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Saturday, June 2, 2012

Unknown keto+glucose oxygen-sparing metabolism?

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I came across this in the following papers. May be a false lead, may be not.

"Cerebral metabolic adaptation and ketone metabolism after
brain injury", Mayumi L Prins, 2008


"In vivo 13C NMR studies of compartmentalized cerebral carbohydrate metabolism", Rolf Gruetter, 2002

"Brain Metabolism during Fasting", 0.E.OWEN et al., 1967

The papers review ketone and glucose metabolism in brain tissue. Among many of the issues discussed one finds that at a time of trauma, injury, hypoxia or during birth, brain tissue switches to some unspecified (unknown?) type of metabolism characterised by:
  1. increased processing of glucose through the pentose phosphate pathway (PPP),
  2. increased expression of ketone-metabolizing enzymes,
  3. relative reduction of oxygen use and CO2 release, in comparision with the overall rate of metabolism.
It is important to notice that PPP, as described in the literature is a pure glucose pathway oxydative-reductive (oxygen-sparing as compared with the normal glucose oxidative pathway) that is normally associated with NADPH production, used in reductive biosynthesis reactions within cells (e.g. fatty acid synthesis, RNA, cholesterol etc). Based on the known biochemistry, PPP is not supposed to have anything to do with ketone bodies or fatty acid metabolism in general.

Ketone metabolism on the other hand is not oxygen-sparing at all! A simple stoichometric analysis indicate similar oxygen usage per calorie compared with glucose oxidation (but with a significantly reduced carbon dioxide production!).

It is very hard to reconcile 1 and 2 with 3 unless one postulates that a new yet unnamed metabolic process is taking place that oxidizes ketone bodies and at the same time reduces (i.e. takes oxygen out of) glucose, with PPP being a side effect.  (It cannot be the traditional anaerobic glucose metabolism because of the reported deficit of lactate)

Quotes (first paper):
Although glycolytic activity is 38% greater in adults than fetal brain, the processing of glucose through the pentose phosphate pathway was 164% higher within the fetal brain compared with adults.
Hypoxic injury reduces oxygen availability and thus decreases oxidative glucose metabolism resulting in increased lactate production. High tolerance to hypoxia has been associated with increased plasma ketone levels...
In addition to neuroprotection from seizures, administration of ketones has been shown to provide protection after hypoxia/ischemia (Table 3).

My comment:

- hard to reconcile with the known metabolism of ketones which requires similar amount of oxygen as glucose (per calorie).

Quote (second paper):
The landmark study by Fox and Raichle in the late 1980s suggested that there is indeed a large increase in glucose metabolism that exceeds the changes in oxygen metabolism (Fox et al., 1988). The concept of uncoupled oxygen metabolism has been supported by reports of small increases in brain lactate during focal activation (Prichard et al., 1991), that initially were very controversial (Merboldt et al., 1992) and that are very difficult to perform. The relatively small magnitude of change in brain lactate is difficult to reconcile with the reported large uncoupling between oxygen and glucose consumption (Madsen et al., 1999).
My comment:

- a well known anaerobic (no oxygen) metabolism involves conversion of glucose to lactate, thus the lack of lactate, is the paradox indicating an unknown oxygen-sparing pathway.

Quote (third paper):

...as stated before, 2.81 mmoles/liter of CO2, should have been produced, with a theoretical respiratory quotient of 0.92 instead of the observed 1.90 mmoles/liter, resulting in a quotient of 0.62. To our knowledge, this deficit in CO2 production can only be explained by a carboxylation [see wiki] reaction with the venous effluent transporting the CO2 in a form not liberated by the acidification used in the standard manometric technique for determination of CO2 and HCO3.   According to most observations, the respiratory quotient of brain, which glucose serves as sole energy source, is close to unity (2,3,25). Brain, however, contains enzymes for all the major metabolic pathways (29-31), including fixation of CO2 (31,32); and oxidation of keto acids has been demonstrated in vitro (30,33,34). In addition, Kety et al. (35) noted decreased respiratory quotients in patients in diabetic ketoacidosis; but direct utilization of keto acids has not been found in this condition (3) or in fat-fed animals (36). Guettstein et al. also observed decreased respiratory quotients in patients with cerebral arteriosclerosis (37). Additional indirect evidence for a novel carboxylation reaction which would result in a low quotient has been Sacks' studies on glucose-14C oxidation in human brain whereby only 50% of glucose-carbon that is oxidized is recovered in effluent CO2 and HCO3,(38).

