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WHAT IS IT?

This model demonstrates the control of glycogen degradation to glucose, or its biosynthesis from glucose, in liver cells. It is designed as a teaching/learning tool rather than an accurate model of the biochemical events.

Glycogen is a polysaccharide that is used to store the body's glucose supplies. Its metabolism is controlled in the liver by two hormones, insulin and glucagon, that are produced by the pancreas and passed to the liver by the blood stream. Insulin stimulates the liver to make glycogen from glucose which will enter the cells from the blood stream (this glucose will ultimately come from the diet). Glucagon stimulates the liver to break down stored glycogen to glucose. Some of this can be used to produce energy within the liver cell but most of it will be passed out into the blood stream to maintain correct blood sugar levels.

Neither of these hormones enters the liver cell. Instead they bind to a receptor molecule on the outside of the cell membrane. The receptor is linked to an enzyme, adenylate cyclase, on the inside of the cell. This enzyme is able to create a compound called cyclic AMP (cAMP) from adenosine triphosphate (ATP). Glucagon, via the link from the receptor, activates this enzyme, while insulin inhibits it, so glucagon will cause cAMP to be produced more rapidly and insulin will slow down its production. cAMP is destroyed in the cell by another enzyme called phosphodiesterase, so its concentration will depend on the balance between the rate at which the cyclase creates it and the phosphodiesterase destroys it.

cAMP can bind to an enzyme called protein kinase. In doing so it activates it. cAMP is not permanently bound. In the fullness of time it will fall off and the enzyme will lose its activity again. As glucagon increases the amount of cAMP it will increase the number of active protein kinase enzymes, while insulin has the opposite effect.

Protein kinase can add a phosphate group to (phosphorylate) an enzyme. It can actually work on two enzymes that concern us here: glycogen synthase and phosphorylase kinase. These phosphate groups can be removed by another enzyme called protein phosphatase. The proportion of phosphorylated enzyme will depend on the balance between the kinase and the phosphatase. Glucagon increases the amount of active protein kinase and therefore increases the proportion of phosphorylated enzyme, while insulin has the opposite effect. Glycogen synthase is the main enzyme involved in making glycogen from glucose and the phosphorylated form of it is inactive. Insulin reduces the amount of inactive, phosphorylated synthase thus increasing generation of glycogen. Glucagon, causing an increase in phosphorylated synthase, will reduce the generation of glycogen. Glycogen stimulates production of glucose from glycogen, so you obviously don't want to be making it at the same time.

Phosphorylase kinase is active in the phosphorylated form, the opposite to the synthase. Its job is to phosphorylate another enzyme, glycogen phosphorylase, which is the main enzyme involved in breaking down glycogen to glucose. Glycogen phsphorylase is again only active in the phosphorylated form and can be dephosphorylated by protein phosphatase. So glucagon by increasing the amount of active phosphorylase kinase also increases the amount of active phosphorylase which increases the amount of glucose produced. Insulin will have the opposite effect.

To summarise:

glucagon --> more cAMP --> more active protein kinase --> more active phosphorylase kinase --> more active phosphorylase --> more glucose (insulin opposite effect)

insulin --> less cAMP --> less active protein kinase --> more active synthase --> more glycogen production (glucagon opposite effect)

These sequences of reactions are known as the "cascade effect" and have the result of greatly amplifying the influence of the enzymes. For instance one glucagon molecule can activate one cyclase enzyme, but that can then produce a number of cAMP molecules. These can activate a number of protein kinases which can each phosphorylate a number of phosphorylase kinases which can each phosphorylate a number of phosphorylases. Finally each of these can release a large number of glucoses from glycogen.

HOW IT WORKS

This model uses some ideas from the enzyme kinetics module in the library that ships with Netlogo. There are quite a lot of comments in the procedures page that should explain how most of it works.

HOW TO USE IT

Familiarise yourself with the items on the interface screen.

