Let's take a look at the actions of metformin in each of the
different organs. In the liver, metformin will activate
AMP-stimulated protein kinases and it will inhibit
gluconeogenesis. This is an important concept to understand
because remember that metformin is acting in
each organ to reduce blood sugar levels.
So, reducing gluconeogenesis reduces blood sugar.
In the kidney it activates AMP-stimulated protein kinase,
just like the liver. And once again it inhibits gluconeogenesis.
In the adipose tissue, it activates AMP-stimulated protein
kinase, and once again it increases glucose uptake,
thereby reducing blood sugar levels. In the gut
and pancreas, it slows glucose uptake.
Now this will reduce plasma glucagon levels as well in the
pancreas. And that's an important consideration because remember that
plasma glucagon will increase blood sugar levels. So the
actions of metformin by reducing plasma glucagon is really important.
Let's take a look at another class of drugs, called the
alpha-glucosidase inhibitors. The prototypical drug is acarbose.
So I am going to mention acarbose by name on multiple
occasions. Now in the gut, without acarbose you have a
tremendous amount of carbohydrate absorption in the small
bowel. With acarbose in the upper small intestine,
you have much less carbohydrate absorption in the upper small
intestine. And in the lower small intestine,
the majority of carbohydrate absorption is occuring. Now that
doesn't neccessarily mean that there is a lot of carbohydrate
absorption occuring in the lower intestine. It just means
that there is a bit of a shift.
This ends up resulting in a lower glycemic excursion,
particularly after meals.
Alpha-glucosidase will convert starches into monosaccharides.
Now, the absorption as I mentioned is slowed,
but not neccessarily reduced. It's taken before meal and it
affects your postprandial glucose.
Obviously if you are going to leave something in the gut for
a longer time, you're gonna have more GI side effects.
And this is really the big problem with this class of drugs
and why we don't use them as much as we probably thought we would have.
Patients hate these medications. They have tremendous amounts
bowel irregularity. They have tremendous amount of flatulence.
And you know, many of my patients call them their little fart pills.
They hate them, and it's just not useful clinically.
It's important for you to know for your exams though, and I
think it's also important for you to know for your exams of the
increased GI side effects. Because your exam will definitely
ask you, if you are talking about acarbose, about the increased GI side effects.
The treatment of overdose of this medication is dextrose, not
sucrose. So remember that, that's an important consideration
when you're writing your exams. The next class of drugs are
called the TZDs. They end in glitazone,
and so for convenient sakes we actually call them the
glitazones, rather than using that big huge name.
Rosiglitazone and pioglitazone are the two drugs in this
drug class. Now these act on something called PPAR-alpha.
Peroxisome proliferator-activated receptor of the gamma type.
So PPAR-gamma is a nuclear receptor, right in the nucleus of the cell itself,
and it has multiple effects. Number 1, is that it increases
glucose uptake in myocytes. Number 2, it increases glucose uptake in adipocytes.
Number 3, it inhibits hepatic gluconeogenesis.
And number 4, it affects fat distribution in the body.
Now, when you are looking at your other drugs and your looking
at the TZDs, they seem to be doing the same thing, don't they?
But the difference is, is where it's using its effectors.
And in this case the effectors are PPAR-gamma.
That's what distinguishes the TZDs from the other drugs.
It does cause a reduction in fasting glucose and in postprandial glucose.
The alpha-glucosidase inhibitors are really
more about the postprandial glucose reduction.
When we talk about the TZDs, hypoglycemia is actually
quite rare. The problem with the TZDs are also its advantage.
So the PPAR-gamma molecule is a good molecule to inhibit, but
we think that it also has other side effects
that cause it to be less of a desirable drug. We know that
it causes fluid retention. Now we believe
that this may lead to an increase in heart failure. And
there is some suggestion when we do meta-analysis trials.
We also believe that there may be an increase in myocardial infarction
rates with this medication, which I think effectively killed the class,
at least in terms of marketing. In terms of the liver, you
need good liver enzyme monitoring regimens.
So you need to be monitoring them on a very regular basis.
There is some suggestion that there may be an increase
in bone fracture risk with these medications. So once again,
we think it might be a PPAR-gamma activated or mediated event.
We're not sure, but we know that these major side effects of
TZDs, have really relegated them to the back burner in most people's minds.