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Everybody says that insulin resistance is bad. Very bad. It’s the root cause of type 2 diabetes (T2D), and metabolic syndrome, isn’t it? So, if it is so bad, why do we all develop it in the first place? What’s the root cause? My friend Dr. Gary Fettke from Tasmania wrote an illuminating book called ‘Inversion’ where he describes how you can learn a lot from looking at things from another perspective. Invert (turn upside down) your perspective, and see how your horizons are immensely broadened. So let’s look at why we develop insulin resistance. Why is it good?
Root Cause Analysis
What is the root cause of insulin resistance? Some people say inflammation or oxidative stress or free radicals causes insulin resistance. Those are total cop-out answers. Inflammation is the body’s non-specific response to injury. But what causes the injury in the first place? That’s the real problem. The inflammation is only the body’s response to whatever is causing the injury.
Think about it this way. Suppose we are battlefield surgeons. After decades on the job, we decide that blood is bad. After all, every time we see blood, bad things are happening. When we don’t see blood, bad things are not happening. It must be the blood that is dangerous. So, deciding that blood is what is killing people, we invent a machine to suction all the blood of people. Genius! The problem, of course, is what’s causing the bleeding, rather than the blood itself. Look for the root cause. Bleeding’s only the response, not the cause. Bleeding is a marker for disease. So is inflammation.
Something causes bleeding, the body’s non specific response. Something causes inflammation, the body’s non specific response. Gunshots cause bleeding, knife wounds cause bleeding, and shrapnel causes bleeding. Those are root causes. You got shot. You bleed. But the problem is the gunshot, not the bleeding. The same applies to inflammation.
Whatever is causing the injury (the root cause) is also stimulating inflammation (the nonspecific response to injury). Inflammation is simply the marker for disease. So people say that cardiovascular disease, diabetes, neurodegenerative disorders, obesity and cancers all involve chronic inflammation. But the inflammation is not causing the disease, it is only a marker of it.
If inflammation was actually a root cause of heart disease, for example, then anti-inflammatory medications (prednisone, ibuprofen, NSAIDs) would be effective in reducing heart disease, or obesity, or cancer. But they are not. Whenever people talk about inflammation being the cause of disease, they just bandying around the latest buzzword.
This is not to say that inflammation (or bleeding) is not useful as a marker of disease. If the bleeding stops, then the treatment (tourniquet) is highly likely to be effective. But it’s not effective because bleeding stopped. It was effective and bleeding stopped (it’s a marker for effectiveness). Similarly in inflammation and T2D, as I previously wrote, insulin therapy does not decrease inflammation, which marks this likely an in-effective treatment overall.
The same goes for oxidative stress (or free radicals). Tell me what is causing the oxidative stress. That’s why antioxidant therapy is so startlingly ineffective. So Vitamin C, or E or N-acetylcysteine or other antioxidant therapies never work whenever they are tested rigorously. Because the oxidative stress is only the response (like inflammation) to whatever the underlying disease process actually is. If somebody goes on and on about oxidative stress (or free radicals or inflammation, or bad gut microbiomes) as the cause of XXX disease, run, don’t walk the other way. “Insulin resistance is caused by inflammation” is like “gunshot wounds are caused by bleeding”.
So, back to insulin resistance. Why does the body develop it so frequently (up to 50% of the American population)? This simply cannot be mal-adaptive. Our bodies are not designed to fail, since we lasted for several millennia before the modern diabesity epidemic. Insulin resistance must serve a protective function, being so common. Maybe this IR is actually protective. Regulation of insulin sensitivity is part of the normal physiologic response – it can go up or down depending on lots of things, including other hormones (eg. pregnancy) or availability of nutrients. So how can IR be protective?
Consider this. Excessive glucose in the blood is bad for us (high blood sugars). If this high glucose level is toxic in the blood, why wouldn’t it also be toxic in the body, too? Shouldn’t we get rid of the toxic levels of glucose instead of merely shoving it from the blood into the tissues of the body? After all, insulin doesn’t actually get rid of the glucose. It shoves the excess glucose out of the blood and forces it into the body. Somewhere. Anywhere. Eyes. Kidneys. Nerves. Heart.
Imagine you have too much garbage in your house. But you like to keep your chair nice and neat by moving everything elsewhere. Instead of actually throwing the garbage out of the house, you merely shift it around in the same house. Not a great idea. For glucose, instead of reducing the total amount of whole-body glucose, we merely shove it from the blood into the body.
So,if this high glucose is toxic, then the natural response of the tissue (body) is to protect itself against this excessive glucose load. Suppose you live on a street of houses in DiabetesVille (each house is a cell of the body). Everybody is friendly and normally leaves their door open (just as a cell is open to glucose in the insulin sensitive state). A truck full of toxic waste (glucose) comes down the street. And the garbageman (Insulin) really wants to get rid of this slime. So, every time he sees a door open, he shovels in some toxic waste (glucose).
After a few days of this, what would you do? You’d bar your f***ing door, is what you’d do! You’d say,”I don’t want this toxic slime!” That’s insulin resistance, baby! You make it really difficult to shove that toxic stuff into your house. It’s not a bad thing, it’s a good thing. The insulin resistance is trying to protect the cell from the toxic levels of glucose that the insulin is trying to shove in the door.
