Is lactate as important as glucose for metabolism?

If the lactate shuttle guys are right, maybe!

Introduction

Before I start this essay, I have to apologize in advance: it’s going to get wonky. But, I think it’s important, so stay with me.

I’ve been puzzled for a while about the whole insulin/glucose system¹. The traditional story, where insulin and glucagon keep your blood sugar in check, while obesity causes insulin resistance and underproduction and so mess up the blood sugar system, works only up to a point. There are a bunch of holes, though, starting with how there’s no consistent relationship with fat and insulin or insulin resistance². 

I’ve speculated before that there’s probably some missing pieces to the story. It’s really hard to break out of the insulin/glucose model in relation to diabetes and obesity, but we need to, because these are human diseases and a human way of looking at the energy system. Insulin is found across the animal kingdom (including, in a modified form, in insects), and glucose is used, well, everywhere. Even prokaryotes use glucose. Trying to understand insulin and glucose by only looking at humans is like understanding eyesight by only looking at human eyes. Like yes, it’s somewhat informative, but a lifetime of studying human eyes would not prepare you for the mantis shrimp. 

Mantis shrimps have famously complex eyes, which can move independently and can detect polarized light. There’s currently a lively debate on whether this actually yields better color vision than humans. Regardless, their eyes are really weird, especially compared to humans’.

While doing research for my last blog on the strange case of the frozen painted turtles, I came across what I think may be some missing piece of the puzzle. If you recall, in my last blog, I introduced to you (or more likely, re-introduced to you) anaerobic respiration. Anaerobic respiration ends up being a big deal for painted turtles because they hide underwater or under mud for the entire winter, which means they have to deal with very low oxygen conditions for months at a time. They deal with this by having their cells switch solely to lactate fermentation, but that raises the issue of lactic acid buildup, which turtles deal with by adding calcium lactate to their cells.

While doing research for my turtle post, I started to realize that I didn’t know much about lactate. All I knew was lactate as a waste product that could also be used as a fuel, sort of like if your car produced canola oil from its exhaust. On the one hand, that would probably be useful to burn if your car’s equipped for it. On the other hand, it’d result in canola oil everywhere, so it can very easily turn into more of a hindrance than a help.

This idea of “lactate as waste product that can also be used as fuel” is in line with how pretty much everyone thinks about lactate, as far as I can tell. That’s what the standard line when I was looking at turtles was. But that seemed unsatisfactory to me. Lactate is everywhere. Even the organisms that can’t easily excrete lactate, like deep sea fish, use lactate as an energy source temporarily before converting into ethanol and excreting it. It’s weird to think of such a universal energy source as a waste product. If every car constantly generated canola oil from its exhaust and used it as fuel, you might just think that the canola oil pipe isn’t a waste product that coincidentally cars can use as fuel. You’d think it was just another part of how cars work. 

Similarly, maybe lactate is just part of how cells work. Maybe there’s a really good reason it’s everywhere, and not just because it’s a necessary evil. Maybe there’s something particularly useful about it. Would make sense, no?

The Lactate Shuttle Hypothesis

Well, apparently, I’m not the only one who’s thought lactate might actually be quite useful. Others also have thought the same thing since at least the 80s under the name the “lactate shuttle hypothesis”. Basically, the theory goes that lactate, far from being a waste product, is actually a universal energy transporter. It’s like oil: definitely a problem if it accumulates in the wrong place, but actually really useful as a means of transferring energy around the body in a way that glucose is not. Because, although glucose is energy dense, it’s also highly specific, and can only be transported by glucose transporters. 

Lactate, in this hypothesis, is less energy dense but more easily transported or “shuttled”. So, in this view, glucose ends up being the fuel for the most important cells which tend to have glucose transporters, like the brain or the immune system, but, whenever there’s a lack of glucose transporters, lactate is there to carry the energy away to be used somewhere else.

To go back to the canola oil analogy, it’d be like if we had a limited number of trucks that could carry gasoline, but any guy with a jug could carry canola oil. So, the gasoline trucks end up preferentially carrying the gasoline to the most important places (like a military installation or a hospital), but, whenever we run out of gasoline trucks (or there are too many gasoline trucks on a single road and there’s a traffic jam), we convert the gasoline to canola oil, pour it in a jug, and tell the nearest guy, “Hey, go find someone who needs energy”. Whoever’s left that needs energy gets canola oil, which is better than nothing.

This is a big claim, of course. It brings lactate from the sidelines to the center of the action. So, like any big claim, it requires some big evidence. Fortunately, we have some, courtesy of this paper, which also was the paper that introduced me to the lactate shuttle idea. The paper is a little confusingly organized, but it can basically be understood as presenting the reasons why people didn’t think lactate was a central fuel source and the reasons why the paper thinks these people are wrong. So, that’s how I’m going to organize my summary of the paper’s evidence as well. I’m going to put why people didn’t think lactate was central in italics, and the paper’s rebuttals in normal font. 

Evidence for the lactate shuttle hypothesis

1. Cultured mammalian cells prefer glucose and grow very well on it.

That’s an artifact of how cultured mammalian cells are grown. Most of them are grown in mediums with serum growth factors, glucose, and no lactate. So, of course they’d prefer glucose. And, when they do end up producing lactate (which most of them do, even in oxygen rich conditions), that lactate gets swept away every time the medium gets changed and the cells get a whole new batch of glucose. So, these cultured mammalian cells have basically no constraints on the amount of glucose they can metabolize or the amount of lactate they can secrete.

