Sunday, July 15, 2012

Low Carb Diets, Mitochondrial Dysfunction and Weight Loss: A Theory

See Mitochondrial Dysfunction for background information

Let’s say we have an obese, insulin resistant person who barely make it from breakfast to lunch without a donut and a soft drink.  Being fed up with their weight and health prospects they turn to the internet, discover paleo/low carb and begin eating that way.  Carb consumption reduces to ~1/3 of the previous amount and they aren’t eating in between meals.  The first week or so is hell, they feel hungry, lethargic and light headed.  They once again consult the internet, are told you’re sugar detoxing so they decide to stick with it.  A few days later the weight is coming off from all the right places, they have more energy and don’t feel hungry.  They have no need of sugar or snacks, in fact because the weight is coming off so quickly now they don’t feel hungry enough for lunch.  A few months later when all the weight has come off their doctor reports the insulin resistance has gone and the triglycerides have come down from 2 to 1 mmol/l. 

The above scenario plays out quite often, especially to begin with, and I think mitochondrial dysfunction and biogenesis is the best explanation for it. 

The elevated ROS and mtDNA mutations that are related to mitochondrial dysfunction can reduce the activity of the electron transport chain (which is seen with obesity and type 2 diabetes [1]).  This in turn decreases PGC-1α, and then also fatty acid oxidation and oxidative phosphorylation [2].  The ratio of glycolytic:oxidative enzymes in muscle is associated with insulin sensitivity.  People who are insulin resistant (and to a lesser extent, the insulin sensitive obese) have higher glycolytic and lower oxidative enzymes than normal [3]. 

So people with insulin resistance, type 2 diabetes or obesity rely more on glycolysis and fermentation (pyruvate to lactate) for ATP and less on aerobic respiration.  Lactate is converted to lactate acid to enter the bloodstream and high lactic acid production is one cause of the metabolic acidosis seen with type 2 diabetes [4] [5]. 

Now, our hypothetical person goes low carb: 

Low carb diets more strongly rely on aerobic respiration.  There’s not as much glucose for glycolysis + fermentation and no easy way to metabolise fats with impaired oxidative phosphorylation from mitochondrial dysfunction, hence why symptoms of low carb flu include hunger and fatigue.  There’s a deficiency of ATP even though there might be plenty of calories.

But people on low carb diets don’t suffer forever.  Ketogenic diets and non-ketogenic low carb diets increase AMPK, which stimulates mitochondrial biogenesis.  One study found that when people with obesity calorie restict people on a low carb diet (20:50:30) their AMPK increased after 5 days whereas AMPK levels from those on a high carb diet (20:20:60) didn't increase [6] (reported in a post by Mike Eades).

Low carb flu lasts roughly one week then all is well: 

When fish are exposed to cold temperatures to stimulate mitochondrial biogenesis the activity of citrate synthase (a marker of mitochondrial respiration) in the liver increases rapidly, doubling in value after 9 days, and then plateaus.  Muscle is more flexible, but takes more time.  There is an initial increase of about 50% in a few days and then a further doubling takes about 2 months [7].  Following muscle injury in rats markers of mitochondrial respiration plummeted, but increased rapidly between day 5 and 10 and citrate synthase returned to baseline after day 10 [8]. 

These time periods in which mitochondrial respiration increases and plateaus (including the increase in AMPK after 5 days) are similar to the duration of low carb flu*.  Then the reduced triglycerides:

Some people may attribute the reduced triglycerides to less de novo lipogenesis of glucose and fructose.  But that’s just as bad as saying high fasting glucose is due to blood glucose spikes from last night’s dinner.  Both are homeostatically regulated.  Mitochondrial dysfunction increases insulin resistance, which causes elevated triglycerides.  After mitochondrial numbers and function return to normal insulin resistance improves, leaving you with normal triglycerides.

If the main benefit of low carb diets is mitochondrial biogenesis then the good news is that you don't have to go very low carb as 30% of calories from carbohydrate is enough to increase AMPK and you get of the benefit very quickly (~1-2 weeks) and pretty much all the benefit within less than 2 months.  Although this isn't an excuse to return to poor eating habits after 2 months

* I know they are animal studies and the circumstances may not apply to low carb diets.  Remember it’s just a theory, but one I believe that explains low carb flu and sone of the benefits of low carb diets quite well.

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