What is Insulin Resistance protecting us from? It’s very name gives the answer away. Insulin Resistance. It’s a reaction against excessive insulin. It’s protecting us from the excessive insulin. In other words, as we’ve written before, Insulin causes Insulin Resistance. But the root cause here is the Insulin, not the Insulin Resistance. The tissues (heart, nerves, kidney, eyes) are all busy increasing their resistance to protect themselves from Insulin which is trying to shove some toxic glucose into their house.
So we call the specialist Dr. Endocrine. Dr. Endo decides that the slime is indeed toxic, and we must get it off the streets immediately. There are some options – like reducing the production of toxic glucose (Low Carb diets) or burning off the toxic glucose (Fasting). But instead, he decides that he will hire more garbage men (insulin) to shove this toxic glucose into the houses. At least then, Dr. Endo won’t be able to see it anymore. Now Dr. Endo can pretend he is doing a great job. Look! The streets are nice and clean. But all the toxic glucose goes into the houses (tissues).
And what happens over time? Well, all the tissues of the body just start to rot. We are inadvertently ‘overcoming’ the tissue-protective insulin resistance developing. Instead of targeting the insulin, and reducing the total amount of glucose that we have to deal with, we are increasing how to get rid of it. So, by prescribing lots of insulin for patients, we are not making things better, we are making them worse.
Warning – Technical talk ahead – feel free to skip ahead. Normally, there is an inverse relationship between blood glucose and free fatty acid (FFA). In the fasted state, glucose is low and FFA is high. The body is burning fat for energy. As you eat, insulin goes up, glucose goes up and lipolysis is inhibited and FFA levels fall.
But in T2D, insulin levels are high. Glucose is high. But because of excessive IR, FFA is also high. So, the tissues of the body are now at risk of receiving both excessive glucose and fat, which is now causes the oxidative stress and the inflammatory response. But the inciting factor here, is the excessive glucose and insulin. (See pretty picture above for graphical explanation). Excess glucose to the mitochondrion overloads the electron transport chain and results in excessive ATP production as well as Reactive Oxygen Species – all causing oxidative stress.
Glucose metabolized through the anaplerosis pathways that produce AcCoA and MalCoA which becomes substrate for cholesterol and fatty acid synthesis. MalCoA inhibits FACoA resulting in steatosis, or the production and abnormal deposition of this fat.
OK, technical speak over. Welcome back. So, in the liver, excessive insulin produces fatty liver. We can easily demonstrate this in humans. In this study, 16 test subjects were overfed an extra 1000 calories of sugary snacks per day. This consisted of 1 can of Pepsi, 30 ml of fruit juice and a bag of candy. Over 3 weeks, there was only a 2% increase in total body weight. However, there was a disproportionate 27% increase in liver fat due to DeNovo Lipogenesis.
In other words, insulin is driving much of this excess glucose into the liver and it’s being turned into fat. Some of this fat can be exported out of the liver to other tissues such as muscle and pancreas giving you ‘fatty pancreas’.
In the muscle cells, we get fat deposits between the strands of muscle. You could call this ‘fatty muscle’. Technically, this is called intramyocyte lipid accumulation. Many think this causes insulin resistance, but it is more likely the result of excessive glucose and insulin. The accumulation of fat between muscle fibres (where there should not be any), in cattle, is called delicious.
Cattlemen, of course, know exactly how to develop marbling in cows. The most important determinant is the type of feed. Cows are ruminants, which means that they normally eat grass. However, by feeding a high energy, grain heavy diet, ranchers can increase the growth rate of cows as well as increase marbling.
See if you can spot the difference between well marbled beef and lean beef. The grass fed beef develops no marbling, which gives steak much of its flavour. For this reason, many grass fed cows are ‘finished’ with feeding corn in order to develop the fat marbling. Insulin and glucose. No secret. It works in humans as well.
You can see the same sort of fat deposits in the muscle cells of the heart and this may contribute to congestive heart failure. ‘Fatty Heart’.
A New Paradigm
So inversion forces us to see T2D from a new perspective. The toxic agent here is the excessive glucose, and its co-conspirator, insulin. Moving the toxic glucose out of the blood and forcing it into the body has no net benefit, as has been amply demonstrated by multiple long term randomized studies – ACCORD, ADVANCE, VADT, and ORIGIN.
Instead insulin resistance develops precisely because it is a protecting the tissues against the blood trying to shove all its toxic load into the cells. This is why the development of the insulin resistance is universal. It’s a good thing, not a bad one. Giving exogenous insulin to overcome this IR is actually detrimental. So the problem is not the IR at all. Instead, look for the root cause – the excess glucose and excess insulin. Take that away, and the T2D goes away.
So there are good treatments for T2D, and there are bad ones. The bad ones overcome the tissue insulin resistance which is there precisely to protect the tissues. These are insulin and sulfonylureas. The good treatments get rid of the glucose out of the body. You can do this by preventing it from coming into the body in the first place (LCHF diets, Acarbose), or burning it off (Fasting) or urinating it out (SGLT-2 Inhibitors). This explains the power of this new class of medication in terms of cardiac protection.
Insulin resistance is bad? No, not at all. It is good. Insulin resistance is not the root cause. It’s the natural, protective reaction to the root cause – high insulin levels. It’s the insulin, stupid!
Update – Dec 4
What’s the practical implication? Think about it this way. If your house is full of garbage, you can do 2 things. Stop putting garbage in (LCHF). Or you can start throwing garbage out (Fasting). It would be faster throwing garbage out AND fasting (LCHF + IF).