when you're talking about diabetes in the brain being Alzheimer's, what's really interesting
to me is the fact that neurons are actually mostly using lactate from astrocytes.
Astrocytes are glycolytic.
The astrocytes are these brain cells in your brain which are using glucose mostly, or using
glucose to generate lactate.
Lactate then gets shuttled into neurons, and the reason why neurons like that is because
it's thermodynamically favorable, much like beta-hydroxybutyrate which you mentioned,
BHB, because it can shunt right into the TCA cycle in the mitochondria...
[Peter]: But wait, how does the brain outcompete the liver for lactate?
So, like, if I made you go out there and do a bunch of burpies, right?
So the...I'm blanking on the name of the transporter.
[Rhonda]: MCT.
[Peter]: MCT1 or MCT2?
Which one is the transporter out of the muscle?
[Rhonda]: I don't know which one.
[Peter]: Okay, but the majority lactate is going to be generated in the muscle.
So then MCT is going to transport that out.
And remember, it's going to go through the portal system...it actually it doesn't go
to the portal, it passes through the cava, but it's still passing through the liver.
How does the brain managed to get any without the liver taking it all into the Cori cycle,
which seems to me the preferential place to undergo gluconeogenesis.
[Rhonda]: Yeah.
So what's weird is that...I don't know the answer to your question.
I know that many tissues...and this has been shown through the work of George Brooks at
UC Berkeley who actually pioneered the lactate shuttle hypothesis and the theory.
But it's been shown that it gets taken up by the liver, it gets taken up by the muscle,
it gets taken up by the brain.
In fact, exercise itself has been shown to preferentially cause the brain to the take
up more...
[Peter]: Can we measure...I don't know if you read this literature but there was a lot
of really interesting work back in the '60s done at Harvard with real fasting experiments.
I mean 40-day fasts.
So you'd have inpatient subjects given nothing but water and minerals for 40 days.
And it was done to basically demonstrate what the steady-state fasting levels of glucose,
insulin, BHB, and acetoacetate would be.
And it's actually quite interesting, right?
So you take a normal person.
We'd take you and let's say your insulin level is 10, your glucose level is 95, your BHB
level is unmeasurable because you're on a normal diet, and your acetoacetate level is
unmeasurable, and then we just fast you.
And it turns out that within about seven days, you'll be at a ketone level of 5 to 7 millimolar,
glucose will be down to 3 to 4 millimolar, which is, call it 60 to 70 milligrams per
deciliter.
And you will stay at those levels in...you know, at the end of the 40 days, they're still
in those levels.
[Rhonda]: So they stay the same.
[Peter]: So glucose remember really goes away.
What's changing is the consumption by the neuron which goes from, at the initial state,
being about a 100% glucose...of course, I don't think they were measuring lactate then
so we don't actually...
[Rhonda]: Were they looking at neuron or just brain?
Was it astrocytes or neuron...
[Peter]: They were probably just looking at brain.
Yeah.
But it would fall to maybe 40% or 50%, the rest of it being made up by the combination
of the ketones.
And it's interesting that they never went to zero, right?
So even to your last day of life, if you're being starved to death, you still have glucose
in your blood.
And so it's kind of interesting that, like...what percentage of overall brain metabolism do
you think is driven by lactate?
It must be very, very small and reserved for a very, very specific subset of neurons or
astrocytes or...
[Rhonda]: Well, the astrocytes are using the glucose and they're generating lactate.
So the lactate doesn't have to get in.
[Peter]: So we're not even seeing that, so that might be the issue.
So that's probably why the liver doesn't matter because it's...
[Rhonda]: Yeah, during exercise, I mean.
But it has been shown that lactate will cross over the blood-brain barrier during exercise
as well.
But that is why it doesn't have...
[Peter]: But the dominant source is...
[Rhonda]: The astrocytes, yeah.
The astrocytes are making it in the brain.
And what's fascinating is...
[Peter]: So astrocytes don't have mitochondria?
[Rhonda]: They do.
[Peter]: So why do they make all the lactate?
[Rhonda]: I think they make the lactate because that's how the neurons are getting their energy.
I think that's just the way it works out.
[Peter]: So it's sort of a Warburg effect.
The Warburg effect, of course, to me is interesting because I don't buy the argument that the
Warburg is due to defective mitochondria.
[Rhonda]: It's not.
Warburg showed that...I mean he...
[Peter]: No, there are still a lot of people who think that it's that cancer affects of
mitochondria, and that's why the Warburg.
But I think it's just that the cancer cell's smart enough and it's optimizing for cellular
building blocks, and it sounds like the astrocyte is doing the same thing.