The intimate triad glycogen – lactate – beta-hydroxybutyrate

There is a close relationship between glycogen, lactate and beta-hydroxybutyrate (BHB) that I would like to highlight in this post. Although it looks like a simple relationship, it has important implications. There is more to cover but I’ll focus on the acute phase.

The essence

A first scenario, no matter the available fuel type (fat, glucose) in the circulation and at whatever ratio, glycogen contributes to the metabolism. I’m referring here to glycogen in all cell types, not just the liver or skeletal muscle cells. Glycogen in a cell is a buffer and a measure of available energy. When energy demand is higher than the rate at which glycogen can be build up, we get a declining level of glycogen. Very simple.

In such a way it is a measure of energy supply from the circulation. Increasing glycogen means sufficiency in circulation and declining glycogen the opposite. With declining levels at some point the situation becomes critical. How do you change the situation? How can a cell signal that it requires more energy?

As the glycogen level gets depleted..

  1. It first of all reduces the contribution of the glycogen to metabolism.
  2. It increases lactate production

Point 1 seems contradictory, we need energy so why reduce the contribution from an energy source? If the fuel in circulation is inadequate and glycogen level is low, the cell will dial down the activity to match what is available from the circulation to save as much of the remaining glycogen as possible. It simply cannot afford full depletion. It will use the glycogen for point 2 to attract more energy from outside the cell.

A second scenario, very similar to the first case but a different trigger, is hypoxia. When not enough oxygen is available, the mitochondria will be impaired in providing the necessary ATP. This also increases lactate production. It is something we know from cancer cells but is not uniquely attributable to cancer cells.

Common to both scenarios, the cell is in trouble for sufficient ATP production. So how can a cell rescue itself? There are a few tricks to rescue itself.

I suspect lactate increases GLUT1 expression so it can try and increase glucose supply to continue its glycolysis but still, this produces a low level of ATP versus what the mitochondria are capable of (yet faster production method).

Increasing lactate in the cytosol also increases monocarboxylic transporter 1 (MCT1) membrane expression. It does this to get rid of the lactate because it brings down the pH, but by doing so it opens the gates through which BHB can enter the cell.

BHB can get processed in the mitochondria and will generate more ATP while not requiring oxygen. So whatever the cause (low glycogen or hypoxia) it can provide more energy in a situation where there is a shortage in energy.

Once the lactate is out of the cell, we are not finished yet. It has to get into the blood circulation and we need to get BHB from the circulation into the cells. Endothelial cells need to get both substances across using the same transporters.

How this happens is not clear. A cytosolic increase in lactate increases the MCT1 expression but now we are outside of the cells. How do we get the endothelial layer to increase locally its MCT1 expression?

I wonder if this is a potential reason for why red blood cells have no mitochondria. They can only process glucose anaerobically so they are a constant source of lactate in the blood. Perhaps they keep the endothelial cells ready (since birth!) for cases where a local rise in lactate may emerge?

We also see the brain producing an excess amount of lactate making it export lactate at rest. Why wouldn’t it absorb all? After all it has a high need for energy and it can metabolize lactate without a problem. How important is it to ‘prime’ the system for adapting to shifts in metabolic substrates throughout the body? During exercise we see the flow of lactate reversed from circulation to the brain.

Is it comparable to a throttling car? It is much easier to start driving when already throttling compared to a cold engine that is not running at all.

References

“Monocarboxylate Transporter 1 Deficiency and Ketone Utilization” https://www.nejm.org/doi/full/10.1056/NEJMoa1407778

“The energy-less red blood cell is lost: erythrocyte enzyme abnormalities of glycolysis” https://ashpublications.org/blood/article/106/13/4034/133232/The-energy-less-red-blood-cell-is-lost-erythrocyte

“Long-Term Glucose Starvation Induces Inflammatory Responses and Phenotype Switch in Primary Cortical Rat Astrocytes” https://link.springer.com/article/10.1007/s12031-021-01800-2

In the next part I’ll go a bit more in depth and show what implications it has in practice.

Mechanisms

Glucose metabolism

Lactate is produced in cells through glycolysis. In the cytosol, glucose gets broken down to pyruvate. Pyruvate gets broken down further to lactate (referring to it as cytosolic glycolysis (cGY)). But for the majority of pyruvate is imported in the mitochondria where it is further converted to acetyl-CoA and processed in the TCA to produce much more ATP (mitochondrial glycolysis (mGY)). So only cGY produces lactate.

