The different fuel types that are available for our body need to be converted into acetyl-Coa to enter into the citric acid cycle and are processed equally. But the processes to turn glucose and fatty acids (and ketones) into acetyl-Coa are different. One of these differences is that glucose produces carbon dioxide (CO2) while doing this and fatty acids utilize oxygen (O2).
I have a theory in mind that states tissue level oxygen is slightly lower when using glucose for fuel than when utilizing fatty acids for fuel. As a consequence it would make you more susceptible to diseases that are either caused by or contributed by lack of sufficient oxygen. Numerous chronic diseases such as COPD, CVD, cancer, Alzheimer’s, TBI all are affected one way or the other by insufficient oxygen.
It is hard to figure out what goes on at tissue level. Most measures are done in arterials but this is already the level at which the mechanism of O2/CO2 exchange is adapting. There are theoretical models of O2 perfusion taking into account perfusion, diffusion based on diameter, blood flow rate, arterial saturation etc.. but those are theoretical and as far as I’m aware do not take into account the exchange effects of CO2 and other effects that could be of influence such as glycated haemoglobin which holds on to oxygen more strongly.
Something that can give us a clue is the following paper that looked at the effect of diet on CO2. In short the result showed us: high carb versus low carb (25%~20%) changed the ratio expired air versus CO2 (down, meaning a lower expired volume per minute (Ve) of CO2 per volume expired gas (VCO2)) or oxygen O2 (up, meaning a higher oxygen uptake (VO2) per expired volume of gas).
“Influence of diet on CO2 production and ventilation in constant-load exercise.”, Hughson RL, Kowalchuk JM, 1981, https://www.ncbi.nlm.nih.gov/pubmed/6801742
This would seem self-evident when you know that the Respiratory Quotient (RQ) changes based on the fuel that you use for metabolism. For glucose the RQ is 1 meaning equal part of oxygen inhaled for an equal part of CO2 exhaled. For fat this RQ is 0.7, protein is 0.8 and a mix of the fuels will be between those values. There are exceptions to this but that is out of scope for now.
As stated in the paper, previously they believed that as Ve goes up, VCO2 would go up in proportion because CO2 would be the driving factor. I’m not so much interested in the driving factors. I’m interested in the difference that the diet brings.
A carb-centric diet produces more CO2 and thereby causes a higher tissue saturation of CO2, the partial pressure of tissue CO2 would be higher and as a consequence of this, less oxygen becomes available.
This is contrary to how we know the adaptation to low oxygen works. When more CO2 is produced, our system adapts to increase the ability to take in oxygen. Where CO2 concentration is higher in the arterials, it will widen up so that more oxygen diffusion can take place. CO2 itself causes O2 to detach from the haemoglobin so with higher CO2 production more O2 is released to compensate.
So what could be wrong with this? It seems like our body adapts just fine. Well, my speculation on this is that indeed it is compensated but it is not designed to do this systemic wide and chronically.
This is really important to know because a lot of chronic diseases are connected with hypoxia. I’m sure there are well defined rules for a diagnosis of hypoxia but what I have in mind is a level of tissue oxygen that is slightly below sufficient. So when I use the term hypoxia here in this article, I mean the ‘slightly below sufficient’ level. The level that causes small areas of cells to experience insufficient oxygen enough so that it can stabilize HIF-1alpha. This is the factor where cells start to adapt agains low oxygen.
Back to the Ve/VCO2. The way I understand gas diffusion is that it will always try to spread out evenly across the given space. Based on this principle we are able to pump up our tires. Compress air in the pump and the air will diffuse into the tire so that the pressure is equal everywhere (in the pump and in the tire). You may now understand where I’m going at with Ve/VCO2. For a given volume of air expired, we see less CO2 coming out on a low carb diet. It is already well established in research that a carb diet produces more CO2 versus a low carb diet so we completely expect this. But I consider the effect on the Ve/VCO2 a strong piece of evidence that the tissue CO2 level is higher. The higher CO2 production leads to a higher pressure of CO2 in the tissue so that there is a stronger diffusion effect.
