T2 L5: Metabolism in Fed and Starved states

• What is the 'switch' that determines the metabolic changes of the 'fed' and 'fasting' stages?

  ratio of insulin to glucagon in blood
• What is the 'fed' (absorptive) state characterised by?

  high insulin/glucagon ratio
• What is the 'fasting' (post-absorptive) state characterised by?

  low insulin/glucagon ratio
• What is the energy store for most cells in absorptive phase?

  glucose
• What is the energy source for most cells in the post-absorptive phase?

  fatty acids
• How is metabolism like in fed state?

  insulin release

  inhibited glucagon secretion

  glucose utilisation in brain unchanged

  afffects metabolism in liver, muscle and adipose tissue
• What characteristics does metabolism in the liver have in fed state?

  increased insulin:glucagon ratio

  glucose -> glycogen

  glycerol -> triacylglycerides

  excess amino acids -> pyruvate & metabolised in TCA cycle or converted to triacylglycerols
• What characteristics does metabolism in muscle have in fed state?

  glucose enters muscle via insulin stimulated GLUT4 transport system

  converted to glycogen or metabolised via glycolysis and TCA cycle

  fatty acids enter muscle both from diet via chylomicrons and from liver via VLDL; these are oxidised via beta-oxidation to acetyl CoA for ATP
• What characteristics does metabolism in adipose tissue have in fed state?

  glucose enters adipose tissue by insulin dependent GLUT4 transport system

  converted via glycolysis and PDH (pyruvate dehydrogenase) into acetyl CoA and then to fatty acids and triacylglycerol

  fatty acids enter from VLDL and chylomicrons; converted to triacylglycerol
• Effect of insulin on lipoprotein lipase and hormone-sensitive lipase?

  increases activity of LPL

  inhibits activity of HSL
• What are the characteristics of metabolism in brain in fed state?

  takes up glucose via GLUT1 and GLUT3

  glycolysis and TCA cycle
• How is metabolism like overall in the early fasting state?

  liver switches from a glucose utilisation to glucose production

  decrease in glycogen synthesis and increase in glycogenolysis

  gluconeogenesis
• How is metabolism in liver like in early fasting state?

  as plasma glucose falls, no longer enters liver as GLUT2 transporters have low affinity

  reduced insulin:glucagon ratio

  glucagon stimulates cAMP production

  activates glycogenolysis & gluconeogenesis.

  fatty acids oxidised -> citrate & Acetyl CoA

  activate gluconeogenesis

  inhibit glycolysis
• How is metabolism in muscle like in early fasting state?

  fall in insulin reduces glucose entry

  glycogenolysis does not occur as there are no glucagon receptors in skeletal muscle

  switch to fatty acid oxidation as energy source; inhibits glycolysis & glucose utilisation

  proteins broken down to amino acids
• How is metabolism in adipose tissue like in early fasting state?

  glucose entry through GLUT4 reduced

  glycolysis inhibited

  TGs used to make fatty acids (bc of low insulin:glucagon ratio + noradrenaline release by sympathetic NS)

  fatty acids used directly within tissue OR released into blood to support glucose-independent energy production

  glycerol cannot be metabolised - recycled to liver for gluconeogenesis
• How is metabolism in brain like in early fasting state?

  high affinity of GLUT1 and GLUT3

  also insulin independence

  so continues to take up glucose

  glucose continues to be metabolised

  brain CANNOT switch to fatty acids as fuel bc they can't cross blood-brain barrier
• How is metabolism like overall in the starved state?

  chronic low insulin, high glucagon state

  decrease in concentration of thyroid hormones - decreases metabolic rate

  free fatty acids become the major energy source

  production of ketone bodies as alternative fuel source
• How is metabolism in liver like in the starved state?

  no glucose enters liver

  glycogen stores depleted within 24 hours

  plasma glucose dependent on:

  • gluconeogenesis from lactate
  • glycerol & alanine from fat and protein breakdown

  kidney becomes important source of gluconeogenesis

  urea synthesis stimulated (to cope with increasing amino groups entering liver)

  glycogenesis and glycolysis inhibited

  production of ketone bodies
• How are ketone bodies produced in the liver in response to starved state?

  fatty acids enter liver

  provide energy to support gluconeogenesis

  excess Acetyl CoA converted to ketone bodies

  released for oxidation by other tissues (not used by liver)
• How is metabolism in muscle like in the starved state?

  little glucose entry falls further with low insulin

  switch to fatty acids as fuel

  ketone bodies taken up

  used as alternative fuel source to conserve glucose

  ketone bodies reduce proteolysis and decrease muscle wasting
• What is the glucose-fatty acid cycle?

  incrased glucagon/adrenaline

  increased oxidation of fatty acids to Acetyl CoA

  excess Acetyl CoA converted to citrate in TCA cycle

  citrate build up in cytoplasm inhibits PFK-1

  causes build up of G6P which inhibits hexokinase

  prevent glucose phosphorylation

  increase in glucose prevent glucose entry

  conserves glucose
• How is metabolism in adipose tissue like in starved state?

  fall in insulin secretion so little glucose entry

  body switches to using fatty acids for energy supply

  lipolysis greatly activated (bc of low insulin:glucagon ratio)

  blood levels of fatty acids rise 10-fold

  glycerol exported to liver for gluconeogenesis
• How is metabolism like in brain in the starved state?

  ketone bodies cross blood-brain barrier

  used as some energy source

  but cannot completely replace glucose need so brain continues to take up glucose

  hence net glucose synthesis during starvation is essential
• Plasma ketone body concentration increases during fasting or starvation.
• How does glucose utilisation vary in different metabolic states?

  fed state: glucose provided by diet

  fasted state: glucose provided by breakdown of liver glycogen (mostly), increase in gluconeogenesis

  starved state: glucose provided by gluconeogenesis (mostly), breakdown of protein and fats provide amino acids and glycerol as substrates
• How does the reciprocal regulation of phosphorylase & glycogen synthase by glucagon and adrenaline work?

  glucagon in liver, adrenaline in muscle

  increase cAMP levels

  activate cAMP dependent protein kinase

  phosphorylates:

  • Phosphorylase kinase (activated)
  • Glycogen synthase (inactivated)

  activated phosphorylase kinase:

  phosphorylates glycogen phosphorylase (activated)
• How does regulation of phosphorylase and glycogen synthase by insulin work?

  insulin activates phosphatase 1

  dephosphorylates:

  • glycogen phosphorylase (inactivated)
  • glycogen synthase (activated)