The Citric Acid Cycle – The biochemistry of insulin resistance

I’ve talked about insulin resistance many times previously (and in The Diabetes Code) and how a fundamental mis-understanding of it using the ‘lock and key’ paradigm has set the stage for our current failure to treat type 2 diabetes. Rather than insulin resistance being a paradigm of ‘internal starvation’, it should really be considered a paradigm of overflow.

If you have an excess of intra-cellular glucose, the liver will try to decompress itself by turning it into fat. It exports this fat as VLDL leading to high triglycerides, low HDL and this fat will deposit in other visceral organs leading to fatty liver, fatty pancreas, and abdominal obesity. What’s the biochemical mechanism behind this? How does an overloaded cell block glucose entry into the cell? For this we need to discuss the citric acid cycle. (Warning: This discussion assumes some basic knowledge of biochemistry)

When we eat, we consume a blend of three macronutrients – carbohydrates, proteins and fats. No matter what macronutrients go in, we want the same output – cellular energy in the form of ATP. Proteins, broken down into their component amino acids, are not purely used for energy, and are used as building blocks for new proteins. There are some essential fatty acids, too, but for the most part, dietary fat and carbohydrates are mainly useful as sources of energy. So we have 3 inputs (carbs, amino acids, and fats) and 1 output – cellular ATP. How does our body metabolize food into ATP? That’s the job of the citric acid cycle (also called the tricarboxylic acid or TCA Cycle).

The TCA cycle, which takes place inside the organelle known as the mitochondrion is pictured on the right. Glucose is first changed into pyruvate through the process of glycolysis (literally – the breaking down of glucose). Under anaerobic conditions, this can be used as a source of energy, with the end result being the production of lactic acid. But under normal aerobic conditions, it undergoes further pyruvate oxidation into Acetyl CoA. This can then undergo the TCA Cycle which generates the NADH and FADH2 necessary for the cell to undergo oxidative phosphorylation.

Each cycle of the TCA cycle regenerates the original substrate oxaloacetate so that it may continue running. Each Acetyl CoA provides 2 carbons, which get turned into carbon dioxide, but in the process generate 3 NADH and 1 FADH2, along with an ATP or GTP. So there’s not a whole lot of ATP generated with the TCA cycle directly. But indirectly, you can continue onto oxidative phosphorylation to generate 36 ATP per glucose, which requires the NADH and FADH2 for the electron transport chain.

Other than glucose, there are other places that amino acids and fatty acids may enter this cycle to ultimately produce ATP. This is how all foods may ultimately be turned into cellular ATP. Amino acids are generally not used for energy, but if in excess, they can have their amino groups removed, making ammonia (NH3) as a waste product, which is then turned into NH4+ and excreted in the urine. Different amino acids enter at different points in the cycle. For example, glutamate enters the cycle as alpha ketoglutarate.

Fat (triglycerides) are broken into glycerol and their fatty acid chains. Glycerol enters similar to glucose. Fatty acids are broken down by beta oxidation and combine with CoA to form acetyl CoA, allowing it to enter the TCA cycle smoothly.

But what happens in the case that there is too much ATP? Consider an analogous situation. Suppose that you normally buy gasoline to power your car. You drive to and from work everyday and you need about 50 liters or about 13 gallons each and every week. All of a sudden, instead of buying 50 L, you get 200 L per week. At first, you store some of the excess in your gas tank. When that gets full, you buy some jerry cans to store the extra. After that, it gets dangerous. All that excess gasoline is now sloshing around and pretty soon it’s going to explode like in a Tom Cruise Hollywood action movie.

Inside the cell, there is only so much ATP that it can hold. Once these stores are full, it cannot hold any more. The logical action is to stop putting more gas in the tank. For the cell, this means that it must stop the inflow of nutrients into the cell.

The cell does this through a negative feedback loop. When there is too much ATP, the ATP itself, as well as some of the intermediates acts upon the entire process to slow it down. In your gas tank, when you are pumping gas, when it gets full, the pump will automatically stop so that you don’t spill gasoline everywhere. The cell does the same thing.

