Download VV08

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.