Friday, July 24, 2015

This is what I think of carbs

My Big Fat Carbohydrate Post

(I wrote this first two years ago, then I scrapped it all and started over a year ago and now I think I can finally publish. This morphed into a big block in blogging so maybe I'll actually start blogging again)

To understand whether to eat no / few / "moderate" / high / all the carbs we should first try to understand the physiological and metabolic role of carbohydrates in humans.

Blood sugar - the bad

You already know that your body has tight control over your blood sugar unless you have diabetes, pre-diabetes, or lost your pancreas some way. And if your body doesn't do it for you, then you have to do it with drugs, e.g. insulin. Now, without any control at all there's the risk of coma and death but even with enough control to avoid that there is still damage happening to the body. Glucose, the molecule commonly know as blood sugar, is reactive and forms covalent, reversible adducts to proteins and other biomolecules in your body. This means that they become one molecule but they can spontaneously break apart again. So while the glucose adducts impairs proteins this is only temporary and function is restored. But the adducts can react with oxygen which cleaves the glucose and now the protein is permanently impaired. 
Carbohydrate reactions with proteins is completely reversible until the point where O2 (molecular oxygen) comes into the picture. After that the protein is doomed and the glycation even progresses to another reactive, damaging product. Credit R&D Systems.
Furthermore, the cleavage product on the surface of the protein is also reactive and can react more with the same protein or, even worse, react with another protein, chemically linking them together and eventually forming harmful aggregates. 
This is one of the reasons why diabetics are at much higher risk of blindness and amputation. The peripheral nerves become compromised over time by swings in blood sugar.

tl;dr Blood sugar must be tightly controlled to minimize damage from glycation.

Why do we even want carbohydrates then?

If glucose is so bad then why is it such an intricate part of life? Well, it is quite benign until oxygen cleaves it. All sorts of micro-organisms live in environments without any oxygen and they have no worries about sugars. 
As you may or may not remember from biology class your genes are encoded on DNA and that's the same for all life on Earth (except some viruses that store their genetic information in RNA but that's almost the same). And you might also know that DNA is a polymer with sugar-phosphate backbone. If you don't remember, that's okay, you just need to know that DNA is alternating sugar (ribose) and phosphate. The bases are bound to the sugar - there are four different bases and their order encodes information the same way the 26 letters of the alphabet encodes information when strung after each other in a certain way. Genetic information could have been (and probably was) encoded in a variety of molecules at the dawn of life but the sugar-phosphate with four bases won out in the end. In addition, bacteria found it useful to decorate the outside of their cells with carbohydrates, a glycocalyx, for a multitude of complicated reasons. We, eukaryotes, also decorate our cells with a glycocalyx.
Carbohydrates are very versatile molecules and they are easy to synthesize from just carbon dioxide, water, and energy. And in an environment without oxygen they are stable and compatible with the other molecules of life. But after 1.4 billion years of life on Earth something changed. Oxygen from photosynthesis had finally oxidised everything readily oxidised by oxygen (such as iron turning to rust when it reacts with air) and started to build up in the atmosphere. If there were any bacteria living on land they were probably wiped out before they could adapt - the oceans had oxygen-free areas just as today. And bacteria adapted and some of them (well, archaea) were able to evolve into eukaryotes because of the availability of oxygen (and all animals, plants, fungi, etc are descendants of those eukaryotes). Multicellular life, as we know it, did not emerge until after about 3 billion years of life on Earth when the oxygen content finally rose above 5% (about 800 million years ago).
It doesn't make evolutionary sense to give up on carbohydrates - they are as mentioned a great product to make via photosynthesis from CO2 + H2O and for those of us that aren't photosynthetic it is a readily available source of energy and metabolic building blocks. It would be too far an evolutionary leap to give up on carbohydrates. So instead of evolving away from the use of them life has evolved to control how much free carbohydrate and free oxygen is around. A bit further down I'll get into how integral a part of human biology carbohydrates are.

tl;dr Life evolved in an oxygen-free atmosphere and carbohydrates are easy to make from CO2 and H2O as long as you have some energy.