Response to lactate

Important to know is that MCT1 (and MCT4) can be quickly upregulated. Especially during exercise this is needed but also during acute issues in metabolism. Lactate is an acid and would lower the pH of the cytosol while this needs to be kept in balance. The lower the pH, the more spontaneous reactions happen while it has to be kept under control.

“Exercise rapidly increases expression of the monocarboxylate transporters MCT1 and MCT4 in rat muscle” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1665342/

GLUT1 expression

As mentioned earlier, lactate may increase GLUT1 expression which seems like a logical consequence. Under stimulation of hypoglycemia, the blood-brain-barrier increases GLUT1 concentration to increase glucose uptake. It needs a signal to do this.

“Blood-brain barrier glucose transporter: effects of hypo- and hyperglycemia revisited” https://pubmed.ncbi.nlm.nih.gov/9886075/

“Chronic hypoglycemia increases brain glucose transport” https://pubmed.ncbi.nlm.nih.gov/3532819/

During exhaustive exercise, the rat brain has upregulated GLUT1 in the cortex.

“Astrocytic glycogen-derived lactate fuels the brain during exhaustive exercise to maintain endurance capacity” https://www.pnas.org/content/114/24/6358

Cells that experience hypoxia upregulate GLUT1 expression as we can observe in cancer cells. Hypoxia itself is directly responsible for this.

“Hypoxia and Mitochondrial Inhibitors Regulate Expression of Glucose Transporter-1 via Distinct Cis-acting Sequences” https://www.sciencedirect.com/science/article/pii/S0021925818877146

Rats that are put on a ketogenic diet have an increased brain uptake of glucose (and acetoacetate). They found a 2-fold upregulation of MCT1 yet no increase in GLUT1 in the following study.

“Mild experimental ketosis increases brain uptake of 11C-acetoacetate and 18F-fluorodeoxyglucose: a dual-tracer PET imaging study in rats” https://pubmed.ncbi.nlm.nih.gov/21605500/

So it remains to be seen if GLUT1 upregulation is only due to hypoxia or if it can be done by lactate itself but perhaps requires a certain minimum dosage. A last paper on this topic did note an increase in GLUT1 expression in all cases when testing glucose deprivation and hypoxia separately and combined.

r/ketoscience - Keto increases the ability to receive glucose in the brain?

“Glucose deprivation and hypoxia increase the expression of the GLUT1 glucose transporter via a specific mRNA cis-acting regulatory element” https://onlinelibrary.wiley.com/doi/pdfdirect/10.1046/j.0022-3042.2001.00756.x

Again, we see an adaptation when cellular ATP production is impaired, the cell tries to increase influx of substrates that do not require oxygen to produce ATP. Glucose, lactate, BHB fit that job. ATP shortage needs to be fixed acutely.

Glucose sparing

Once BHB can enter the cell, it helps to save glucose usage. We see this for example in CD8+ T-cells where it helps them build up a glycogen buffer.

“Ketogenesis-generated β-hydroxybutyrate is an epigenetic regulator of CD8 + T-cell memory development” https://pubmed.ncbi.nlm.nih.gov/31871320/

A test in mice muscle showed a statistical effect as of 4mmol/L BHB post-exercise. They have a fast metabolism so potentially require higher levels versus humans.

“Effects of β-hydroxybutyrate treatment on glycogen repletion and its related signaling cascades in epitrochlearis muscle during 120 min of postexercise recovery” https://cdnsciencepub.com/doi/10.1139/apnm-2018-0860

Metabolic emergencies

When ATP supply is in danger, it is a metabolic emergency. We see this reflected in a couple of situations.

The failing heart

Different papers have come out showing increased ketogenesis and/or support from ketones under conditions of a failing heart.

“Ketone bodies for the failing heart: fuels that can fix the engine?” https://pubmed.ncbi.nlm.nih.gov/34456121/ – “Cardiovascular Effects of Treatment With the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients” https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.036459 – “Ketone therapy for heart failure: current evidence for clinical use” https://academic.oup.com/cardiovascres/advance-article-abstract/doi/10.1093/cvr/cvab068/6168424 – “Blood ketone bodies in congestive heart failure” https://pubmed.ncbi.nlm.nih.gov/8772754/ – “The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense” https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC6478419/ – “Nutritional modulation of heart failure in mitochondrial pyruvate carrier–deficient mice” https://www.nature.com/articles/s42255-020-00296-1

Different scenarios for failure exist but animal models show a reduction in fatty acid utilization.

