metabolism in fed and starved states

Question 1

what is the feed fast cycle? 5

Answer 1

• Human metabolism oscillates between the fed and fasting states
• The switch that determines metabolic changes is the molar ratio of insulin to glucagon in the blood
• Fed state= during meals and for several hours afterwards. Characterised by high insulin and low glucagon (a high insulin/ glucagon ratio)
• Fasting state= 6-12 hours after a meal. Characterised by low insulin and high glucagon (a low insulin/ glucagon ratio)
• Fasting that lasts in excess of 12 hours is prolonged fasting or starvation

Question 2

describe metabolism in the fed state? 3

Answer 2

• Food intakes stimulate insulin release and insulin inhibits glucagon secretion
• This affects metabolism in the liver, muscle and adipose tissue
• Glucose utilisation in the brain remains unchanged

Question 3

describe metabolism in the fed state in the liver? 5

Answer 3

• High concentrations of nutrients lead to an increase in the insulin: glucagon ratio
• High blood glucose means it enters the liver and is converted to glycogen and Tgs which are secreted as VLDL. Some enters the TCA cycle
• Glycerol from peripheral tissues is also converted to triacylglycerol’s
• Excess amino acids entering from the gut are converted to pyruvate and metabolised via the TCA cycle for energy or converted to triacylglycerol’s
• Excess amino acids entering from the gut are converted to pyruvate and metabolised via the TCA cycle for energy or converted to triacylglycerols

Question 4

describe metabolism in the fed state in the muscle? 3

Answer 4

• Glucose enters the muscle via insulin stimulated Glut 4 transport system and is converted to glycogen or metabolised via glycolysis and the TCA cycle
• Fatty acids enter muscle both from the diet via chylomicrons and from the liver via VLDL. These are oxidised via beta oxidation to acetyl CoA to produce ATP to support contraction
• Amino acids are incorporated into proteins

Question 5

describe metabolism in the fed state in the adipose tissue? 4

Answer 5

• 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 triacylglycerol
• Glycerol released from TGs is returned to the liver for re-use
• LPL activity is increased and HSL activity inhibited by insulin

Question 6

describe metabolism in the fed state in the brain?

Answer 6

• The brain takes up glucose via glut 1 and 3 transporters and metabolises it oxidatively by glycolysis and the TCA cycle to produce ATP

Question 7

describe metabolism in the early fasting state? 3

Answer 7

• During fasting the liver switches from a glucose utilising to a glucose producing organ
• Decrease in glycogen synthesis and increase in glycogenolysis
• Gluconeogenesis

Question 8

describe metabolism in the early fasting state in the liver? 6

Answer 8

• As plasma glucose falls it no longer enters the liver as the glut 2 transporter has a low affinity
• Liver changes from a user to exporter of glucose
• Reduced insulin: glucagon ratio activates glycogenolysis and gluconeogenesis from lactate and alanine, via cAMP production in response to glucagon
• Protein in the liver and other tissues are broken down to amino acids to fuel gluconeogenesis
• Fatty acids from lipolysis used to produce energy via beta oxidation
• Citrate and acetyl CoA produced from oxidation of fatty acids activate gluconeogenesis and inhibit glycolysis

Question 9

describe metabolism in the early fasting state in the muscle? 3

Answer 9

• The fall in insulin reduces 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 10

describe metabolism in the early fasting state in the adipose tissue? 4

Answer 10

• Entry of glucose into adipose tissue via the glut 4 transport system is reduced in response to the lowered insulin and metabolism of glucose via glycolysis being severely inhibited
• Mobilisation of TGs occurs in response to the reduced insulin: glucagon ratio and activation of the sympathetic nervous system by release or noradrenaline
• Some fatty acids are used directly within the tissue to produce energy- the remainder are released into the bloodstream to support glucose-independent energy production in muscle and other tissues
• Glycerol cannot be metabolised and is recycled to the liver to support gluconeogenesis

Question 11

describe metabolism in the early fasting state in the brain? 3

Answer 11

• Continues to take up glucose because of the high affinity of the glut 1 and 3 transport systems and independence from insulin
• Glucose continues to be metabolised despite the fact that no glucose is provided in the diet
• Brain cannot switch to fatty acids as source of fuel as free fatty acids do not cross the blood brain barrier

Question 12

describe metabolism in the starved state? 4

Answer 12

• Chronic low insulin, high glucagon state
• Accompanied by decrease in concentration of thyroid hormones- decreases metabolic rate
• Free fatty acids become the major energy source
• Production of ketone bodies as an alternative fuel source

Question 13

describe metabolism in the starved state in the liver? 5

Answer 13

• No glucose enters the liver and glycogen stores are depleted within 24 hours
• Plasma glucose dependent on gluconeogenesis from lactate, glycerol and alanine from fat and protein breakdown. The kidney also becomes an important source of gluconeogenesis
• Urea synthesis stimulated to cope with increasing amino groups entering the 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 (acetoacetate and beta hydroxybutyrate). These are no used by the liver but released for oxidation by other tissues

