metabolism in fed & starved states

Question 1

what is the feed-fast cycle?

Answer 1

• human metabolism oscillates between the fed and fasting states
• the ‘switch’ determines metabolic changes in the molar ration of insulin to glucagon in the blood

Question 2

what is the fed state?

Answer 2

• during meals or several hours after

- high insulin and low glucagon (high insulin to glucagon ratio)

Question 3

what is the fasting state?

Answer 3

• 6-12 hours after a meal

- low insulin and high glucagon (low insulin to glucagon ratio)

Question 4

how is general metabolism in the fed state?

Answer 4

• food intake stimulates insulin release and insulin inhibits glucagon secretion
• this affects metabolism in the liver, muscle and adipose tissue
• glucose utilisation in the brain reminds unchanged

Question 5

how is metabolism in the liver in the fed state?

Answer 5

• 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 TCA cycle)
• glycerol from peripheral tissues is also converted to triacylglycerols
• excess amino acids entering from the gut are converted to pyruvate and metabolised via the TCa cycle for energy or converted to triacylgylcerols

Question 6

how is metabolism in the muscle in the fed state?

Answer 6

• glucose enters the muscle via insulin-stimulates Glut 4 transport system
• converted to glycogen or metabolised via glycolysis and 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 7

how is metabolism in the adipose tissue in the fed state?

Answer 7

• 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 liver for re-use

Question 8

how is metabolism in the brain in the fed state?

Answer 8

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 9

how is general metabolism in the early fasting state?

Answer 9

• during fasting, the liver switches from a glucose-utilising to a glucose-producing organ
• decrease in glycogen synthesis and increase in glycogenolysis
• gluconeogenesis

Question 10

how is metabolism in the liver in the early fasting state?

Answer 10

• as plasma glucose falls no longer enters liver as Glut 2 transporter has low affinity
• liver changes from user to exporter of glucose
• reduced insulin: glucagon ratio activates glycogenolysis and glyconeogenesis via cAMP production in response to glucagon
• protein in liver and other tissues are broken down into 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 11

how is metabolism in the muscle in the early fasting state?

Answer 11

• 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 12

how is metabolism in the adipose tissue in the early fasting state?

Answer 12

• entry go glucose into adipose tissue via the Glut 4 transport system is reduced in response to the lowered insulin and metabolism of glucose via glycolysis is severely inhibited
• mobilisation of TGs occurs in response to the reduced insulin:glucagon ratio and activation of the sympathetic NS by release of noradrenaline
• some fatty acids are used directly within the tissue to produce energy: reminded are elated into bloodstream to support glucose-independent energy production in muscle and other tissues
• glycerol cannot be metabolised and is recycled to the liver to supper gluconeogenesis

Question 13

how is metabolism in the brain in the early fasting state?

Answer 13

• continued to take up glucose because of the high affinity of Glut 1 and 3 transport system and independence from insulin
• glucose continues to be metabolised due to the fact that no glucose is provided in the diet
• brain cannot switch to fatty acids as a source of fuel as free fatty acids do not cross the blood brain barrier

Question 14

how is general metabolism in the starved state?

Answer 14

• chronic low insulin, high glucagon state
• accompanies by decrease in concentration of thyroid hormones: decrease metabolic rate
• free fatty acids become the major energy source
• production of ketone bodies as alternative fuel source

Question 15

how is metabolism in the liver in the starved state?

Answer 15

• no glucose enters liver and glycogen stores are depleted within 24 hours
• plasma glucose dependent of 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 liver
• glycogen synthesis and glycolysis is inhibited
• fatty acids enter the liver and provide energy to support gluconeogenesis with excess acetyl CoA being converted to ketone bodies
• these are not used by the liver but released for oxidation by there tissues

Question 16

how is metabolism in the muscle in the starved state?

Answer 16

• little glucose entry with fall in insulin and switch to fatty acids as fuel
• 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
• ketone bodies reduce proteolysis and decrease muscle wasting

Question 17

what is the glucose-fatty acid cycle?

Answer 17

• mobilisation of fatty acids in response to glucagon or adrenaline increases fatty acid oxidation of acetyl CoA in peripheral tissues
• excess acetyl CoA converted to citrate in TCA cycle which builds up in cytoplasm and inhibits PFK-1
• build up of G-6-P inhibits hexokinase and prevents glucose phosphorylation
• increase in glucose prevents further glucose entry and so conserves glucose

Question 18

how is metabolism in the adipose tissue in the starved state?

Answer 18

• 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 19

how is metabolism in the brain in the starved state?

Answer 19

• 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 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 leading to net glucose synthesis during starvation is essential

Question 20

how is glucose utilised in the fed state?

Answer 20

glucose provided by diet

Question 21

how is glucose utilised in the fasted state?

Answer 21

most glucose provided by the breakdown of liver glycogen, increasing amounts by gluconeogenesis

Question 22

how is glucose utilised in the starved state?

Answer 22

most glucose comes from gluconeogenesis, the breakdown of proteins and fats provide amino acids and glycerol as substrates

Question 23

how is glycogenolysis and glycogen synthesis controlled by hormones?

Answer 23

• enzymes involved are subject to allosteric control
• enzymes involved are also subject to hormonal control by glucagon, adrenaline, cortisol and inulin
• hormonal control is mediated by changed in phosphorylation

Question 24

how is glycogen mobilisation regulated by hormones?

Answer 24

• insulin released in response to increases in blood glucose promoting glucose oxidation, glycogen synthesis and TG synthesis
• glucagon and adrenaline released in response to low blood glucose, thus releasing glucose from glycogen in the liver to increase blood glucose
• adrenaline is part of the fight or flight response; levels rise greatly during exercise when glycogen breakdown is required support muscle contraction

Question 25

describe the process of reciprocal regulation of phosphorylase and glycogen synthase by phosphorylation

Answer 25

• glucagon (liver) and adrenaline (muscle) activate glycogen breakdown and inhibits synthesis by activating cAMP PK with ultimate phosphorylation if phosphorylase and glycogen synthase
• mimicked by increasing Ca2+ during contraction
• insulin activated protein phosphatase to reverse these effects

Question 26

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

Answer 26

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

Question 27

describe the process of reciprocal regulation of phosphorylase and glycogen synthase

Answer 27

• phosphorylase kinase exist in an a and b form
• the phosphorylase form is the active a form
• the phosphorylase kinase phosphorylates 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 process of reciprocal regulation of phosphorylase and glycogen synthase by insulin

Answer 28

• insulin activates protein phosphatase-1 which removes the phosphates from phosphorylase, glycogen synthase and phosphorylase kinase
• this switched off glycogen breakdown and switched on glycogen synthesis