Is t2 diabetes result of mitochondrial destruction?

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1. A hypothesis:

- Metabolic syndrome and diabetes t2 results from mitochondrial destruction caused by overfeeding with glucose (and fructose but only in the liver), taking place over many years. An individual mitochondrion has (hypothetical assumption!) a fixed maximal total energy yield out of the two main energy sources: glucose (or glucose+fructose in the liver) plus fatty acids.

There is a self-clamping regulatory mechanism preventing mitochondrial overfeeding by fatty acids, by means of Malonyl-CoA/CPT1 feedback (see Peter’s discussion), but there are no very effective self-regulation feedbacks for glucose, only a partial mechanism reducing the glucose transport into in the cells! This partial mechanism is mediated by insulin regulating the transport of glucose into a cell through the cellullar membrane. This regulatory mechanism is not always effective or fast because the insulin secretion is not local to the cell, rather it is produced in the pancreas whose rate of secretion is regulated by the autonomous nervous system and pancreating glucose concentration involving many factors other than some particular mitochondria overload. Furthermore, the insulin regulation (blocking) of glucose can be overriden by high glucose concentration.

2. Conclusions.

A straight conclusion would be that a high carbohydrate diet can indeed be healthy and avoid diabetes as long as it restricts calories to prevent mitichondrial overfeeding. What is the limit? In my guesstimate (based on published literature) - probably around 25kcal/kg for women and 30kcal/kg for men.

A second straight conclusion is that a high fat low carb diet automatically avoids mitochondrial deterioration and thus diabetes among other degenerative diseases, by its built-in biochemical overfeeding protection mechanism. (note: my daily caloric intake on a high animal fat diet, is and has been around 20-25kcal/kg since 1999).

A third conclusion concerns a situation of the cells with the insufficient number of or worn-out mitochondria. Having lower total mitochondrial energy throughput, such cells may be forced to over-rely upon and and over-utilize the Penthose Phosphate Pathway (PPP) (also called the Penthose Shunt) which takes place in the cytosol volume outside of the mitochondria. This has originally been proposed by Dr. Jan Kwasniewski, the author of Optimal Diet in the 1970-ties. I found his idea fascinating, largely because there was no easy or obvious way of proving it at the time, and last but not least - it flew right against the medical dogma! Interestingly the PPP is mainly a synthesis pathways resulting in lipids and lipoproteins manufactured inside the cells, in-situ. Such as the infamous "cholesterol" plaque perhaps? Out of glucose? Like suggested by R.W. Stout in his 1968 and 1969 Lancet papers?

--- Part 2 (9-Oct-2011) ---

3. Declining energy syndrome and carbo-loading trap.

More conclusions can be drawn out of this simple hypothesis. If t2 diabetes is the results of mitochondrial decline caused by overfeeding (carbs or by a combination of carbs and fats) then it should be accompanied by a steadily declining energy yield.

Suppose for the sake of discussion that a healthy individual consumes 30kcal/kg/day, leading active live. If he looses 10% of his mitochondria he would be able to process only 27kcal/kg/day. Less energy to work, more lethargic, getting tired sooner. What do we do when that happens? I was in that situation 15 years ago. Falling energy level at work, especially after 3pm. I snacked! I snacked on carbs! Why on carbs? Because I couldn't snack on fat! (even if I didn't believe that fat is harmful...) Fats don't work if you have mitochondrial deficiency because of the Malonyl-CoA/CPT1 feedback(*). A mitochondrion can only process a certain maximum amount of energy out of fat and that's it! If your total mitochndrial yield declined from 30 to 27 during the first 20 years of dietary abuse, then 27 is all what you can get out of fat! But you can still push your partially worn-out "engine" into overdrive by flooding it with extra glucose! It will sputter and spew out lots of smoke polluting your cells with free radicals, AGE's etc but it would allow you to bring your yield back to the previous level of 30. At least for a time being because the process of mitochondrial decline has accelerated due to the pushing them over the limit and the ensuing end product toxicity. So instead of 27kcak/kg/d, now the maximum available yield drops by another 10%, this time over 2 years. You can now safely draw 24kcal/kg/d out of fat or carbs or a combination of both. However if you want to stay awake at work you have got to load up on carb snack now by 20% not 10% over your maximum limits creating more problems, requiring a lot more insulin to overcame the natural barrier that your body cells have enacted against your plan. It also requires maintaining a high blood glucose level to speed up diffusion across cellular boundaries. Which particular cells of your body will be the first in line to see the high glucose and high insulin? Your arterial endothelium! Your liver!