Main graphics window:

The black area which makes up the major part of this window represents the interior of a liver cell. The lighter coloured, grey, area at the top represents extracellular fluid. The brown bar separating them is the cell membrane. The grey, elliptical, shapes which cross the membrane are the protein complexes containing the hormone receptor and the cyclase enzyme. The slider at the top can be used to adjust the speed of the reactions.

Setup and Go buttons:

Click the setup button to initialise the model. It also clears the graphs. Click the go button to start and click it a second time to stop the model.

Hide switches:

These switches enable you to hide or show different enzymes and compounds on the screen. The object is hidden when the switch is on. It's suggested that you make a lot of use of the hide feature as the screen can be very confusing with everything shown. By hiding everything but one object you can see which colour and shape represents each object. Enzymes have a brighter colour when they are activated.

Hormone sliders:

These let you add insulin or glucagon to the extracellular fluid. At the start they are both set to zero, but can be increased up to 20

Feed switch:

This lets you start the provision of glucose to the cell when glycogen is being synthesise. It doesn't work when you're studying glycogen breakdown

Direction chooser:

Lets you switch between studying control of glycogen breakdown, by phosphorylase, and glycogen synthesis, by synthase. It's set to breakdown by default. These are the two modes of the model.

Monitors:

The row of monitors, below the main graphic window, shows the number of cAMP and glucose molecules and the number of active protein kinase, phosphorylase kinase, phosphorylase and synthase molecules currently in the model.

Graphs

Clicking on the Pens label will display a legend to indicate the meaning of the colours in the graphs. Clicking a second time will hide it again. The large graph (heading: Molecular Ratios) simply gives you a graphic display of the figures in the monitors. It gives you a good indication of the ratios of the main players in the model. The Glucose graph simply plot the number of glucose molecules currently in the model. The Enzymes graph plots the number of active phosphorylase or synthase enzymes, which one you see depends on the mode that is operating.

THINGS TO NOTICE

You probably won't get much out of this model by just pressing Setup and Go and watching the pretty coloured dots. You need a more structured approach so I'll make one or two suggestions to start you off and you'll then have a better idea of how to experiment.

Start:

By default the model starts in glycogen breakdown mode with both of the hormone sliders set to zero. Leave them like that. Set all the hide switches to ON except the ones for ATP and cAMP. Click on the Setup button, which will initially turn black, when it's back to its original colour setup is complete. Click the Go button. You should see a large number of yellow symbols in the bottom section of the display. These are ATPs. If you look carefully you'll also see some small circular symbols, also yellow. These are cAMP. Hide the ATP using the switch and you'll see the cAMP more clearly.

The blue hexagonal symbols that you can also see on the screen are glucose molecules. Although you have glucose hidden they do appear initially when they are first generated. Turn off the hide switches for glucose and glycogen and you'll see the glucose molecules being spawned from the glycogen.

Enzyme activation:

Hide the glucose and glycogen again and turn off the hide switch on protein kinase. You'll see a lot of dull green symbols which are protein kinase. A small number of these will be a brighter shade of green and have a cAMP symbol attached to them. These are active enzymes. If you watch carefully you'll see that eventually the cAMP falls off of the kinase, which then becomes inactive. Similarly, loose cAMPs will bind themselves to inactive enzymes and activate them. This will be easier to follow if you slow the model down slightly with the slider at the top of the graphics display.

Turn off the hide on phosphorylase kinase, which will appear as blue symbols. Again, they can be in the inactive (dull blue) or active (bright blue) forms. They are turned from inactive to active by contact with an active, bright green, protein kinase. There will normally be more active phosphorylase kinases than active protein kinases as each of the latter can activae more than one of the former. You'll see this in the figures in the monitors under the graphics screen.

Hide protein kinase and cAMP and unhide phosphorylase. This enzyme is a pinkish colour. Again see the active forms in the bright colour which have been activated by phosphorylase kinase present in a larger number than the active phosphorylase kinase.