When the cell notices an excess of ATP, it then puts the brakes on the whole system. ATP will directly inhibit glycolysis, pyruvate oxidation and the citric acid cycle in a desperate effort to slow down cellular production of ATP to avoid the ‘car exploding’ scenario.

Specifically, ATP and citrate (remember this is one of the key molecules produced by the citric acid cycle) will inhibit the enzyme phosphofructokinase (PFK), which blocks the conversion of glucose to pyruvate, the first step in the chain. ATP also acts blocks the action of pyruvate dehydrogenase (PDH) to block the conversion of pyruvate to Acetyl CoA, the second step in the chain. ATP then acts at multiple sites within the TCA cycle to stop its own production.

This is a fantastically elegant system that ensures that ATP is produced when needed, but never to excess. When this process grinds to a halt, glucose being at the very top of the chain, backs up. This slows down production of ATP and restores the system to normal. But what if we keep feeding glucose into the system?

As glucose increases within the cells, there is less and less of a concentration gradient for glucose to flow from outside to inside the cell. Remember that insulin opens a gate for glucose to enter. Normally, the glucose concentration outside the cell is higher than that inside the cell, and therefore will flow inside following its concentration gradient. If this gradient is minimized or eliminated, insulin has a harder and harder time pushing glucose inside the cell, and hence you see the glucose levels in the blood outside rise, leading to the term ‘insulin resistance’. But this is not a lock and key problem. It’s an overflow situation. The underlying problem of ‘insulin resistance’ as commonly used comes down to two simple things – too much glucose, which leads to  too much insulin.

The solution, therefore, is rather simple and only consists of two things.

  1. Don’t put more glucose into your body
  2. Burn off the glucose

You’ll also note that ‘insulin resistance’ while carbohydrate dominated, can also be activated through, for example, too much fat (triglycerides). Any macronutrient may produce ATP, which will overload the system and cause glucose to back up. Proteins and fats, however, are more difficult to overeat, because they naturally activate satiety hormones that prevent this exact situation. The logical solution? Fasting. Boom.

2019-09-18T12:13:38-04:0021 Comments

About the Author:

Dr. Fung is a Toronto based kidney specialist, having graduated from the University of Toronto and finishing his medical specialty at the University of California, Los Angeles in 2001. He is the author of the bestsellers ‘The Obesity Code’ and ‘The Complete Guide to Fasting’. He has pioneered the use of therapeutic fasting for weight loss and type 2 diabetes reversal in his IDM clinic.

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uday pasricha
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uday pasricha

once the basic biochem terms are understood to be common, then the explanation is so clear. Is it possible that the simplicity prevents its understanding to the medical community? Since the results are there, the only logic is that commerce trumps science. Now that we have the net .. this can change !! Thank you Dr.

Glen Rubin
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Glen Rubin

Following this logic, us diabetics should engage in activities that maximize mitochondrial biogenesis.

MH
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MH

Yes! I would love for Dr. Fung to touch on the biochemistry of HIIT training as other scientists have shown that has adrenal benefits that lead to weight loss and specifically abdominal fat.

Pete
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Pete

Ahhh…it’s good to see Dr. Fung posting stuff here again!

Barb
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Barb

Stupid question, does this mean we shouldn’t eat foods with the additive of citric acid?

David
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David

I don’t believe it means that at all. I think the takeaway points are as follows: 1) Don’t overeat. 2) It is easier to overeat Carbs but you can overeat Fat and Protein. 3) Exercise (burn off glucose). 4) Fasting can be a great solution to burning off excess glucose.

bob
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bob

Thank you for the reminder of the Citric Acid cycle. You have posed an interesting hypothesis of the cause of insulin resistance. “Normal” people can also engorge themselves and not even fast and yet not show the effects of insulin resistance and Diabetes . Why?
I look forward to explanation. Thank you for a clear presentation.

