The road to degenerative metabolism: An hypothesis

In the following theory, keep in mind that the pentose phosphate pathway (PPP) cannot be used as a major sink by the body for excess glucose. Except in the brain where glucose is a major contributor to PPP, in skeletal muscles and the body generally the PPP is a minor use of glucose, and the PPP can be slowed down by nutrient deficiencies. I have in mind a particular nutrient, thiamine, that is needed to drive the non-oxidative part of PPP, and that I think is particularly deficient in Americans by virtue of a lot of things, including widespread abuse of alcohol, the commonality of diabetes and liver and kidney disease, the fact that less than half of Americans supplement and those who do are not very regular about it, that the vitamin is heat and oxygen labile, and that most foods containing it are cooked and often reheated, while the best raw food source of the vitamin (green leafy vegetables) is rarely consumed. If I am correct, thiamine deficiency not only inhibits the use of glucose by PPP, creating a possible deficiency in the ground zero antioxidant, NADPH, it also favors glycolysis and fermentation of sugars over the complete oxidation of sugars by the tricarboxylic acid cycle TCA and oxidative phosphorylation (OXPHOS) because the linking step between glycolysis and TCA and the TCA itself both require thiamine while glycolysis and lactic acid production do not. In addition, the two key thiamine requiring enzymes also require potassium and magnesium, whose deficiencies are acknowledged even by our government that denies that thiamine deficiency is a real problem.

Degenerative metabolism is characterized by poor mitochondrial function and heavy reliance on sugar fermentation, with lactic acid and methyl glyoxal production, and for cells to meet their basic energy survival needs, with substrate level phosphorylation. This protocol provides too little energy for processes not necessary to short-term survival, especially when the cells are also reproducing (as in cancer).

In nature we find high fat, low sugar foods like nuts and coconut (coconut tastes very sweet, but it is actually high MCT fat, relatively low sugar); we find high sugar, low fat foods like fruits, and we find balanced foods like whole milk. We do not find extremely high fat plus extremely high sugar. Our bodies cannot cope with that combination because the sugar needs to be burned all the way to carbon dioxide (to circumvent the problems that the degenerative metabolic production of lactic acid and methyl glyoxal leads to) and water, and the high fat inhibits that process, especially when antioxidant vitamins are low and endogenous antioxidant enzymes are too low to control the level of free radicals such oxidations of fat inevitably produce and the enzymes fail to induce to proper levels.

For losing weight, a high carbohydrate, moderate protein, low fat diet (with sufficient essential fats) works without disrupting metabolism (with the possible exception of inefficient germ killing in the stomach, insufficient satiation of hunger, insufficient release of bile and toxins-in-bile, insufficient fat soluble nutrient absorption, and possibly insufficient essential fat absorption, etc).

For short term weight loss, provided one has healthy liver and kidneys, a high protein, moderate fat (with sufficient essential fats), low carbohydrate diet works without disrupting metabolism.

High fat + high carbohydrate is the killer combo.

Key elements in the degeneration of metabolism include:

1. The standard American diet, SAD, with high sugar and high fat, from pure sugar and pure fat added to foods during preparation.

2. Lack of periodic fasting or at least periods of serious glucose deprivation – this keeps the body in a state of near repletion of all four of the fuel storage depots: muscle glycogen, liver glycogen levels, muscle fat levels and extra-muscular fat levels. The concept of adequate muscle fat stores and whole body fat stores is not well developed. I am defining them by rough analogy to the well-known levels of glycogen repletion. A body has a fat demand when Fatty Acid Synthase has been induced. Periods of glucose deprivation are essential for creating demand for sugar in both liver and muscles. Periods of calorie deprivation prior to feasting is necessary to create demand for fat.

3. Lack of exercise in both of its forms. Lack of aerobic exercise, so important for keeping the fat burning, respiratory engine healthy and strong. In addition, lack of resistance training leads to muscle atrophy as we age and this too reduces the total muscular demand for sugar even after a period of fasting.

The poster child of the SAD is premium ice cream. I believe that regular eating of this and similar foods with lots of purified sugar (and white flour in pastries and breads) and lots of added fat (butter or vegetable oil added to pastries), reprograms metabolism, already perturbed by psychological problems, lack of periodic fasting, lack of exercise, and by lack of quality sleep, epigenetically and biochemically toward a path that is degenerative.