“Beta-Hydroxybutyrate, Friend or Foe for Stressed Hearts” https://www.frontiersin.org/articles/10.3389/fragi.2021.681513/full

Acute heart failure is presented with increased lactate. I would guess the source of lactate is from the heart but with a failing heart, hypoperfusion could lead to systemic lower oxygen which would affect all cells in the body. In this paper they noted the increase in lactate without hypoperfusion.

“Increased blood lactate is prevalent and identifies poor prognosis in patients with acute heart failure without overt peripheral hypoperfusion” https://pubmed.ncbi.nlm.nih.gov/29431284/

It is guess work until I find better evidence but my thought is that the shift away from fatty acid oxidation will result in a higher lactate production to make use of the triad to bring in BHB. What is wrong with the heart that it cannot utilize fatty acids though? Or is it a deliberate shift?

Hypoxia

Just on a side note, lactate production, in response to hypoxia, stimulates angiogenesis. A neat way to prevent future hypoxic events. Lactate has many different roles, we’ve come a long way from seeing it as purely a waste product to how we know it today.

“A lactate-induced response to hypoxia” https://pubmed.ncbi.nlm.nih.gov/25892225/

When mice were stressed under hypoxic conditions they could see an improved tolerance. They had to combine iv glucagon and BHB because each alone did not improve tolerance. This is when they wanted to mimic the improved tolerance that is observed under fasting conditions under which glucagon and BHB are increased.

“Hypoxic tolerance enhanced by beta-hydroxybutyrate-glucagon in the mouse” https://pubmed.ncbi.nlm.nih.gov/6775395/

Further study of squirrels and rats indicate survival time linked to the level of BHB reached in the blood.

“Beta-hydroxybutyrate and response to hypoxia in the ground squirrel, Spermophilus tridecimlineatus” https://pubmed.ncbi.nlm.nih.gov/2364670/

In the following paper, the observed a lower circulating lactate level under hypoxic conditions (4.7 mmol vs 6.1 mmol) when comparing the KD with standard (high-carb) in rats, showcasing the ATP that is derived from ketones as a rescue of the metabolic emergency.

“Adaptation to Chronic Hypoxia During Diet-Induced Ketosis” https://link.springer.com/chapter/10.1007/0-387-26206-7_8

An other test on humans was performed to see how cognitive impairment is impacted by acute hypoxia, specifically due to reduced ATP production. A ketone ester (exogenous ketones) restored cognitive performance.

“A Metabolic Intervention for Improving Human Cognitive Performance During Hypoxia” https://doi.org/10.3357/AMHP.5767.2021

Non-alcoholic fatty liver (NAFLD)

Hepatic insulin resistance is part of NAFLD. Knowing that glycogen synthesis requires insulin, it should not be a surprise to observe higher lactate production by the liver due to lack of glycogen buildup.

In the following study in NALFD patients the hepatic lactate production was even higher before a KD diet. The KD diet resolves insulin resistance so we can expect glycogen to build up in these NAFLD patients but not much. A KD still requires low glycogen levels so the liver remains a source of lactate production.

“Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease” https://www.pnas.org/content/117/13/7347

Ketogenic diet

Under normal circumstances, the brain is already producing lactate in surplus so that there is an efflux from the brain to the blood circulation.

“Lactate transport and signaling in the brain: potential therapeutic targets and roles in body–brain interaction” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4426752/

“Striking differences in glucose and lactate levels between brain extracellular fluid and plasma in conscious human subjects: effects of hyperglycemia and hypoglycemia” https://pubmed.ncbi.nlm.nih.gov/11891432/

Under a ketogenic diet we generally see a reduction in glucose roughly as of >= 1mmol/L BHB (anecdotal observation). The brain can’t rely on fatty acids from the circulation so it would end up in energy starvation. On top of that, the skeletal muscle also needs to deal with the reduced glucose availability.

As we have seen above, this would start to deplete the glycogen in the cells so you get an increase in lactate production.

If the skeletal muscle would do this then it would also absorb the BHB that the brain is in need for. Instead, a ketogenic diet increases fat utilization in the skeletal muscle. This reduces the glycolytic action on glucose and thereby reduces lactate production so that it lowers MCT1 expression and lowers uptake of BHB.

