Gary Krieger asks, “Could you please compare and contrast cataract degenesis
(meaning the formation of cataracts) as it relates to the polyol pathway and MGO (meaning
methylglyoxal). Thank you.” And then he adds, “Are they independent or related causes?” So,
I think I understand what you're asking, Gary. So,
there’s pretty strong evidence the cataracts are driven by glycation of lens proteins. And although
the word “glycation” implies that it's sugar behind it, I did my doctoral dissertation
on methylglyoxal and I've made very clear in what I've written and spoken elsewhere
that that's not true. That's kind of a misnomer and that most glycation happens within the body
driven by small dicarbonyls that are actually derived at least from ketones (meaning fat
and carbohydrate) and probably also released through amino acid metabolism. And so,
in this process of glycation driven by these dicarbonyls, a prominent one of which
is methylglyoxal, they cause proteins to stick together. And if you glycated the lens proteins,
the lens proteins stick together and that's a key process in the generation of cataracts.
So, I believe what Gary is asking is “Is the polyol pathway activation
and methylglyoxal independent causes of cataract formation or are they related to one another?”
And the answer is a little bit of both. You know, if independent means unrelated, then they’re
related. Not independent. But they are independent in the sense that you could have more of one. You
know, you could do something that increases one and not the other or at least disproportionately
increases one versus the other. So, the polyol pathway, I think the best way to describe that
is under conditions of severe hyperglycemia where you have too much sugar to be disposed
of in the normal routes. You can use the sugar to synthesize polyols. You know, in chemistry,
something that ends in OL is an alcohol. Sugars are alcohols. And when something has multiple
alcohol groups added to it, you wind up with something called the polyol. Anyway, polyol
chemistry is not the key thing here. The key thing here is in the polyol pathway, you consume NADPH.
And NADPH is needed to recycle glutathione. Glutathione is needed, among other things, to
detoxify methylglyoxal. And methylglyoxal causes cataracts. Now, that's not to say
that there aren’t other things going on. I mean, certainly glutathione is also needed to defend
against oxidative stress. But then again, this might not be the only way that oxidative stress
contributes to cataracts, but oxidative stress increases methylglyoxal generation
in part by decreasing the activity of glyceraldehyde 3-phosphate dehydrogenase or GAPDH,
which is the enzyme within glycolysis that is responsible for clearing
what are known as triose phosphates. If you know glycolysis, this is glyceraldehyde
3-phosphate and dihydroxyacetone phosphate. So, this is probably beyond maybe what you
want to get into, but just in case it's not since I’m down this pathway already.
Glyceraldehyde 3-phosphate and dihydroxyacetone phosphate, which you can conceive of as basically
on their way to being half of a sugar molecule, they interconvert with one another. And the
intermediate in between them can spontaneously dephosphorylate it and generate methylglyoxal.
And that is one of the origins of methylglyoxal. I said before you can also derive methylglyoxal from
fat through ketogenesis because acetone, which is a byproduct of ketogenesis— If you get ketone
breath that smells like nail polish remover for ladies or paint thinner for the dudes—
Okay. I know some dudes might wanna wear the nail polish. Some women might wanna paint houses.
I know. Okay. So, acetone is metabolized in a 2-step process to generate first acetal and then
methylglyoxal. Right? Okay. So, methylglyoxal can be derived from more than one pathway
and NADPH does multiple things. Glutathione does multiple things. And so, hyperglycemia
driving the polyol pathway may do many things. However, they're connected in the sense that
polyol pathway means lower NADPH, which means less recycling of glutathione,
which means less detoxification of methylglyoxal. Less glutathione also means more oxidative stress,
which means less GAPDH activity, which means more triose phosphates, which means more
triose phosphates spontaneously dephosphorylate to produce methylglyoxal in the glycolytic pathway.
And so, at least in the context of hyperglycemia, those two are going to be very connected because
the polyol pathway via NADPH depletion is driving both an increase in methylglyoxal production and
a decrease in methylglyoxal detoxification, which means more methylglyoxal, which means
more glycation of lens proteins, which means more cataracts. However, it’s possible to drive the
polyol pathway without hyperglycemia actually through galactose consumption. One hypothesis
is that drinking milk beyond the capacity to metabolize the galactose can drive cataracts,
which is through an alternative means of activating the polyol pathway.
But like I said before, you would be wrong to conclude from this that you should just go on
a milk-free ketogenic diet and thereby avoid the polyol activation because you might wind up with
more methylglyoxal as a result of more acetone, in which case that really has nothing to do with
activating the polyol pathway. So, when the polyol pathway is activated, they're very connected,
but methylglyoxal does not have to be connected to the polyol pathway. All right. Gary, I hope
that answers your question and I apologize if that was more detail than you wanted.