This appears to be a run-away process where your tissues cells would keep enacting more and more barriers agaisnt excessive metabolism, your conscious brain will make you snack like crazy on carbs to maintain the same energy level, your pancreas will try keeping up with that pumping your insulin, your immune system will work overtime trying to clean up the mess after glucose and eventually it will also try saving your body tissue by attacking the source of the excessive insulin - pancreating beta cells, in some cases it will try even to sequester the excessive insulin floating in your bloodstream, and last but not least your poor mitochondria will keep dying! Eventually one of more of the players described above will give up. If you stop snacking and keep below your maximum metabolic yield, you will feel hungry and lethargic. Especially if you have to work 9-5. If you don's stop snacking your blood glucose would go up until you develop kidney failure. If you force you blood glucose below renal dumping threshold (about 160mg/dl) by injecting insulin you will develop heart failure or arteriosclerosis (or both). What to do? This will be the next subject.

4. The way out - what exactly happens (and when) if you start curing yourself of diabetes using a high fat low carb diet.


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More references, links and thoughts are in this file.

Footnote:

*) I am speculating but there seems to be cases when the fat-clamp mechanism may also be defeated, leading to fatty acids overload(+). This condition is also harmful creating large amount of toxins that require a massive cleanup operation my the immune system (see Masterjohn's article, in my reference file above). I suspect that this is one reason behind the so-called "low-carb flu" syndrome sometimes reported by inexperienced diabetic low carb dieters. It is interesting that fat overload (if that does happen, however unlikely) may be as unpleasant as glucose overload!

Footnote to a footnote:

+) Indeed it does happen! Peter just posted an interesting discussion about this issue here. A must read! It appears that when the adipose tissue develops insulin resistance, it is then capable of releasing fat into triglyceride particles and into the bloodstream under the condition of falling but still higher than normal insulin level! Fatty acids are then forced into the cells and a smaller fraction are then forced into mitochondria. The free fatty acids left-over inside the cell (but outside of the mitochondria) become the main cause of the insulin resistance and the cause of major cellullar cleanup operation. I have a mental picture of my old sputtering "Komar" motorbike with its carburator overflooded with gasoline...


This makes a fascinating fork in the metabolic failure modes under overfeeding. On one hand, the overfeeding with glucose may be wearing off the mitochondria and also forcing the excess fuel into adipocytes. On the other hand releasing those excessive fats from the adipocytes into the bloodstream may be setting up the physiological insulin resistance and still damaging the cells even more through the high free fatty acids level in the cytosol. Interestingly this excessive fatty acids may as likely (if not more so) come from the internal source (adipose tissue) than from a diet! It also explains why many obese people experience a health breakdown only AFTER they undergo a weight loss, especially after a repeatable weight loss and weight gain cycling.


A weight loss diet is therefore ALWAYS a HIGH FAT diet even if a person eats nothing but lean veggies!

--- Part 3 (15-Oct-2011) ---

The reason I am considering this mitochondrial decline model seriously is because of my experience. Back in July 1999 when I started my low carb high animal fat diet (almost by accident) I did experience a noticeable lack of energy, light-headedness and dizziness for a couple of weeks. Also: low blood pressure and reduced blood clotting that showed up by excessive and random bruising on my hands.
The worst part of it (dizziness and weakness) last only for 2 weeks. I didn't have diabetes just metabolic syndrome and hypoglycemic episodes. In my case, I was able to combat those initial low carb startup difficulties by carrying with me some high fat snacks such as Swiss cheese, Polish saussage and nuts.

The main problem is: when you stop consuming excessive carbohydrates then your damaged mitochondria might not be able to deliver enough energy out of fat and carbs to sustain your previous energy expenditure. You do feel the loss of energy immediately, and more hunger, therefore:    You must slow down!

 The only way for your mitochondria to recover or for your tissue to stop deteriorating and then regenerate(**) is to maintain the lower caloric intake compatible with your maximal mitochondrial yield. It will recover! This is the good news. The bad news is that it will take a few years!

Footnote:

**) I am not sure if mitochondria can individually regenerate by themselves or if the only way is for the body to regrow the new cells from stem-cells.

Yes to both, see this comment by Dr. Jack Kruse, on Peter's blog.

The low carb high fat therapy can be divided into 3 stages.

a) Switch-over

This is when the initial difficulty will show up. For diabetics and elderly this could be severe enough to warrant some medical supervision. Your body, digestive system and metabolic apparatus is switching over from carbohydrates to animal fats as the main energy source. There are hundreds of grams of enzymes circulating in your system that are no longer needed and have to be disposed off. Enzymes are protein. you will excrete their end products in urine, during this stage. Ketone bodies will show up in urine since your liver will be producing them more than your body tissue are able (yet) to utilize as fuel. Fortunately ketones in urine are in this case inconsequential but one has to be aware of it because of the rampant scare-mongering propagated by some uninformed people. I have seen many cases of people being scared by ketones and abandoned a low carb high fat diet, to their detriment. This stage last typically from 2 week to 2 months.

b) Rapid at first, then gradual improvement, disappearance of most chronic disease symptomes.