Now Ve/VCO2 shows us more CO2 has to go out on a high carb diet but we also see Ve/O2 is higher on a low carb diet so a high carb diet is not able to bring in as much O2. Whether that makes glucose a more efficient fuel or not because it uses less O2, I leave that for another discussion. The difference in these gasses is not just during exercise, it is also at rest.
Could it be that oxygen is better distributed across the whole body under fat metabolism versus under glucose metabolism? If I’m right then having a systemic 100% metabolism of glucose causes a greater delivery of oxygen too early leaving other areas downstream under more hypoxic conditions.
One of the variables on O2 diffusion is the diameter of the artery. What would be the consequence of a chronic CO2 production? Wouldn’t the artery dilate chronically? If that would be the case then O2 diffusion becomes chronically less effective as the diffusion distance lowers by the increasing diameter. The coronary artery is already sensitive to oxygen as shown in the reference below where they tried to model the oxygen concentration in different 3D models. The second paper shows us how the diameter influences the diffusion distance. It is looking at kidneys in mice and it is not full prove as you have to take the wall thickness into account but it is the quickest reference I could find. There are papers around that show pressure is lower with increasing diameter (think about your garden hose) and such increase would further lower the WSS talked about in the 3D model.
“Oxygen mass transfer in a model three-dimensional artery”, G Coppola, C Caro, 2008, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2607427/
“Vascular geometry and oxygen diffusion in the vicinity of artery-vein pairs in the kidney”, Jennifer P. Ngo, Saptarshi Kar, Michelle M. Kett, Bruce S. Gardiner, James T. Pearson, David W. Smith, John Ludbrook, John F. Bertram, and Roger G. Evans, 2014, https://www.physiology.org/doi/full/10.1152/ajprenal.00382.2014
To further strengthen my idea, it is not until very recent (2015) that there is a publication where they express the difference that doctors have experienced between blood oxygen levels and tissue oxygen levels. In other words, the 2 are not necessarily in line with each other.
The following articles discusses about research that showed how important nitric oxyde (NO) is to the tissue oxygenation. Without NO, the mice died of heart attacks and heart failure.
“Molecular and functional basis established for nitric oxide joining oxygen and carbon dioxide in respiratory cycle”. ScienceDaily. 10 April 2015. https://www.sciencedaily.com/releases/2015/04/150410095506.htm
Insulin does stimulate NO production in endothelial cells so it facilitates its own distribution. I’m referring to insulin here because it is generally increased more due to carbohydrate intake and thus you could conclude that eating carbohydrates actually promotes oxygen delivery due to the effect of insulin.
“Nitric Oxide Directly Promotes Vascular Endothelial Insulin Transport”, Hong Wang⇑, Aileen X. Wang, Kevin Aylor and Eugene J. Barrett, 2013, https://diabetes.diabetesjournals.org/content/62/12/4030
When we look at hyperglycemia or elevated blood glucose levels as seen post-prandial after a high-carb meal then we find that it actually reduces eNOS production by as much as 67%.
“Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site”, Du XL1, Edelstein D, Dimmeler S, Ju Q, Sui C, Brownlee M, 2001, https://www.ncbi.nlm.nih.gov/pubmed/11696579
We also find lower eNOS in obesity and insulin resistance, which raises blood glucose levels. Type 2 diabetics have an increased risk for atherosclerosis and Dr Joseph Kraft even goes as far to say that those with cardiovascular disease, not identified with diabetes are simply undiagnosed. This is telling to the effect high blood glucose has and how its inhibiting effect on eNOS is stronger than the eNOS stimulating effect of insulin.
Well, it is not a scientific publication and won’t be peer reviewed so this will remain just an idea until science moves on showing this is all rubbish or there may actually be some truth in it. I’m handing it over to you now to further investigate and make up your mind.
Previously I did already write about this on Reddit with the assumption that tissue oxygenation is slightly lower. It contains some more material to look into and help you on your own way to optimize your lifestyle.
Feel free to leave a comment and raise other publications that confirm or refute some of the stuff I have written. That way we can further progress on our knowledge 😉