Question 14

describe metabolism in the starved states in the muscle? 4

Answer 14

• Little glucose entry with fall in insulin and switch to fatty acids as the fuel
• Ketone bodies are taken up by the muscle and other peripheral tissues and used as a further source of fuel in heart and muscle conserving glucose
• Ketone bodies reduce proteolysis and decrease muscle wasting
• Fatty acid oxidation supplies the energy needed for muscle contraction

Question 15

what is the glucose-fatty acids cycle? 5

Answer 15

• Spares glucose during fatty acid oxidation
• Mobilisation of fatty acids in response to glucagon or adrenaline increases fatty acid oxidation to acetyl CoA in peripheral tissues
• Excess acetyl CoA converted to citrate in the TCA cycle which builds up in the cytoplasm and inhibits PFK-1
• Build-up of G-6-P inhibits hexokinase and prevents glucose phosphorylation
• Increase in glucose prevent further glucose entry and so conserves glucose

Question 16

describe metabolism in the starved state in the adipose tissue? 4

Answer 16

• 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 17

describe metabolism in the starved state in the brain? 2

Answer 17

• Although fatty acids cannot be used by the brain, as the levels of ketone bodies rise in the plasma, these can cross the blood brain barrier and enter the brain as an 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

describe glucose utilisation in various metabolism states? 3

Answer 18

• Fed state= glucose provided by diet
• Fasted state= most glucose provided by the breakdown of liver glycogen, increasing amounts of gluconeogenesis
• Starved state= most glucose comes from gluconeogenesis, the breakdown of protein and fats provide amino acids and glycerol as substrates

Question 19

describe the hormonal control of glycogenolysis and glycogen synthesis? 3

Answer 19

• Enzymes involved in glycogenolysis are subject to allosteric control
• Enzymes involved in glycogenolysis are also subject to hormonal control by glucagon, adrenaline, cortisol and insulin
• Hormonal control is mediated by changes in phosphorylation

Question 20

glucagon:

• source
• initiator
• effect on glycogenolysis/ gluconeogenesis

Answer 20

• pancreatic alpha cells
• hypoglycaemia
• rapid activation

Question 21

adrenaline:

• source
• initiator
• effect on glycogenolysis/ gluconeogenesis

Answer 21

• adrenal medulla
• stress, hypoglycaemia
• rapid activation

Question 22

cortisol:

• source
• initiator
• effect on glycogenolysis/ gluconeogenesis

Answer 22

• adrenal cortex
• stress
• chronic activation

Question 23

insulin:

• source
• initiator
• effect on glycogenolysis/ gluconeogenesis

Answer 23

• pancreatic beta cells
• hyperglycaemia
• inactivation

Question 24

describe the hormonal regulation of glycogen mobilisation (covalent modification)? 3

Answer 24

• Insulin released in response to increases in blood glucose promoting glucose oxidation, glycogen synthesis and TG synthesis
• Glucagon and adrenaline (epinephrine) released in response to low blood glucose, this releasing glucose from glycogen in the liver to increase blood glucose
• Adrenaline is also part of the fight or flight response; levels rise greatly during exercise when glycogen breakdown is required to support muscle contraction

Question 25

describe the reciprocal regulation of phosphorylase and glycogen synthase by phosphorylation? 3

Answer 25

• Glucagon (liver) and adrenaline (muscle) activate glycogen breakdown and inhibit synthesis by activating cAMP PK with ultimate phosphorylation of phosphorylase and glycogen synthase
• Mimicked by increasing Ca2+ during contraction
• Insulin activates protein phosphatase to reverse these effects

Question 26

describe the reciprocal regulation of phosphorylase and glycogen synthase by glucagon and adrenaline? 4

Answer 26

• Glucagon and adrenaline increase cAMP production and activate cAMP PK
• cAMP PK phosphorylates glycogen synthase switching it off
• does not phosphorylate phosphorylase but another kinase, phosphorylase kinase leading to activation
• phosphorylase kinase can also phosphorylate glycogen synthase ensuring its inactive

Question 27

describe the reciprocal regulation of phosphorylase and glycogen synthase? 4

Answer 27

• Phosphorylase kinase exists in an a and b form
• The phosphorylated form is the active a form
• Phosphorylase kinase phosphorylates phosphorylase, switching it on allowing glycogen degradation at the same time that it inhibits glycogen synthesis
• Phosphorylase kinase can also be activated allosterically by Ca2+ ions linking muscle contraction with glycogen breakdown ensuring adequate ATP

Question 28

describe the regulation of phosphorylase and glycogen synthase by insulin? 2

Answer 28

• Insulin activates protein phosphatse-1 which removes the phosphates from phosphorylase, glycogen synthase and phosphorylase kinase
• This switches off glycogen breakdown and switches on glycogen synthesis

Question 29

describe glycogen metabolism in the liver and muscle? 3

Answer 29

• Glucagon stimulates glycogenolysis= in liver the second messenger is cAMP
• Adrenaline stimulates glycogenolysis= in muscle and liver via beta adrenergic receptors, 2nd messenger is cAMP. In liver via alpha1-adrenergic receptors, second messenger is Ca2/’
• Insulin stimulates glycogen synthesis in both tissues