Low ketone levels so I utilize them better?

One of the pervasive thoughts in the keto community is that when they measure lower levels of ketones, the longer they are on the ketogenic diet, that this is caused by a better utilization of the ketones in the body. This is an effect noticed over several months or even years.

But is this true?

I have already highlighted this before here that there is a dependency on metabolism and fat mass but I wanted to highlight a few other things by looking at it from the angle of what it would take to have an increased utilization that would lead to lower measurable levels.

Blood circulation

One of the things to start with is the blood circulation. An interesting article that was actually about something else, showed in a simplified way the blood circulation. Their main point was about glucagon levels where glucagon release from the pancreas flows directly into the liver which processes most of it. What you measure in the arteries is the left over. In a similar way, we need to check where BHB originates from and what it passes when we measure via our finger tip.

What you see on the simplified diagram is that the blood flowing out of the liver goes to the heart and lungs. From there it is spread into the arteries. Our upper extremities including the arms and head get the same supply. Although the head can be a big consumer of ketones, it does not ‘steal’ away ketones from the blood to then leave low ketone levels to the arm, where you measure your BHB level. Both the arms and head get the same fresh supply of blood.

Image sourced from “Four grams of glucose.” Wasserman DH, 2009 https://www.ncbi.nlm.nih.gov/pubmed/18840763

So the only place where a higher consumption could build up over time, leading to a lower measurement, could take place in the heart and/or lungs.

MCT1

One key element for that to investigate is the monocarboxylic transporter 1 (MCT1). This transporter is what brings BHB across and into the cell. In order for the cells to take up more BHB it has to upregulate its MCT1 expression. There are other MCT’s but we’ll focus on MCT1.

MCT1 is important enough for the usage of BHB that it would cause ketoacidosis if not sufficiently expressed. It also disregulates lactate efflux from the cells. Keep that in mind when going further down in this article.

“Monocarboxylate Transporter 1 Deficiency and Ketone Utilization”, Peter M. van Hasselt, M.D., Ph.D., Sacha Ferdinandusse, Ph.D., Glen R. Monroe, M.Sc., Jos P.N. Ruiter, B.Sc., Marjolein Turkenburg, B.Sc., Maartje J. Geerlings, M.Sc., Karen Duran, B.Sc., Magdalena Harakalova, M.D., Ph.D., Bert van der Zwaag, Ph.D., Ardeshir A. Monavari, M.D., Ilyas Okur, M.D., Ph.D., Mark J. Sharrard, F.R.C.P.C.H., Maureen Cleary, M.D., Nuala O’Connell, M.B., Ch.B., Valerie Walker, M.D., M. Estela Rubio­Gozalbo, M.D., Ph.D., Maaike C. de Vries, M.D., Gepke Visser, M.D., Ph.D., Roderick H.J. Houwen, M.D., Ph.D., Jasper J. van der Smagt, M.D., Nanda M. Verhoeven­Duif, Ph.D., Ronald J.A. Wanders, Ph.D., and Gijs van Haaften, Ph.D., 2014, https://www.nejm.org/doi/pdf/10.1056/NEJMoa1407778

Endothelial cells

To get BHB from the blood into the tissue, it first has to pass the endthelial cells. With the endothelial cells being a first barrier for transport from the arteries towards the organ tissue, this is already a limitation for organs to increase their uptake.

To my knowledge there is no organ specific endothelial adaptation to increase uptake. I don’t think this research has been done so we’ll keep this option open.

We do see a change in starvation whereby uptake through the blood-brain-barrier increases with 50%~60% in rat brains. This reached its maximum in about 2 days. So there is some adaptation in expression of MCT1 but still the question is if this is at specific locations or systemic. This is important to know for the heart and lungs.

“Regional ketone body utilization by rat brain in starvation and diabetes.” Hawkins RA, Mans AM, Davis DW, 1986 https://www.ncbi.nlm.nih.gov/pubmed/2937307/

Heart

The heart probably has already sufficient MCT1 expression. We can guess this from its ability to take up BHB in case of acute heart failure. But we can look at the mRNA at several organs in mice and we see that there is no change at the level of the heart. Luckily they also checked for protein expression and also here found no change.

If you check the reference, you’ll notice that expression is up in liver and kidneys. These are the 2 most important organs for gluconeogenesis. I suspect they primarily do this to take up lactate and convert it into glucose.

“Tissue-Specific Expression of Monocarboxylate Transporters during Fasting in Mice”, Alexandra Schutkowski, Nicole Wege, Gabriele I. Stangl, and Bettina König, 2014, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229183/

Lungs

On the lungs we don’t find much data. One article shows MCT1 expression similar to the heart but this is not about fasting or low carb/ketogenic diet. It is in pigs and they were specifically bread to have higher AMPK which induces MCT expression.

“Chronic activation of AMP-activated protein kinase increases monocarboxylate transporter 2 and 4 expression in skeletal muscle”, E. M. England, H. Shi, S. K. Matarneh, E. M. Oliver, E. T. Helm, T. L. Scheffler, E. Puolanne, and D. E. Gerrard, 2017, https://www.ncbi.nlm.nih.gov/pubmed/28805903

When it comes to lactate production, they are close to zero unless there is a respiratory issue. More on lactate further down.