Hide phosphorylase kinase and unhide glycogen. You'll see active phosphorylase sticking to the glycogen and generating glucose. If you unhide the glucose you'll see it being produced from the glycogen. Binding of phosphorylase to glycogen is a temporary one. It will eventually fall off and glucose production will stop.

The graphs:

Look at the Molecular Ratios graph. The columns represent the amounts of cAMP, the three enzymes we've just been discussing and glucose. Notice the increasing height as you go from protein kinase to glucose which demonstrates the cascade effect. The Glucose and Enzymes graphs plot the levels of glucose and active phosphorylase against time. Notice how they follow each other very closely.

The hormones:

Hide everything except cAMP. Drag the insulin slider halfway to give a figure of 10. The insulin symbols will appear ( red "I"s) and move around trying to bind to acceptors. When they do the cyclase enzyme on the inside of the membrane will turn red to show that it's been inhibited. If you've slowed the model down previously you'll probably see this better if you turn it up to full speed again. Notice the reduction in the number of cAMPs and the corresponding decrease in active enzymes and glucose. See this in the graphs and the monitors. You'll notice that the insulin molecules do not stay bound for ever. Eventually they will fall off of the receptor which will then give a small burst of cAMP until it binds another insulin. You can adjust the amount of insulin to alter the level of its effects.

Now set insulin to zero and set glucagon to about 10. You'll see the opposite effect to insulin as glucagon activates adenylate cyclase. A lot of glucagon will bring about a large increase in glucose production. The scaling on the graphs will increase as necessary to accommodate this.

Glycogen biosynthesis:

Press the Go button to stop the model and pick "glycogen synthesis" from the direction slider. Set both hormone sliders to zero and turn the "Feed" switch off. Click the Go button. Watch the Enzymes graph, which is now showing the amount of active synthase. It will fall to come to equilibrium with the current situation in the cell. Once it's roughly levelled out (it will always go up and down a bit as all the changes are random) turn on the Feed switch. Glucose is now being supplied to the cell from the "blood stream" and the cells glucose level will rise unless it is stored as glycogen by the active synthase. You'll see the Glucose graph rising - you might also like to see the effect on the display screen by turning of the hide on glucose. Eventually the Glucose graph will level out as the supply of glucose is balanced by the amount being converted to glycogen. Turn off the feed switch and the glucose level will fall.

Slide the insulin slider completely to the right (20) and again wait until the level of active synthase levels out in the Enzymes graph. Turn on Feed again, wait till the Glucose graph levels out and switch off Feed. Slide insulin to zero and glucagon to 20 and repeat the same exercise with the feed button. Compare the results with insulin, glucagon and no hormones.

THINGS TO TRY

In both modes try using different amounts of insulin or glycogen and compare the results. In the model there are only seven receptors but, because hormones bind by weak bonds, seven insulins will not permanently inhibit cyclase, or seven glucagons permanently activate it. The more hormone you have the closer you are to saturating the receptor. You might also like to add glucagon and insulin at the same time to see how they compete with each other for binding.

Make use of the hide switches to examine different enzymes and look at the change in active enzymes as a result of the hormones.

EXTENDING THE MODEL

This section could give some ideas of things to add or change in the procedures tab to make the model more complicated, detailed, accurate, etc.

NETLOGO FEATURES

This section could point out any especially interesting or unusual features of NetLogo that the model makes use of, particularly in the Procedures tab. It might also point out places where workarounds were needed because of missing features.

RELATED MODELS

This section could give the names of models in the NetLogo Models Library or elsewhere which are of related interest.

CREDITS AND REFERENCES

Copyright: Dr. P. L. Birch - University of Paisley.

Permission is granted to copy, distribute and adapt this model for non-commercial use as long as this copyright notice is maintained.

A Web version is available at:

http://www-biol.paisley.ac.uk/courses/cellsug/glycogen.html