Here’s how. In this description, as an example, picture a person with nearly replete muscle and liver glycogen and negligible fat demand because of nearly replete levels of muscle and total body fat feasting all day on Thanksgiving (a 5,000 calorie turkey day is not unusual in America).

On another day, picture the same unfasted, unexercised person eating an entire pint of premium ice cream as a snack after a regular meal, long before any fasting has taken place.

This high fat, high sugar diet (both are required) sets up the problem. Excessively high intracellular glucose cannot be disposed of even in part by glycogen synthesis because these stores in both muscle and liver are nearly replete.

Excessively high intracellular glucose stimulates the polyol pathway, temporarily trapping some glucose in sorbitol (because the oxidation to fructose requires NAD+)  and its negative sequelae. Excessively high intracellular glucose reduces the “NAD+ current”; hence, as noted, sorbitol builds up, and triose phosphates build up (since the oxidation of glyceraldehyde-3-phosphate requires NAD+), generating excessive methylglyoxal from the transition state between the trioses, dihydroxyacetone phosphate and glyceraldehyde-3-phosphate, and methylglyoxal and other such reactive aldehydes generate AGE and its negative sequelae.

Moreover, when intracellular glucose is excessively high, the cell generates fructose-2,6-diphosphate, which stimulates phosphofructokinase and accelerates flow through glycolysis, creating more trioses, including pyruvate. Over time the extremely high doses of sugar induce glycolytic enzymes and forces the insulin system to work too fast, resulting in amylin-containing precipitates in pancreatic cells, which may in turn set up future shortages of insulin.

In a person whose muscles are already replete with fat, there is little built up demand for fat synthesis and storage when an extremely high fat food is ingested, and even when there is some fat demand, there is a speed limit to de novo fatty acid synthesis.

With demand for fat synthesis, the extremely high fat concentration (by definition too high to be efficiently taken up by cells, and what is taken up is still too high to be oxidized by the existing combined fatty acid oxidation machinery in mitochondria, peroxisomes, and the ER) leaves circulating free fatty acids, FFA, high, (circulating FFAs aggravate insulin resistance and a lot of other negative processes), and those FFAs that were taken up by cells have flooded the mitochondria, inhibiting ATP generation by OXPHOS by proton leak (reducing the proton motive force), and increasing free radical formation, which overwhelm endogenous antioxidant enzymes and available antioxidant vitamins, and which damage mitochondria and other cellular structures, and which further inhibits ATP generation by inducing uncoupling proteins, which also trigger proton leak and reduce proton motive force.

While continued flux of oxidized fatty acids through OXPHOS does regenerate NAD+, which through NAD+ current, regenerates NAD+ in the cytoplasm, even though NAD+ cannot cross the inner mitochondrial membrane, it generates little of the needed ATP and wastes energy as heat. This is sometimes called the futile cycle. It is not sustainable.

Over time, damage to mitochondria reduces OXPHOS capability, so that less OXPHOS occurs even when high fat food is not consumed, and forces an ever greater reliance on sugar fermentation and substrate level phosphorylation, which together do not quite meet the demands for cellular energy, forcing the cell to sacrifice certain less essential things that require small amounts of periodic energy input such as the maintenance of higher order structures (like the respiratory complexes in mitochondria). In a vicious cycle, this leads to impaired mitochondria and degenerative diseases.

It is likely that free radical generation generates a trigger (via UCPs?) to inhibit most if not all of the enzymes (many of them Flavin-containing enzymes) that support free radical generation, including PDH, alpha-ketoglutarate dehydrogenase, the enzymes of fatty acid oxidation, the enzymes of OXPHOS complexes I and III, etc.

As OXPHOS ATP production decreases, glycolytic ATP and substrate level phosphorylation must rise to maintain a viable rate of ATP regeneration or the cell will die. No doubt some do – natural selection in action. Over time cells that do fermentation tend to overgrow the populations of cells that cannot do high level sugar fermentation.