“Lactate Production by the Lungs in Acute Lung Injury”; DANIEL DE BACKER , JACQUES CRETEUR , HAIBO ZHANG , MICHELLE NORRENBERG , and JEAN-LOUIS VINCENT, 1997, https://www.atsjournals.org/doi/full/10.1164/ajrccm.156.4.9701048

Cancer

We have to be careful with this interpretation but what we see in cancer is that there is an increase in MCT1 expression upon glucose deprivation. So it is possible that, in order for MCT1 to be increased in expression, we must experience a reduction in blood glucose. Glucose deprivation seems to stabilize MCT1 and CD147.

Not only glucose deprivation but also hypoxia stabilizes and upregulates MCT1. Hypoxia will result in reduced oxidative phosphorylation and more lactate production. We’ll get back to this further below.

“Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration” C J De Saedeleer, P E Porporato, T Copetti, J Pérez-Escuredo, V L Payen, L Brisson, O Feron & P Sonveaux, 2013, https://www.nature.com/articles/onc2013454

I have highlighted CD147 specifically because this is required to increase MCT1 movement into the membrane. This is shown in a study on Saccharomyces. A long stretch from humans but MCT1 is maintained across all eukaryotes and we see this in the research on tumors as well.

“Co-expression of a mammalian accessory trafficking protein enables functional expression of the rat MCT1 monocarboxylate transporter in Saccharomyces cerevisiae”, Judita Makuc, Corinna Cappellaro, Eckhard Boles, 2004, https://academic.oup.com/femsyr/article/4/8/795/627683

pH

MCT1 is not only used to bring in BHB, it is also used bi-directional to regulate pH intracellular affected by lactate concentrations. This was already highlighted in our MCT1 deficient cases above. It is also a hallmark of cancer cells which export all the lactate to maintain pH balance.

We also see that with exercise, MCT1 is rapidly adjusted in its expression in skeletal muscle and depends on the metabolism of the cell. It is interesting that it adjusts so quickly. Could it mean the skeletal muscle prevents, as much as possible, the uptake of ketones in a resting state to preserve it for the brain? The higher fat metabolism will certainly not create more lactate at rest.

“Lactate transport in skeletal muscle — role and regulation of the monocarboxylate transporter”, Carsten Juel Andrew P. Halestrap, 2004, https://physoc.onlinelibrary.wiley.com/doi/full/10.1111/j.1469-7793.1999.0633s.x

Brain lactate

When we check what is going on with the brain under fasting, we see that it increases lactate in the brain. This lactate could potentially increase MCT1 in the blood-brain-barrier, causing a local effect in the epithelial cells. This would be a novel way for the brain to increase its absorption of BHB. If other organs don’t do this then higher levels may mean its all to favor the brain.

“Human Brain β-Hydroxybutyrate and Lactate Increase in Fasting-Induced Ketosis”, Jullie W. Pan, Douglas L. Rothman, Kevin L. Behar, Daniel T. Stein, Hoby P. Hetherington, 2000, https://journals.sagepub.com/doi/10.1097/00004647-200010000-00012

Interestingly, in fasted rats they observed normal lactate levels. I suspect that upon increased fat metabolism our lactate production goes down because you need glycolysis for that. But the brain may be increasing its lactate production and export so that plasma levels of lactate appear unaffected.

“Diet-induced ketosis increases monocarboxylate transporter (MCT1) levels in rat brain”, Richard L. Leino, David Z. Gerhart, Roman Duelli, Bradley E. Enerson, Lester R. Drewes, 2001, https://www.sciencedirect.com/science/article/abs/pii/S0197018600001029

We see basal lactate unaffected in the FASTER study of athletes who were at least 6 months on a low carb diet. But here we have highly trained athletes so their lactate disposal may be optimized.

image source: https://www.sciencedirect.com/science/article/pii/S0026049515003340

The following study discusses the increase in lactate production by astrocytes when glucose levels are on the downward trend. This further supports the idea of an increase in brain lactate production under a low carb diet.

“Astrocyte glycogen and brain energy metabolism” https://pubmed.ncbi.nlm.nih.gov/17659525/

Putting things together

So first of all we have the endothelial cells to keep in mind which are lining the blood vessels. MCT1 expression is influenced by glucose availability but we are not witnessing an increasingly lower glucose over time when we see a lower BHB production. On the contrary, a reduction in glucose is giving us higher BHB measurement. After all, that is part of what BHB is supposed to do, serve as an alternative fuel to the brain. Only when BHB goes up significantly we’ll see a drop in glucose.

Lactate also stays at normal level, there is no hypoxia in endothelial cells so we have to conclude there is no systemic trigger to increase MCT1 in the endothelial cells.

Then there is the possible local effect of lactate on MCT1 expression so do the heart or lungs generate more lactate as the brain seems to do? Also here we have to say no. We don’t see any increase in protein levels in the heart which evidence no increased requirement for lactate export. There is also no reason to assume the lungs do.

We’ll have to conclude for now that if you are measuring low BHB, you are producing low BHB. There is no reason to believe that your body is better at utilizing BHB.

After all, the brain is the one most in need of BHB as glucose levels drop. Would it make sense for all other organs to consume increasingly higher levels? No.

The blood in our finger is of the same composition as what travels to the brain.

— THE END —

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