Metabolism in the fed and starved states

Question 1

Fed state

Answer 1

During meals and for several hours afterwards

Characterised by high insulin and low glucagon

Absorptive phase

Question 2

Fasting state

Answer 2

6-12 hours after a meal

Fasting that lasts in excess of 12 hours is prolonged fasting or starvation

Characterised by low insulin and high glucagon

Post- absorptive state

Question 3

Metabolism in the fed state

Answer 3

Food intake stimulates insulin release; this inhibits glucagon secretion

This affects metabolism in the liver, adipose tissue and muscle

Glucose utilisation in the brain remains unchanged

Question 4

Metabolism in the fed state- liver

Answer 4

High concentrations of nutrients leads to an increase in insulin: glucagon ration

High blood glucose enters the liver, converted to glycogen and triacylglycerols which are secreted as VLDL, some enter TCA cycle

Lactate returning from rbcs and muscle and glycerol from peripheral tissues also converted to triacylglycerols

Excess amino acids entering from the gut are converted to pyruvate and metabolised via the TCA for energy or converted to triacylglycerols

Question 5

Metabolism in the fed state- muscle

Answer 5

Glucose enters the muscle via insulin stimulated Glut-4 transport system- converted to glycogen or metabolised via glycolysis and TCA cycle

Fatty acids enter muscle both from diet via chylomircons and from the liver via VLDL; oxidised via B-oxidation to acetyl CoA to produce energy to support contraction

Amino acids are incorporated into proteins

Question 6

Metabolism in the fed state- adipose tissue and brain

Answer 6

Glucose enters adipose tissue by the insulin dependent Glut 4 transport system- converted via glycolysis and PDH into acetyl CoA and then to fatty acids and triacylglycerol

Fatty acids enter from VLDL and chylomicrons and are converted to triacyglycerol

Glycerol released from TAGs is returned to liver for re-use

Brain takes up glucose via Glut 1 and 3 transporters and metabolises it oxidatively by glycolysis and the TCA cycle to produce energy

Question 7

Metabolism in the early fasting state

Answer 7

During fasting, the liver switches from a glucose utilising to a glucose producing organ

Decrease in glycoen synthesis and increase in glycogenolysis

Gluconeogenesis

Question 8

The early fasting state- liver

Answer 8

Plasma glucose falls, no longer enters liver as Glut 2 transport has low affinity, liver changes from user to exporter of glucose

Reduced insulin glucagon ration activates glycogenolysis and gluconeogenesis via cAMP production in response to glucagon

Protein in liver and other tissues are broken down to amino acids to fuel gluconeogenesis

Fatty acids from lipolysis enter the liver and produce energy via B-oxidation; citrate and acetyl CoA produced from oxidation of fatty acids activte gluconeogenesis and inhibit glycolysis

Question 9

The early fasting state- adipose tissue

Answer 9

Entry of glucose into adipose tissue via Glut 4 transport system is reduced in response to the lowered insulin and metabolism of glucose via glycolysis is severely inhibited

Mobilsation of TAGS occurs in response to the reduced insulin: glucagon ration and activation of the sympathetic NS by release of noradrenaline

Some of the fatty acids are used directly in tissue to produce energy, remainder released into bloodstream to support glucose independent production in muscle and other peripheral tissues

Glycerol cannot be metabolised and is recycled to the liver to support gluconeogenesis

Question 10

The early fasting state- muscle

Answer 10

Fall in insulin reduced glucose entry, glycogenolysis does not occur as there are no glucagon receptors in skeletal muscle to cause activation

Muscle and other peripheral tissues switch to fatty acid oxidation as a source of energy which inhibits glycolysis and glucose utilisation

Proteins are broken down to amino acids and the carbon skeletons can be used for energy or exported to the liver in the form of alanine

Question 11

The early fasting state- brain

Answer 11

Continues to take up glucose because of the high affinity of Glut 1 and Glut 3 transport system and independence from insulin

Glucose continues to be metabolised despite the fact that no glucose is provided in the brain

Brain cannot switch to fatty acids as a source of fuel as free fatty acids do not cross the blood brain barrier

Question 12

Metabolism in the late fasting state

Answer 12

Chronic low- insulin, high glucagon state

Accompanied by decrease in concentration of thyroid hormones- decrease metabolic rate

Free fatty acids become the major energy source

Question 13

The late fasting state- liver

Answer 13

No glucose enters liver and glycogen stores are depleted within 24 hours

Plasma glucose dependent on gluconeogenesis from lactate, glycerol and alanine from fat and protein breakdwon; the kidney also becomes an important source of gluconeogenesis

Urea synthesis stimulated to cope with increases amino groups entering liver

Glycogen synthesis and glycolysis are inhibited

Fatty acids enter the liver and provide energy to support gluconeogenesis with excess acetyl CoA being converted to ketone bodies