But sugar is toxic! Fructose is the devil!

What we normally call sugar is sucrose, a single molecule consisting of one glucose and one fructose covalently linked. Now, sucrose is exceptionally easily cleaved to glucose and fructose by our bodies and no studies have yet found a metabolic difference between sucrose and fructose corn sirup (HFCS is 45% fructose and 55% glucose). But HFCS is sweeter and tastier and has very different crystallization properties so you can use it in some foods where sucrose doesn't work well. And because of corn subsidies it is absurdly cheap in the US. Fructose is more reactive than glucose - so is galactose (lactose is similar to sucrose but is made from one glucose and one galactose). If they weren't then we would probably have evolved with one of those molecules as our blood sugar instead. As it is, fructose and galactose are taken up in the small intestine and both removed from the blood stream as soon as they reach the liver. Galactose is converted to glucose through a multi-step pathway but fructose is cleaved in a pathway analogous to glycolysis. Glycolysis produces DHAP and glyceraldehyde-3-phosphate whereas the catabolism of fructose produces DHAP and glyceraldehyde. Glyceraldehyde can be phosphorylated to glyceraldehyde-3-phosphate or made into glycerol. These metabolite fed into a later step in glycolysis so functionally fructose, glucose, and galactose pretty much have the same thing going on in the liver. The big, massive difference is that fructose and galactose must be metabolised in the liver. And if your blood sugar is high then the liver isn't going to turn them into glucose and export them. And if your glycogen stores in the liver are full then these glucose can't be saved for when blood sugar goes down again. So the only option for the liver is to use the raw material and energy from the fructose and galactose and produce fat and attempt to export that fat and move it via the circulation to your fat cells. This is analogous to when the liver degrades excessive amounts of alcohol and has nowhere to dump the energy produced in the process (except that your liver can't produce glucose from alcohol). Which is why I think that excessive fructose/galactose consumption combined with large glucose consumption is the cause of non-alcoholic fatty liver disease (whether glucose from starch, sugar, HFCS, or other sources).
So basically, I think there's a threshold value underneath which fructose and galactose are completely harmless.

tl;dr A high-carbohydrate diet with lots of fructose and lactose is problematic, but in a diet with moderate carbohydrate content you will probably not have a problem with moderate fructose / sucrose / lactose (unless you have fructose malabsorption or you are lactose-intolerant or allergic to dairy of course).

Energy storage (and the low-carb flu blues).

Storage of energy is pretty important; it is basically what our civilization is built upon. First by the storage of food calories in dried and smoked meats and later in grain seeds stored for 1+ years and even later the combustion energy stored in fossil fuels. One of the big challenges in moving forward into a renewable energy society is how we should store energy for when the sun doesn't shine and the wind doesn't blow. And energy for airplanes and rockets etc.
In animals, plants, and fungi energy is stored as glucose polymers and fat. In animals the carbohydrate polymers are called glycogen and in plants we call them starch. The glycogen is more branched than starch so it can be faster broken down or have more glucose added. There are multiple kinds of starch and some are quite branched and digested almost as fast as the glucose monomer and others are quite linear and more slowly digested.
Glycogen binds a lot of water so while the calorie per mass ratio between carbohydrate and fat is ~1:2, the calorie per mass ratio between hydrated glycogen and stored fat is between 1:8 and 1:10. So a quick thought experiment: a mid-thirties man of 78 kg with a body fat of approximately 10% has all the calories stored in his fat magically transformed into glycogen. 0.1 * 78 is 7.8 so he has 7.8 kg fat and glycogen representing the same calories would weigh between 62.4 and 78 kg. So his bodyweight would be in the 132.6 to 210.6 kg range. This is not practical. He would get eaten by a sabre-tooth tiger almost immediately. Therefore glycogen storage is limited and there aren't any specialised cells to store glycogen like there is for fat. Glycogen is mainly stored in the liver and muscle cells. Example guy from before would maximally be able to store 450-650 g of glycogen in his body (about 60 g fat energy equivalent).
That was a bit of a long introduction. But now you know that there's a good reason for storage of carbohydrates to be limited and, from before, you know that there's a good reason for tight control of the concentration of carbohydrates in the bloodstream. So when you habitually eat massive amounts of carbohydrates your body needs to prioritise glucose metabolism over fat metabolism. Every fatty acid metabolised for energy is a bunch of glucose molecules either sitting around in your bloodstream or having to be turned into fatty acids (possibly in the liver or other sensitive tissue). So the rational thing to do is to shut down all fat metabolising enzymes and pathways so there's no resource waste on maintaining them and no energy produced from them.
If you go from a very high carbohydrate consumption to a quite low one, you will feel like you have no energy. And obviously, if you rub your belly a bit, it is clear that you are carrying around plenty of energy. People call this "the low-carb flu" and it takes about 3 to 7 days to clear. It doesn't happen for everyone and it doesn't have the same impact for everyone either. Personally, I think the reason it takes so long must be that transcriptional on-off switches have to be changed (bromo-domain proteins have to change the modification patterns of histones) but I've never seen any research that compares mRNA patterns in humans to macro-nutrient intake. If it were as simple as activating a transcription factor that works directly on DNA then it shouldn't take more than a couple of hours to upregulate the energy-from-fat pathways.

