We re-drew the figure from last time that showed that, once taken up, glucose could be stored (as glycogen) or oxidized (down glycolysis).

We’d already said in the previous lecture that the fate of glucose would depend on the relative rates of these two pathways… and that this, in turn, would depend on the activities of the slows, rate-limiting steps in those pathways.

So now was a good time to talk more about rate limiting steps and the way that they are controlled…

So cue my favourite example… the flux through the gates at Redfern Station.

This analogy allowed us to explore the different ways of regulating flux through the gates – opening more gates (changing them from closed to open, but not actually changing the total number of gates), increasing the activity of each gate (ie, allowing more people to move through per ticket or perhaps making the jaws open faster), brining in another set of gates when needed or, even, actually building new gates when needed!

The first two of these were likened to covalent modification (also known as reversible phosphorylation) and allosteric modulation. See V&V p402-404 for more.

We then identified the rate limiting steps glycogen synthase and phosphofructokinase as being regulated by reversible phosphorylation and allosteric binding, respectively.

And we noted that GS was stimulated by insulin (which stimulates the phosphatase that dephosphorylates and activates GS) and that PFK was stimulated by a rise in ADP and/or AMP levels. The latter would happen whenever ATP was being used – as, for example, when the anabolic glycogen synthase reaction was in full swing! So this was a great example of how the consumption of ATP by an anabolic pathway drives the oxidation of glucose.

Sadly, this section is not well complemented by V&V which treats the regulation of GS is MUCH more detail. In common with most textbooks, it covers the whole network of glycogen-associated kinases, phosphatases, and phosphorylations instead of just stating the simple… ie, that insulin stimulates GS by activating PP1!!

We will return to the regulation of glycogen metabolism (and will cover all those reversible phosphorylations!) when we cover starvation and exercise.

We also saw how the muscle recruits GLUT-4 transporters (which normally live in the Golgi) to the cell surface when insulin binds to its receptors on the cell surface. This facilitates the massive uptake of glucose into the cells. An example of moving in an extra set of gates at the station!!

Then we turned out attention to the trapping step – the conversion of glucose into glucose 6-phosphate.

We learnt that the enzyme that does this exists in two distinct forms – with the major consequence being that, in the liver, glucose can be efficiently trapped even when its concentration is very high… whereas in the peripheral tissues, it is the rate of USE of glucose 6-phosphate that largely determines the rate of trapping.

V&V p749 is pretty good on the hexokinase/glucokinase differences but fails to mention the most important factor – the GLUT-2s!!

A responsive glucokinase, coupled with the fact that the glucose rapidly equilibrates across the liver cell membrane (because liver has the very active) GLUT-2 transporters, means that the liver is quit efficient at soaking up much of the glucose that arrives in the hepatic portal vein after consumption of a high-carbohydrate meal.