Anne
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Anne

I am not a doctor or anything. I think I know why. Native Americans get diabetes more. They are more adapted to starvation than people in Europe who had become accustomed to more food. So some people are just adapted to more starvation. Back in the day nearly everyone starved at some point. For the hunter gatherer, sometimes you just don’t find anything. For the agriculturalist sometimes the crops fail. Too much food is not good for anyone, they may not bet diabetes. I would bet that too much food thing is behind cancer and other assorted nasty disease. add… Read more »

Stephanie
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Stephanie

Many First Nations peoples have been stripped of their native cultural and ancestral habitats and forced into living conditions that are not in line with their traditional lifestyle and diet. Being moved from their lands onto reserves and becoming dependent on the so called western diet has greatly reduced the health and longevity of First Nation Peoples. The typical western diet is a disaster for everyone but the impact has been greater on cultures who have been forced away from their natural and traditional diet. Process foods were never a part of their diet, great knowledge and wisdom could of… Read more »

Rajith
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Rajith

Thank you for this comment of facts. The SAD is a disaster for us all. I think we need to be sure every one has access to healthy food. I’m so grateful to learn about fasting & linger Intermittent fasting. Weight is coming off with regularity even though slow.

Shawna
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Shawna

I think it will be understood in the future as a Microbiome issue. That is how you can have a couple, one is skinny and the other isn’t and yet they eat the exact same foods. I think there is a lot of just coming to terms with the microbiome that we inherit. Which I think will be shown to have some genetic connection because my brother is eat what he wants and is skinny and I do the same thing and then carry a tonne of weight.

Anne
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Anne

Thanks for explaining this. From a historical perspective, a lot of the people that believe in the paleo diet say that hunter gatherers were more healthy, and agriculture and grains ruined everything. I see it differently. The invention of agriculture made it possible to over eat! Hunter gatherers starve more. The poor people in ancient Egypt ate grains, like a kind of cream of wheat thing. Those people also starved a lot, so they didn’t get overweight. Plus it’s even worse now because before people maybe ate some small thing, then they went out to work in the fields and… Read more »

dave
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dave

Anne, I’m not sure there is evidence that the poor people of Egypt were healthy. I think Egyptians as a whole were very unhealthy. I have heard that most of this evidence comes from the mummies who presumably were upper class but I doubt the lower classes were much healthier. You should also check out Dr. Fung’s posts on the differences between starvation and fasting.

Tom M
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Tom M

I don’t understand the half of it, but it seems that this would be basic biochemistry that a doctor would be introduced to during his studies. I gather that more glucose would never solve the problems of type 2 diabetes and problematic fat. Now I have heard something about inventing another class of diabetic…type 3. Is this another idea to push more drugs?

Brett WOLMARANS
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Brett WOLMARANS

minor typo near the last few sentences “lock a key” I know you meant to type “lock and key”. great article. wish I had this information 20 or 30 years ago but I’ll take it now.

rachel
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All fixed! Thank you.

Grid
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Grid

The whole Krebs cycle was part of a discussion I was having just a few days ago with one of my physical trainers. She proposed that fasting was problematic when working out as we need an influx of amino acids from food for TCA to progress. It’s been a _long_ time since I took biochem, but for some reason I thought that most if not all of the AA’s used are reformed in other portions of the cycle. Is she right? Should I not be fasting when working out? I’ve felt fine lightly working out when doing a 3-4 day… Read more »

Prashant Gokhale
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Prashant Gokhale

Hi Dr, great article. Thanks. So one can get fat on eating too much fat or protein ? The assumption is that the satiety cycle kicks in for fat and protein faster than glucose – is that the only protection? so if one has a lower satiety signal for what ever reason, then one could overeat fat and put on weight? thanks v much

rachel
Guest

Correct. eat fat until satiation.

Christina M
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Christina M

What if there is no satiety? I can eat a ton of fat and protein. My leptin is coming down, but not to where it stops me yet. SIgh.

rachel
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If you don’t feel satiety, I would highly suggest a food log.