Lactate and ketone metabolism in context of brain energetics and lactate shuttle | Peter Attia

Lactate and ketone metabolism in context of brain energetics and lactate shuttle | Peter Attia

February 12, 2020 2 By Jose Scott


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.