My comment:

Reduction of respiratory quotient to 0.62 meant that the process releases less CO2 than should have been base don the known and expected metabolic pathway. That indicates that the unknown metabolic process does not oxidize carbon to CO2 but leaves it in the residua, while probably (speculating) oxidizing only the hydrogen from ketone bodies with the oxygen atoms reduced from glucose. The result is less need for external oxygen input and less CO2 production. (Mental note: next post about Dr. Jan Kwasniewski!)

(Kudos for Dr. Dav0 for pointing out those papers, and his work on ketone metabolism, please keep it up!)
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5 comments :

FredT said...

Fat burning produces more h20, less co2 than CHO burning. Co2/O2 ratio is 0.7 for fat, and about 1.0 for CHO, but how can you measure the water production? The issue of testing is we measure what we can measure. Also Fat burning produces more waste heat, but what do I know.

Stan Bleszynski said...

That was the whole point. They measured CO2 but if the metabolic pathway does not release it then it is going to slip under the radar without detection. Water cannot be easily traced except if they used deuterium.

It remind me seeing some study reporting that all known metabolic energy sources provide only account for only ~70% of the power that heart is delivering. That is probably because of the measuring methods are insensitive to hydrogen pathways if they only track carbon residua, or because of some yet unknown type of fuel.

Interesting isn't it?

Dr. Jan Kwasniewski has always been stressing an importance of hydrogen transport. His way of arguing that fat (animal fat) is the superior fuel was because it contains more hydrogen, and that the reason polyunsaturated fats are not so good is because they contain less H. I used to think that this was a silly argument. Not anymore.

G. L. said...

Stan, if you have time could you please say more on Dr. K's view of the PPP/Pentose Shunt and NADPH?

I am trying to make my way through his writings, at his website, using Google Translate.

This excerpt is from the end of his letter/answer in the following post.

Bronchial asthma.
14-11-2006

https://translate.google.com/translate?sl=auto&tl=en&u=http%3A%2F%2Fwww.dr-kwasniewski.pl

The heart is the biggest when it has to burn glucose in the process of glycolysis, smaller when it has to process glucose in the so-called pentose pathway, smaller when it needs to burn ketones and free fatty acids, and the smallest when it does not burn anything and all the energy needed to he obtains his work from active phosphate compounds, mainly from ATP. It is "electric" energy coming from batteries.

After the energy from ATP is taken up by the brain and heart, the compound is sent back to the liver, exercised muscles and other tissues, recharged and the cycle repeats hundreds of thousands of times a day. ATP itself manages daily body 50-100 kg, depending on the weight of the body and the intensity of the effort, especially mental, but also physical. And other active phosphorus compounds (accumulators) are produced in the human body a dozen or so. And they are also used as sources of clean energy.

With intense mental work, ATP levels in brain tissue are rapidly declining, and biochemists, physiologists and physicians continue to claim that glucose is the only source of energy for the brain, and in the absence of glucose, ketone bodies can cover up to 75%. brain demand for energy.

Glucose is not burnt in the brain at all. It is transformed into NADPH a key compound needed for almost all syntheses and for pentoses, i.e. compounds (sugars) necessary for the construction of many structures in the body.

They are a component of nucleic acids (DNA, RNA), structures responsible for inheritance and for all electromagnetic communication between cells, organs and environment, they are needed to build many enzymes and numerous glycoproteins, ie protein-sugar compounds - pentoses such as ribose, ribulose, arabinose, xylose, lysosose, xylulose. Without these sugars, pentoses (five-carbon sugars), there would be no life on Earth.