Question 14

The late fasting state- adipose tissue

Answer 14

Little glucose entry with fall in insulin secretion

Body switches to using fatty acids from triacylglycerol to supply all the energetic needs of the major tissues

Lipolysis is greatly activated because of the low insulin: glucagon ratio and blood levels of fatty acids rise 10 fold

Glycerol exported to the liver to be converted into glucose

Question 15

The late fasting state- muscle

Answer 15

Little glucose entry with fall in insulin and switch to fatty acids as the fuel

Fatty acid oxidation supplies the energy needed for muscle contraction

Ketone bodies are taken up by muscle and other peripheral tissues and used as a further source of fuel in heart and muscle conserving glucose

Protein breakdown (proteolysis) stimulated by noradrenaline and cortisol supply carbon skeletons for net glucose synthesis in the form of alanine

Ketone bodies reduce proteolysis and decrease muscle wasting

Question 16

The glucose fatty acid cycle

Answer 16

Mobilsation of fatty acids in response to glucagon or adrenaline increases fatty acid oxidation in peripheral tissues to acetyl CoA

Excess acetyl CoA converted to citrate in TCA cycle which build up in cytoplasm and inhibits PFK-1

Build up of G6P inhibits hexokinase and prevents glucose phosphorylation

Increase in glucose prevents further glucose entry and so conserves glucose

Question 17

The late fasting state- brain

Answer 17

Although fatty acids cannot be used by the brain, as levels of ketone bodies rise in the plasma, these can cross the blood brain barrier and enter the brain as a source of energy sparing use of glucose

Ketone bodies cannot completely replace the need for glucose and therefore brain continues to take up glucose and metabolise through glycolysis- net glucose synthesis during starvation is essential

Question 18

Glucose utilisation in various metabolic states

Answer 18

Fed state- glucose provided by diet

Fasted state- most glucose provided by the breakdown of liver glycogen, increasing amounts by gluconeogeneis

Starved state- most glucose comes from gluconeogenesis, the breakdown of protein and fats provide amino acids and glycerol as substrates

Question 19

Hormonal control of glycogenolysis and glycogen synthesis

Answer 19

Enzymes involved in glycogenolysis/ synthesis are subject to allosteric control

Enzymes are also subject to hormonal control by glucagon, adrenaline, cortisol and insulin

Hormonal control is mediated by changes in phosphorylation

Question 20

Hormonal regulation of glycogen mobilisation

Answer 20

Hormones glucagon and epinephrine are released in response to low blood glucose so increase glucose from glycogen in the liver

Epinephrine is also part of fight or flight response, levels rise greatly during exercise when metabolic demands of muscle are high and glycogen breakdown is required to support muscle contraction

Prepares the muscle for strenuous activity

Question 21

Reciprocal regulation of phosphorylase and glycogen synthase by phosphorylation

Answer 21

Glucagon (liver) and adrenaline (muscle) activate glycogen breakdown and inhibit synthesis by activating cAMP PK with ultimate phosphorylation and phosphorylase and glycogen synthase

Mimicked by increasing Ca2+ during contraction

Insulin activates protein phosphatase to reverse these effects

cAMP PK phosphorylates glycogen switching it off, phosphorylates phosphorylase kinase leading to activated which can also phosphorylate glycogen synthase ensuring it is inactive

Question 22

Phosphorylase kinase

Answer 22

Exists in a and b form

Phosphorylated form is the active a form

Phosphorylase kinase phosphorylates phosphorylase switching it ON, allows glycogen degradation at the same time that it inhibits synthesis

Can be activated allosterically by Ca2+ ions linking muscle contraction with glycogen breakdown ensuring adequate ATP

Question 23

Control of glycogen metabolism by adrenaline

Answer 23

Adrenaline stimulates glycogenolysis in muscle via B-oxidation receptors and cAMP formation, but in liver uses a1- adrenergic receptors and Ca2+ and diacylglycerol as second messengers

Question 24

Regulation of glycogen metabolism

Answer 24

Coordinated regulation of both phosphorylase and glycogen synthase actvity to prevent futile cycling of intermediates (allosteric and covalent modification)

During exercise glycogen stimulated to provide energy for muscle contraction while glycogen synthesis is inhibited

Epinephrine stimulates breakdown and inhibits synthesis in skeletal muscle to prepare the body for physical work

In liver glycogen breakdown is stimulated by epinephrine and glucagon, whereas glycogen synthesis is inhibited in order to elevate blood glucose

Insulin stimulates glycogen synthesis in response to feeding and high blood glucose whereas simultaneously switches off glycogen breakdown in both liver and muscle