T2 L3: Liver and glucose homeostasis

• Ways to aquire glucose in the blood?

  diet

  liver glycogen breakdown

  liver gluconeogenesis
• Why is the brain most vulnerable to hypoglycaemia?

  cerebral cells derive energy predominantly from aerobic metabolism of glucose

  they also cannot:

  • store or synthesise glucose
  • metabolise substrates other than glucose or ketone bodies
  • extract sufficient glucose from extracellular fluid at low concentrations as glucose entry to brain is not hormone facilitated
• What are the mechanisms controlling blood glucose?

  increased by glucagon, adrenaline, cortisol and growth hormone:

  • glycogenolysis: breakdown of liver glycogen stores into glucose
  • gluconeogenesis: glucose synthesis in liver and kidneys from non-carbohydrate precursors

  increased by insulin:

  • glycolysis: oxidation of glucose by peripheral tissues
  • glycogen and fat synthesis
• What is the main source of blood glucose in between meals?

  glycogenolysis
• As dietary glucose starts to decline, rate of glycogenolysis increases.
• When is there a (gradual) dependence on gluconeogenesis:?

  during sleep / fasting
• What are the 3 main body fuels?

  • glucose (stored as glycogen in liver and muscle)
  • long chain fatty acids (stored as triacylglycerol in adipose tissue)
  • amino acids
• How is glucose transported into tissues?

  facilitated diffusion

  through GLUT channels

  all cells exhibit at least 1 of the 5 GLUT isotypes

  different GLUTs have different affinities to glucose
• Which GLUT channel is sensitive to insulin, and which cells express it?

  GLUT 4, skeletal muscle and adipose tissue
• What are the properties of the GLUT1 transporter?

  wide spread; high affinity for glucose (can take up even in low concentrations)
• What are the properties of the GLUT2 transporter?

  in liver, beta cells of pancreas, kidney, small intestine

  low affinity for glucose; only takes up at high concentrations

  when glucose concentration is low, won't take up glucose to leave it for other tissues, eg brain
• What are the properties of the GLUT3 transporter?

  in CNS

  high affinity; allows glucose uptake irrespective of concentration
• What are the properties of the GLUT4 transporter?

  in skeletal muscle and adipose tissue

  insulin sensitive

  uptake controlled by plasma glucose levels + number of transporters currently active
• GLUT 1, 2 and 3 are always in cell membrane, whereas GLUT4 only present in the presence of insulin.
• What are the immediate cellular effects of insulin?

  increases rate of glucose uptake in muscle and adipocytes

  modulation of activity of enzymes involved in glucose metabolism

  • occur within minutes
  • do not require protein synthesis
  • occur at low insulin concentrations
• What are the longer-lasting cellular effects of insulin?

  increase gene expression of liver enzymes that synthesise glycogen & adipocyte enzymes that synthesise triacylglycerols

  inhibits lipolysis in adipose tissue

  these effects:

  • occur over several hours
  • require continuos exposure to insulin at lower concentrations
• What is the pentose phosphate pathway?

  cytosolic pathway present in all cells

  branches from glycolysis at G6P

  two products:

  • Ribose phosphate - used to synthesise RNA and DNA
  • NADPH - used for reductive biosynthesis and to maintain redox balance of the cell

  tissues very active in biosynthesis are rich in PPP enzymes

  however ALL cells require NADPH for redox balance, so if less active PP intermediates are recycled back into glycolysis
• Liver glucose metabolism?


  OXPHOS

  Lactate fermentation

  Glucogenesis

  Lipogenesis

  GLUT2 channels
• Muscle & Heart glucose metabolism?


  OXPHOS

  Lactate fermentation

  Glucogenesis

  No lipogenesis

  GLUT4 channels
• Adipose tissue glucose metabolism?


  OXPHOS

  Lipogenesis

  no lactate fermentation

  no glucogenesis

  GLUT4 channels
• Brain glucose metabolism?


  OXPHOS only
• RBC glucose metabolism?


  lactate fermentation only