When the body needs more pentoses or NADPH, more carbohydrates are directed to processing in the pentose pathway, which is not beneficial for the body. With the best model of nutrition, the body performs the least "stupid" work and is the slowest to remodel. Once it adapts to Optimal Nutrition, it does not have to adapt to other products, it does not have to lose energy, NADPH and - pentoz.

Therefore, in people using Optimal Nutrition, so-called basic metabolism is the smallest compared to all other nutrition models, and it should be that way, and it's good.

"Dorodna" - means the so-called grown-up youth is a very bad result of nutrition, which forces the synthesis of larger amounts of NADPH or pentozes, a lot of unnecessary work, acceleration of maturation and menopause and leads to a significant reduction in the duration of human life.

Thanks very much. :)

Stan Bleszynski said...

G.L. - based on my understanding, pentoze cycle (pentoze phosphate shunt) takes place when body uses sugar in the anabolic mode. It is also the most atherosclerogenic mode (when taking place continuously for a long time) but it has also some advantages, for example it spares oxygen, thus it is used and favored by the body under hypoxia conditions.

To induce pentoze cycle, one has to consume both sugar and fat. For example, consume coconut fat with coconut juice (sweet) half and half. Kwasniewski mentions South Asian pearl diver using that method to maximize underwater stay.

To maximize the use of carbohydrates for extracting energy (which is hexose pathway), one needs to consume carbohydrates with very little fat.

This is of course a moot point on a high animal fat low carb diet, where most energy comes form fat, and carbohydrates (a small amount) are used either in pentose pathway (with no danger of atheroscleropsis) or otherwise.

The statement ""Dorodna" - means the so-called grown-up youth is a very bad result of nutrition,..." "Dorodna youth" in this context means fast growing youth (teenagers) taller than for their age. This is not a sign of health and results from the anabolic effects of hiperinsulineamia and the dominance of the pentoze cycle.

Regarding heart and brain metabolism, Kwasniewski was (strangely and unexplainably) way ahead of his time. In the 1970-ties it was not known that the ATP is actually distributed throughouth the system directly to those two crtitical organs such as the heart and brain. Now recently it has been recognized by analyzing the energy flow, they found that about 30% of the energy is not accounted for, after taking glucose, ketone bodies and lipoprotain particles out of the balance. What remains is the extracellullar ATP transport. Unfortunatley we still do know the details.

Best-to-worst fuels for heart and brain are:

1. ATP (best)

2. Ketone bodies (very healthy as long as there is a little bit of insulin produced, typ 6 iu per day is sufficient)

3. Glucose in pentose pathways (prolongued usage is atherosclerogenic due to its anabolic effect, and requires most insulin! Typically over 40iu)

4. Glucose in hexose pathway (requires less insulin than 3 , probably about 20-30iu, but a prolongued usage causes heart enlargement and cardiomyopathy, see many athlets dying due to their "carbo-loading" practices)

Note - There are probably (most likely!) other energy sources and energy transports in the body that we haven't yet found out.

Stan

G. L. said...

Stan, thank you so very much.

I feel like I am following Dr. K's recommendations very much based on what you and Peter D. have experienced and recommended.

When I read Homo Optimus, or the things at Dr. K's site, using Google translator, I am not able to follow the biochemistry much. I just take what Dr. K states on faith in what you and Peter have written, for years.

In my experiences with food and PFC amounts, it does seem that Dr. K's Golden Ratios really are golden.

You wrote something after another post, some years ago, that has really stayed in my mind. It was about not being able to overfeed the mitochondria into giving more energy. I find this the great puzzle. Keeping the ratios, but making sure there is not more food going in than can be utilized. If too much food, even at the proper ratios, it overloads the system.

Right ratios, best food sources I can manage, not too much. Enough rest.

Thank you so much for your help, and for your blog all these years. I really enjoy what you find, combined with your insights.

All the best to you.

G. L.