triglycerides

A 70kg man will have 15kg of TG

Although the liver makes FA we get most from our diet

These are delivered by the chylomicrons

Glucose is transported by GLUT4
GLUT4 is insulin sensitive

Mostly from liver

Question 4

Kidney

Answer 4

Major role is to produce urine

The plasma is filtered up 60 times daily

Only a small volume of urine is produced

Water soluble material largely reabsorbed to prevent loss

Although only 0.5% body mass they consume 10% of the energy

During starvation the kidney may contribute half of the blood glucose through gluconeogenesis

Question 5

Liver

Answer 5

Plays a central role in regulating metabolism
Carbohydrate
Fatty acid
Amino acids

Most compounds absorbed by gut pass through the liver

Provides fuel for brain, muscle and other peripheral organs

Takes its energy from α-ketoacids

Question 6

Control of blood glucose by liver metabolism

Answer 6

Glucose is transported into hepatocytes by GLUT2 (not insulin-sensitive) and immediately phosphorylated by glucokinase.

Glucose-6-phosphate from glycogen breakdown (or gluconeogenesis) is converted to glucose by the action of glucose-6 phosphatase and transported out of the cell and into the blood by GLUT2

Bidirectional transporter

Question 7

Muscle glucose metabolism

Answer 7

Glucose uptake by GLUT4 is insulin-dependent

Glucose is converted into G6P by hexokinase (Km 0.1mM for glucose)

Low free [glucose] in cell

Glucose is mobilised from glycogen in exercise

Glycolysis of the G6P is a rapid source of ATP

Question 8

Comparison of hexokinase and glucokinase activities

Answer 8

HK saturated at relatively low [glucose]

Question 9

Fuel for a sprint or a marathon

Answer 9

ATP directly powers myosin

Converts chemical energy to movement

Muscle ATP stores are small

Power and speed is dependent on rate of ATP production + availability

Resting muscle uses fatty acids as a major source of energy

Question 10

100 sprint powered by

Answer 10

ATP stores
Glycolysis
Glycogen
Creatine phosphate

5-6 s of energy reserves

Anaerobic breakdown of glycogen stores gives lactate and a fall in pH

Activity of glycogen phosphorylase enhanced by phosphorylation whereas glycogen synthase inhibited

Question 11

Muscle creatine phosphate

Answer 11

Small store of ATP

Creatine phosphate +ADP ⇋ ATP + creatine

By creatine kinase

Question 12

Fuel for a marathon

Answer 12

For a marathon need 150 moles ATP

Body glycogen will provide only 103 moles

Requires co-operation between muscle, liver and adipose tissue (use both fat/glycogen which is regulated by synthesis of acetyl CoA from fat thus regulates glucose into krebs)

Why because the amount of ATP required exceeds that stored by the muscle

Complete oxidation slow

Fats are a large source of ATP, the metabolism is even slower than glycogen and x10 slower than creatine phosphate

At end of a marathon about ½ glycogen is left

Liver to provide glucose from non carbohydrate sources

Question 13

Interaction between liver and muscle

Answer 13

During exercise glycolysis exceeds the capacity of the citric acid cycle, pyruvate converted to lactate and transported to liver Cori cycle (lactate back to glucose)

Question 14

What happens when we stop eating?

Answer 14

1st priority to maintain glucose levels

2nd priority to preserve protein (as breakdown of proteins will lead to loss of functionality)

To achieve this metabolism shifts from glucose to fatty acids and ketone bodies

Question 15

Post absorptive phase

Answer 15

Blood glucose falls insulin levels fall and glucagon levels rise

Phosphorylase a activity increases as does Glycogen breakdown

Drop in insulin reduces glucose uptake by muscle and adipose tissue

Question 16

Early starvation (24 hrs)

Answer 16

Glucose released from the liver due to gluconeogenesis and glycogenolysis

Mobilisation of FA from adipose tissue

Glucose use falls as muscle switches to FA oxidation

Insulin drops causing GLUT4 expression by muscle to fall reducing glucose uptake

After 12hrs 45% of resting energy from FA and 40% from glucose

Question 17

Intermediate starvation (3-20 days)

Answer 17

Glycogen stores depleted

Increased lipolysis and ketogenesis (FA generate ketone bodies)

Increased gluconeogenesis to maintain blood glucose

60hrs FA account for ¾ energy provision

After 8 days β hydroxybutyrate is raised 50 fold

Further starvation sees the kidney take over gluconeogenesis from the liver

Question 18

Prolonged starvation (> 3wks)

Answer 18

β hydroxybutyrate plateaux at 20 days

As brain starts to move to using ketone bodies the need for glucose falls from 100g to 40g/day

Other sources of gluconeogenic precursors are lactate and glycerol

Lactate recycled by the Cori cycle

Glycerol and amino acids are oxidized

Proteins are broken down muscle forming amino acid precursors

Brain switches metabolism away from glucose

SM first then CM broken down

Question 19

Skeletal muscle breakdown

Answer 19

Alanine also formed by transamination of pyruvate and released into blood where it is taken up by liver and converted to glucose (glutamate to alpha-ketoglutarate)

Why because muscle can use amino acids for carbon skeleton but can not form urea therefore the liver removes nitrogen and releases pyruvate

Muscle changes metabolism to ketone bodies (from FA in adipose tissue)