Lecture 5 - Glucose Control in Health and Disease Flashcards
What is the normal blood glucose concentration?
Around 4.5 mM
aka 60-90 mg/100mL
Describe what happens to the body at the various concentrations of blood glucose
4.5 - 5.6 mM: normal range
- 4.5: • Hunger • Glucagon release • Adrenaline release • Corticol release • Sweating, trembling
V low:
• Lethargy
• Convulsions
• Coma
Very very low:
• Permanent brain damage
• Death
Resting blood glucose:
• 4.5-5.6: normal
• 5.6-7: intermediate
• > 7: elevated
Describe the source of blood glucose
Dietary glucose:
• Glucose taken up from the digested food in the intestine into the blood
Describe the absorption of the various nutrients found in food
Glucose: into blood
Amino acids: into blood
Lipid:
• Packaged into Chylomicrons
• Lacteals → Lymphatics → Blood
Describe the mechanism resulting in insulin secretion
- Blood glucose conc. rises
- ↑ ATP production through metabolism of glucose in β islets cells
- ATP inhibits ATP-gated K+ channel; K+ sequestered in the cell
- Plasma membrane is depolarised (build up of +ve charge inside the cell)
- A voltage gated Ca2+ channel opens (in response to +ve charge in cell)
- Ca2+ enters β islet cell, as well as being released from intracellular stores in the ER
- ↑ intracellular Ca2+ triggers insulin release by exocytosis of insulin granules from the secretory pathway
What are the outcomes of insulin secretion?
• Uptake of glucose from the blood (through GLUT deposition in membranes)
• Storage of fuels (glycogenesis)
• ↑ glucose metabolism
• ↑ synthesis of TAGs
( • Synthesis of proteins
• -ve regulation of gluconeogenesis in liver
• -ve regulation of glycogenolysis)
Describe the structure of insulin
Preproinsulin → Proinsulin → Mature insulin
Mature insulin:
• Two chains:
• A and B chain
Proinsulin:
• A, B and C chain
• 2x Disulphide bonds between A and B chains
• Disulphide bond one A chain
Preproinsulin:
• A, B and C chain + Signal sequence
• No disulphide bonds
Describe the features of GLUT molecules
• Transmembrane proteins
• 12 alpha helical ™ domains
• N and C termini are intracellular
• Different isoforms in different tissues
• Chain loops outside the cell
• Domains arranged such that they create a polar pore (through which glucose can move)
( • 14 different isoforms)
Which GLUT is found in myocytes?
GLUT4
Describe how glucose gains access to cells
- Glucose binds GLUT externally
- GLUT undergoes a conformational change
- GLUT opens on the intracellular side
- Glc moves into the cell
Which tissue takes up most of the blood glucose in response to insulin?
Muscle tissue (around 90%)
Why is transport of glucose into the cell so important?
It is the rate limiting step of the use of glucose by the cell
Failure of GLUT4 transport to the plasma membrane is an early features of insulin resistance
Describe the regulation of GLUT4 in myocytes
“Regulated exocytosis”
- GLUT “stored” within cells in membrane vesicles
- Insulin signalling → vesicles to move to surface, fuse with plasma membrane, depositing the GLUT in the membrane
- Drop in insulin levels → GLUT4 removed from the plasma membrane by endocytosis to form small vesicles
- Smaller vesicles fuse with larger endosome
- Patches of the endosome enriched with GLUT4 bud off to become small vesicles (ready to again return to the surface)
Describe the mechanism of release and action of glucagon
- Decreased blood glucose conc.
- Detected by hypothalamus: activation of K+/ATP channels
- Autonomic nerve signalling to α cells of islets
- Release of glucagon from α islet cellsLiver is main target tissue, as well as adipose tissue
- Glucagon binds to cell surface receptors in liver & adipose tissue, activation of cell signalling pathways
Describe the structure of glucagon
A peptide (like insulin)
Where are glucagon and insulin produced?
Glucagon: α cells
Insulin: β cells
of the Islets of Langerhans in the pancreas
List the outcomes of glucagon signalling
Liver: ↓ Glycogenesis ↑ Glycogenolysis ↑ Gluconeogenesis ↓ Glycolysis
Adipose:
↑ Mobilisation of fatty acids
Regulation of which enzyme alters glycogenesis?
Glycogen synthase
Regulation of which enzyme alters glycolysis?
Phosphofructokinase-1
Regulation of which enzyme alters gluconeogenesis?
Pyruvate kinase
Fructose-1,6-bisphosphatase
Regulation of which enzyme alters glycogenolysis?
Glycogen phosphorylase
Regulation of which enzyme alters fatty acid mobilisation?
Triacyglycerol lipase