Stan Bleszynski's post at his blog, Heretic, "Is Type II Diabetes Result of Mitochondrial Destruction?", from Tuesday, October 4, 2011, has been one of my favorites.

Excerpt:

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!


.... [The information represented by the ellipsis is fascinating. I recommend going to Stan's blog and reading.]

After some comments, Stan posted this:

- It seems that the problems some (but not all) diabetics experience on an Atkins-like diet stem from the fact that they attempt to increase their metabolic yield through overfeeding!.

If they overfeed using fat it brings the symptoms like I described above. If they try overfeeding with protein it brings other problems, one of them being conversion of excessive protein into glucose and then the body having to deal with excess fat, protein and glucose at the same time.

I realize that a high fat low carb diet is easy for me but it may be quite difficult for a diabetic patient. It requires a certain amount of determination to maintain a discipline because one of the diabetic symptoms is an incessant hunger. There is no easy "fix"! For a type 2 diabetic, the easiest way is perhaps the scenario (a) - the road to "hell". From my own observation of diabetic people than I know, the second easiest path is (c) because of the hunger-quenching property of fat, although it does require an acceptance of low energy level (if you are diabetic). I believe that (b) is actually the hardest.
H.


More on mitochondria in next post....