At this stage, most diabetic patients will experience disappearance of all or of most of the symptoms. Also, other chronic disease will show a lesser or stronger reversal, for example: auto-immune diseases, chronic intestinal diseases, arteriosclerosis, cardiac diseases, vascular diseases, neurological etc. However, the energy level may still be lower than on the standard high carb high caloric diet. Good news is that this yield will no longer be deteriorating. It will begin to slowly improve.

Many changes will take place at this stage, for example:

• Eating and snacking habits will be completely modified.
 
• Hunger will disappear, one will have to eat only once or twice a day. There will be no "toxic" hunger!(***) Total caloric intake will automatically and painlessly come down by about 30%, compared with the previous high carb nutrition. Please notice how close this ties with the Caloric Restriction programme! The low carb high fat diet is the Caloric Restriction program without hunger! For diabetic patients, all symptoms should disappear during this period. Most patients (except dm t1) will no longer need diabetic drugs or insulin. However - if they go back to a high carb diet, their diabetes will return.
 
• Breathing rate will go down. An interesting side effect will be an ability to free-dive for a longer periods of time due to lower carbon dioxide release per calorie due to fat oxidation chemistry and due to an overall lower energy expenditure!.
 
• Ability to better withstand cold temperature and cold weather.
 
• Greater resistant to stress and alleviation of some neurological disorders, mood disorders, bad temper etc. This is a big and important effect! The low carb high fat metabolism is accompanied by a significantly different endocrine reaction against stress stimuli. A stress will no longer trigger a "panic paralyzis" reaction or initiate a panic attack, but will instead stimulate a generally pleasant and always useful rush of energy! The effects of stress hormones upon the neural tissues will be much less harmful in the presence of ketone bodies as in ketogenic diet, than in their absence as is more typical under the high carb diets in metabolic syndrome.  Ketone bodies are not produced when insulin and glucose levels are too high! More on the effect of stress hormones, ketone bodies and glucose upon the neural tissue is discussed here.
 
• Greater resistant against infections, viral and bacterial. No more seasonal flu!
 
• Complete prevention of tooth decay and dental plaque. I have seen cases of molar teeth broken in half self-healed by sealing off of the cleavage.
 
• Improved cholesterol level and profile.  One notable exception: patients with fatty liver disease, the level of LDL may climb to a very high value, I have seen as high as 700md/dl sustained over a couple of years. No adverse health impact, other than scaring a "beejesus" out of some doctors... . Note that after the fatty liver recovers, LDL comes down.
 
• Lower capacity to tolerate a once off high carbohydrate meal (or high intake of alcohol).  At this stage, people with metabolic syndrome and diabetics must still be careful to actually measure their daily intake of carbs and ensure it is within the strictly limited band. Typically about 50g per day.   Failure to observe this limit results in unpleasant symptoms and is hazardous to one's health.

Footnote:

***) The term "toxic hunger" as coined by Fuhrman, is in my opinion probably related to a falling level of glucose and insulin from a high value below the level sufficient to sustain glucose metabolism (in metabolic syndrome) but still too high to allow burning of one's body fat. This leads to a condition where some or all body tissues are temporarily starved of energy.   In a non-diabetic, insulin and glucose levels do not go too high thus insulin can quickly go down in between the meals prompting the release of the stored body fat.

High insulin = low leptin = burning glucose not fat.
Low insulin = high leptin = burning fat not glucose.

A very weak feeling of a slight hunger under ketogenic body fat "burning" can be easily overcome or forgotten, and is totally different from a "panicky" acute and almost painful hunger pangs experienced by diabetics and people with metabolic syndrome.  

c) Long term recovery

After several years on the low carb high fat diet, one's energy level will gradually come back to the previous level (like in one's 30-ties). This is probably due to tissue regeneration from stem cells. In my experience this will take a minumum of 7 years. An ability to tolerate a once-off higher intake of carbohydrates (typ. up to 150g) will come back at this stage. People who had diabetes may probably (I am hypothesizing) be able to come back to some kind of medium carb medium caloric diet if they wanted to, without getting diabetes because they will no longer be insulin resistant.

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A must-read:
"Metabolic flexibility and the identical twins"


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