tl;dr High carbohydrate diets prevent you from burning body fat and also make you dependent on constant supplies of carbohydrates through the day to keep energy up.

Glucose as a precursor for important metabolites

Glucose can be metabolised without oxygen to produce a little bit of energy and pyruvate. Anaerobic exercise is an example of when this happens, but your red blood cells also produce energy in this manner (because they lack mitochondria) and some cells in your bone marrow (because that's a low-oxygen environment). Obviously the vast majority of your energy during anaerobic exercise comes from oxygen while none of the energy in red blood cells does. Pyruvate is converted into lactic acid and exported from those cells to be used by other cells or excreted through your skin.
Before the pyruvate step is reached there's 3-phosphoglycerate which can be used to create serine. Serine is reversibly converted to glycine and together these two amino acids are the precursors for the production of a ton of important biomolecules. Think non-essential amino acids, cell membranes, and DNA bases. There is currently research on inhibiting these pathways to limit the reproductive capabilities of cancer cells. Please don't think that this means that a low carb diet means that you'll never get cancer or that someone with a high daily intake of carbohydrates will get cancer.
So, brilliantly, the cells in our bone marrow only have little oxygen available and they also proliferate rapidly, producing lymphocytes and red blood cells. So the increased amounts of glycolysis for energy fits perfectly with higher requirements of raw materials to build new cells.
Basically, carbs are important. But most people don't actually need that much.

tl;dr Glucose is a precursor to molecules important for creating new cells.

Well how much carbohydrate is moderate then?

It depends.
How many new cells are you making? This is dependent on your age (children heal faster than adults and grow in general), your gender (pre-menopausal women produce more new cells than men), and whether you are pregnant.
Apart from that your carbohydrate needs also depends on your activity levels (exercise in the high intensity region consumes some glucose molecules for energy), lean mass (size of muscles and organs) and just plain genetics.
Remember how the storage of carbohydrates is also limited? Carbohydrate requirements are in absolute amounts and not "this fraction of your calorie intake should come from carbohydrates". So if you are really fat you would have a high calorie intake (the slow metabolism idea is a myth, by the way) compared to a skinny person but if age, gender, lean mass etc are comparable then carbohydrate intake should be approximately the same number of grams. So the fat person should have a much lower fraction of their calories from carbohydrates than the skinny bitch.

tl;dr Appropriate carbohydrate intake levels are a function of age, gender, lean mass, activity levels, genetics. Unless you are pregnant.

Please feel free to comment. I am worried that I screwed up the glycogen calculations, so if I am wrong please tell me (and give me some references so I can see how). Please don't get upset if I call your comment stupid. It doesn't mean that I necessarily think that you are stupid. 

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