The brain however, lowered in glucose affecting glycogen, does increase lactate production so that it can increase BHB uptake.

So everything balances out nicely.

The liver

NADH accumulation from beta-oxidation interferes with pyruvate formation. This essentially blocks gluconeogenesis from sources that require this step such as lactate.

NADH slows down the TCA so that acetyl-coa can pile up and can be used to form HMG-coa to push it further towards ketogenesis.

“Ethanol Alters Energy Metabolism in the Liver” https://www.ncbi.nlm.nih.gov/books/NBK22524/

Especially on a ketogenic diet, exercise will generate more free fatty acids that reach the liver. This is because exercise increases fatty acid release and heart rate causing a faster circulation.

Exercise (on a ketogenic diet)

I had a couple of max effort tests to check on my condition. This gave me the chance to compare lactate before and on a ketogenic diet. The grey line on the graph is on keto. At the early stage you can see how lactate is kept lower until 170 where it goes on par with the result from 2016 and as intensity goes up further, keto bypasses 2016.

Why am I showing this? During the first part, as intensity goes up, you see how lactate is kept lower thanks to relying more on fat but as intensity goes up further, reliance on glucose starts to increase. Because glucose in the circulation is lower, glycogen consumption now starts to increase at a higher rate. When we reach the highest intensity, on KD we are reaching lowest levels so most lactate production.

As you could read earlier, the brain needs the BHB and glucose. When we start exercising, lactate production goes up so the skeletal muscle will take up more BHB while also taking up glucose. That is a problem for the brain if it would not be compensated somehow.

The brain can also utilize lactate as a fuel. So we end up with a situation where the skeletal muscle exchanges lactate for BHB and the brain has to change BHB for lactate.

“Lactate transport and signaling in the brain: potential therapeutic targets and roles in body–brain interaction” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4426752/

This process is supported by the liver which reduces its lactate utilization for the gluconeogenesis (GNG) process. Instead it relies more heavily on glycerol for GNG which does not require the step to convert to pyruvate. This step is what is impacted under increased NADH availability. So we see that the liver is sparing lactate for the brain (and is itself even a source of lactate).

Glycogen utilization

A word on glycogen utilization though. It is assumed that on a KD, it spares muscle glycogen. I would argue yes and no.

A first element to take into account is that as glycogen levels start to decline, its utilization is slowed down. This is independent of diet.

A nice experiment was done by looking at glycogen utilization between 2 legs in the same subject. 1 leg started with reduced glycogen while the other leg didn’t. They observed a 60% reduction from glycogen in the ‘reduced’ leg while it took up 30% more glucose. Because arterial supply was the same, this effect could be fully attributed to the glycogen level.

“Effect of muscle glycogen on glucose, lactate and amino acid metabolism during exercise and recovery in human subjects” https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC2269057/

A paper from Timothy D. Noakes et all. also shows this reduced utilization. This could be wrongly interpreted as a glycogen-sparing effect of the ketogenic diet but note the lower level of glycogen that the KD group started with.

“Gluconeogenesis during endurance exercise in cyclists habituated to a long-term low carbohydrate high-fat diet” https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/JP271934

In contrast, a paper from Jeff Volek et all. shows equal utilization. This could incorrectly be interpreted as that there is no glycogen-sparing effect from the KD.

“Metabolic characteristics of keto-adapted ultra-endurance runners” https://www.metabolismjournal.com/article/S0026-0495(15)00334-0/fulltext

What should be taken into account is the intensity at which ATP needs to be generated. When intensity goes up but mitochondrial ATP production is covering the majority requirement then glycogen utilization will be equal among diets.

However, when intensity goes up mitochondrial ATP will not be sufficient. This is where fat metabolism and glucose metabolism make a difference. Glucose metabolism via mitochondria can be sustained at higher levels although yielding lower ATP amounts compared to fatty acids.

The result is that at very high intensities, glycogen will deplete faster on low carb. Circulating BHB will balance out this situation providing an alternative substrate for the TCA to increase mitochondrial ATP production.

Either BHB or medium chain fatty acids (MCFA) are able to support this action. MCFAs are not impaired for import like LCFAs are.

So does a KD help save muscle glycogen? There is no saving effect at low- to medium-intensity but at high-intensity BHB (and MCFA) do fulfil that role. That is, out of necessity. It doesn’t save glycogen more than high-carb but this is where optimization can help via exogenous ketones or MCT oil.

—- T H E – E N D —-

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