In the absence of heat generation requirements, the futile cycle will slow down, fatty acid export will accelerate, raising already high serum free fatty acids, and this in turn reduces the rate of pyruvate dehydrogenase, which is probably already low because of common deficiencies in thiamine, magnesium and potassium, and which feeds pyruvate via acetyl-CoA to the mitochondria for TCA and OXPHOS, which have slowed down from fat overload and fatty acid export. Pyruvate and NADH increase in concentration and stimulate lactic acid and NAD+ production, as well as methylglyoxal from a buildup in trioses, as glyceralde-3-P-dehydrogenase requires optimal NAD+ activity. The transition state of the enzyme triose phosphate isomerase is thought to dissociate from the enzyme at a low rate and convert to methylglyoxal by eliminating phosphate.

The fats are poorly oxidized and little ATP is generated when fat is extremely high and sugar is extremely high. The FFA end up circulating as orphan molecules and some are slowly deposited as fat. Substrate level phosphorylation and the glycolytic pathway, induced by high sugar, end up generating most of the ATP, and lactate production (not the more optimal OXPHOS) ends up regenerating NAD+, which keeps glycolysis running as fast as it can, as required in any diet with extremely high levels of added sugar, given impaired mitochondrial respiration.

Failure to fast on the SAD is extreme. Most Americans eat before they are actually feeling hungry. In this way, glycolytic enzymes remain high. The flux through glycolysis is high and that through OXPHOS is low. Those OXPHOS enzymes tend to decay to baseline levels from disuse and in response to nutrient deficiencies of their cofactors.

2. Periodic fasting or serious glucose deprivation (which can be sustained longer than total fasting) is important because during fasting the over-induced glycolytic enzymes turn over and the entire deranged metabolism can begin to be reset. Selection now operates in reverse – a selective process that favors cells that can respire well. A complete resetting/re-progamming of metabolism likely requires a jolt (likely more than periodic serious glucose deprivation).

3. Aerobic exercise is important because this burns fat at a slow pace, not generating so many free radicals (but enough to induce antioxidant enzymes, provided antioxidant vitamins are not excessive), not flooding the mitochondria with lots of fats, reducing the proton motive force, and forcing export of the fatty acids, and thus the slow burning of fats during light aerobic exercise keeps the OXPHOS system running and the enzymes at levels above baseline.

The solution to the reprogramming of metabolism away from lactic acid fermentation, harmful byproduct (like methylglyoxal) production, and reduced OXPHOS:

0. Always fast and exercise before feasting to create demand for glucose and fat. Fasting selects for cells that respire efficiently and selects against cells that were previously selected for their ability to ferment sugars (cancer cells tend to fit this definition).

1. Eat only whole foods, no added sugar or fat. Milk is OK because it is only somewhat unbalanced fat, protein, and carbohydrate. Ice cream is whole milk with lots of added sugar and fat – avoid this SAD favorite, and avoid all processed foods, especially those made with white flour, butter/oils, and sugar.

2. With no extremely high fat or sugar, the OXPHOS is not inhibited and the pyruvate is not force-converted into lactate.

3. With regular exercise (aerobic walking is best), fat is delivered slowly to mitochondria, and the OXPHOS fat burning engine is maintained in good working order.

4. To reprogram the degenerative metabolism and to lose weight with this strategy, watch total calories. Keep fat moderate, but make sure to have enough of the essential fats, eat much more lean protein like chicken breast meat (protein energy comes from TCA + OXPHOS and some from gluconeogenesis, which picks up when the sugar in the diet is reduced), and keep carbohydrates low to moderate, with plenty of green leafy vegetables (which are naturally low in carbohydrates, but very high in nutrition). In this way, carbohydrates can burn completely to carbon dioxide and water, avoiding the degenerative metabolism of carbohydrates.

5. The major disadvantages of the high protein diet are excessive urea production (only people with healthy livers and kidneys can safely lose weight this way), and the production of PO4 (from digestion of phosphoproteins) and SO4 (from metabolism of excess cysteine and methionine, which are excreted in urine with divalent cations. Extra calcium and magnesium are needed on this diet, ideally in about a 2:1 – 3:1 weight ratio of calcium to magnesium.


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