PHSI3909 Lecture 7 - sdfsd PDF

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PHSI3909 Lecture 7 – Regulation of insulin secretion in pancreatic -cells 1.

Outline the types of diabetes and beta-cell dysfunction

2.

Understand normal insulin secretion by beta cells

3.

Understand the signalling involved in the two phases of insulin secretion

4.

Understand the process of vesicle exocytosis and evidence for a beta cell "synapse"

5.

Outline the use of the Db/db mouse as a model for type 2 diabetes

Types of diabetes 

Type 1 – no insulin (autoimmune disease)



Type 2 – insulin resistance



Gestational diabetes

Type 2 diabetes and beta cell dysfunction 

After a meal: blood [glucose]



Insulin tries to remove glucose from the blood but moving it into cells

1.

Glucose not effectively taken up into tissues

2.

Decrease in Insulin secretion due to -cell problems

Stimulus secretion coupling in -cells

1.

blood [glucose]

2.

Glucose floods into -cell via GLUT2 1. GLUT2 only present in liver and -cells; don’t need insulin to activate and is always open

3.

 [glucose] in -cell generates ATP

4.

ATP rise causes ATP-sensitive K+ channel to close, preventing outflow of K+ from -cell

5.

Membrane potential of the -cell becomes more positive, switching on Ca2+ channels

6.

Ca2+ ions move into the -cell triggering exocytosis of insulin from vesicles

ATP-sensitive K+ channel mutations Some kids found to have mutations in the ATP sensitive K+ channel 

Channel remains open even when glucose floods in so the membrane doesn’t get depolarised



Ca2+ channels will hence remain closed and no insulin will be released

Treatment: 

Sulphonylureas to block off the K+ channels so that everything happens normally again

2 key unknowns 1.

Temporal complexity

2.

Spatial complexity

Temporal (time) complexity: 2 phases in the glucose induced response



Initial peak (10-15mins)



Slower 2nd peak (60mins) o Can be sustainable as long as there is glucose



1st phase of insulin secretion primes the liver responses



When we stimulated cells and looked at calcium produced, there wasn’t a 1:1 ratio of [Glucose] to [Ca2+]



Increase in [Glu] didn’t increase [Ca2+]



[Ca2+] goes up and down in 2nd phase



[Ca2+] release must have contributed to the 1st and 2nd phases on insulin secretion

Model for the 2 phases in glucose-induced response



Insulin is stored in vesicles in the -cells



Only about a 100 out of 9000 vesicles fuse with the membrane at a time



1st phase: 100 vesicles are docked at the membrane and are ready to release the insulin



2nd phase: Movement of vesicles  Fusion with membrane  Movement of vesicles

Spatial: co-localisation of calcium + exocytosis 

There might be a r/s between the calcium channels and the site of exocytosis



Vesicles must be able to see the Ca2+ released for exocytosis



Scientists stuck -cells @ the bottom of the dish



Quinacrine indicates the location of the -cells



Stimulation of cell suggested that [Ca2+] produced in the -cells were asymmetric



Suggests that vesicles are located close to the calcium channels (co-localised)

Spatial: discrete contact with the vasculature



Where the -cells make contact with the capillaries might be where the vesicle fusions happen



Granule fusion is biased towards vasculature

Model in a neuronal synapse that might explain mechanisms in -cells



Voltage dependent/gated Ca2+ channels and synaptic vesicles are coupled



Liprin (Green) is highly expressed near the capillaries in -cells



Laminin (Red) used to stain capillaries

Type 2 diabetes db/db mouse: leptin receptor deficient mouse 

Leptin is secreted by fat cells and goes into the brain



Leptin helps to reduce appetite



Mutation in leptin receptor  mice over eat  develop diabetes



 in insulin secretion is due to a defect in one of the points leading to insulin secretion

GLUT2 decrease 

Poor sensing of glucose



Db/db mice have no GLUT2 transporters



 Glucose uptake  ATP  Change in Ca2+ signalling  Loss of association b/t Ca2+ and site of exocytosis   Insulin content  Loss of -cells   Insulin secretion...