If you made cultured mammalian cells grow in mediums that more closely resemble natural conditions (i.e. a mostly stagnant mix of 5 mM glucose and 1mM lactate), you’d see that they also like to metabolize lactate as their glucose transporters get overwhelmed.

2. When you look at the arterial-venous differential of glucose vs. lactate, you see there’s approximately a 5:1 glucose:lactate metabolite ratio. This suggests that most of the metabolism that’s going on is metabolism of glucose, and a minority of the metabolism is lactate. That minority is just the conversion of lactate waste to glucose fuel.

This is just because lactate has a really rapid turnover. So glucose is taken up slowly and metabolized slowly, so you end up with large, slow-moving pools of glucose metabolites. Meanwhile, lactate is exchanged rapidly and diffused throughout the body, so you don’t end up with large pools.

This is supported by isotope-tracing measurements, where glucose and lactate are radioactively labeled and introduced into the bloodstream. It’s possible to then see how rapidly the radioactive glucose and lactate are diluted by endogenous production (i.e. faster production of lactate results in faster dilution). Using this, we see that lactate production is consistently twice that of glucose on a molar basis, so equal to glucose on a per-carbon basis (lactate is 3 carbons, glucose is 6 carbons). If they’re equal, this puts lactate at least in as central a role as glucose.

3. The brain, the most important organ, uses glucose directly.

Yes, but all the other organs prefer glucose is converted to lactate, according to isotope tracing.

4. Glucose is needed for really important functions: brain, immune system, glycogen, glycosylation. There are no functions or organs that need lactate.

Exactly! It’s not that glucose isn’t important. It’s just that it’s not universal. Glucose gets reserved for the most important functions and organs, and lactate gets used for everything else. This is supported by the fact that the vast majority of glucose is taken up by functions that need glucose, but lactate gets taken up equally almost everywhere.

5. Lactate accumulation is dangerous. There’s no way it could be a central energy source.

Too much lactate in one place is dangerous, yes. But lactate is well-mixed and exchanges rapidly. As long as glycolysis and the citric acid cycle are still happening at a normal rate somewhere in the body, then lactate can easily be cleared out by aerobic metabolism. 

Discussion

To be honest, I don’t have a strong opinion about whether this hypothesis is actually correct. I feel a little too uncomfortable with biochemistry, especially because so much of this argument hinges on isotope-tracing, which is not a technique I’m super familiar with in the human body. But, I will say this isn’t a niche position. The paper I linked to above is by a Princeton professor, and it’s been cited over 400 times since 2020.

So, let’s pretend, for a second, that this is correct. How does this help solve our mysteries? Well, for one thing, it’s an additional control on glucose and, by extension, on insulin. From there, we can get additional controls on fat. Obesity does seem to raise lactate levels, and weight loss does seem to lower it, although it’s difficult to say how fast it lowers it. Whether this is directly through lowered oxygen or by some other mechanism remains to be seen.

I think the best experiments to do would be looking at how rapid interventions, like insulin administration, GLP-1 and GIP agonists and antagonists, and gastric bypass surgery impact lactate consumption and production, especially before there could be any impact on oxygen (i.e. before significant weight loss). It’d be especially interesting if it could be shown to have some impact that’s unrelated to the mitochondria.

However, as mentioned, I’m still unsure about the details. So if you, dear reader, have any interest in this, please let me know your thoughts. I’d love to hear them!

1. Quick reminder of how this system is traditionally understood to work:

You eat and digest a strawberry. This increases the glucose in your blood. If this blood glucose gets high enough, your pancreas releases insulin. The insulin prompts your cells to take up glucose. Some of this glucose goes immediately through glycolysis, where it can be used for very short term storage (pyruvate) on the way to being converted to NADH (other very short term storage) or ATP (immediate fuel). 

Pyruvate can only be converted to NADH or ATP by the electron-transport chain in the mitochondria, which requires oxygen, or lactate dehydrogenase, which doesn’t.  Other parts of this glucose is converted to glycogen through glycogenesis, which is medium term storage in your liver and muscles. If there’s excess glucose, it will be converted to fatty acids and eventually fat (long term storage), which also requires the mitochondria, unlike glycogenesis.

An hour later, you work out and your muscles require energy. They take up glucose from your blood and your blood glucose drops. Your pancreas secretes glucagon. This prompts your liver and muscles to convert their glycogen (medium term storage) into glucose (short term storage) and release it into the bloodstream, raising your blood glucose level. This also prompts your liver to try to convert other substances into glucose, including lactate.

2. Quoting from my own article: It’s true that obesity tends to lead to type 2 diabetes, which leads to underproduction of insulin and insulin resistance. However, directly administering insulin tends to lead to weight gain. Also, insulin resistance goes away almost immediately upon any amount of weight loss, and then re-establishes itself on any amount of weight gain. 

However, both fat cell creation (lipogenesis) and fat cell destruction (lipolysis) also lead to drops in insulin resistance. Oh, and also, pretty much any medication that interacts with GLP-1 receptors or GIP receptors, whether agonizing them or antagonizing them, leads to insulin secretion.