A new paradigm of insulin resistance

Man with big belly

What exactly is insulin resistance? One of insulin’s jobs is to help move glucose from the blood into the cells for energy. When blood glucose remains elevated despite normal or high levels of insulin, this is called insulin resistance. The cells are resisting insulin’s pleas to take up glucose. But why is this happening? What causes insulin resistance?

The current paradigm of understanding insulin resistance is the ‘lock and key’ model. The hormone insulin acts upon a cell surface receptor to do its job. The insulin receptor is like a lock keeping the gates to the cell closed. Insulin is like the proper key. When inserted, the gate opens to let glucose from the blood inside the cell for energy. Once you remove the key (insulin), the gate closes back up and blood glucose can no longer enter the cell.

insul-resistanceDuring the phenomenon of insulin resistance, we imagine that the lock and key no longer fit together very well. The key (insulin) only partially opens the lock (receptor) and not very easily. Glucose cannot pass through the gate normally, and as a result, less gets into the cell. The blood glucose piles up outside the gate, becoming detectable as the clinical diagnosis of type 2 diabetes is made.

Because the cell has less glucose inside, this has been described as a state of ‘internal starvation’. The body’s knee-jerk reaction is to increase insulin production. Since each key works efficiently, the body compensates by producing more keys than usual. This hyperinsulinemia ensures that enough glucose gets into the cells to meet its energy requirement. A nice, neat theory. Too bad it has no basis in reality.

The problems with the ‘lock and key’ model

First, is the problem the key (insulin), or the lock (insulin receptor)? It’s quite easy these days to determine the molecular structure of both insulin and the insulin receptor. Comparing type 2 diabetic patients with normal patients, it immediately becomes clear that there is nothing wrong with either the insulin or the receptor. So what’s the deal?

If both the key and lock look normal, then the only remaining possibility is that there is something that is gumming up the mechanism. Some kind of blocker interferes with the interaction of the lock and key. But what?

Here’s where the trouble starts. All kinds of theories try to explain what is blocking the insulin. Without a clear understanding of what caused the insulin resistance, we have no chance of treating it. All the usual buzzwords come out when doctors and researchers have no real clue as to what is going on. Inflammation. Oxidative Stress. Free Radicals.

While these may sound impressive, they merely reflect our ignorance, shedding no light upon the root cause of insulin resistance. These are all cop-out answers. Inflammation, like oxidative stress and free radicals, are merely non-specific response to injury. But what causes the injury in the first place? That’s the real problem that needs to be solved.

Correlation or causation

Imagine that we are battlefield surgeons. After several decades experience, we deduce that blood is bad for health. After all, every time we see blood, bad things are happening. When we don’t see blood, bad things are not happening. Therefore, blood is dangerous. So, deciding that blood is what is killing people, we invent a machine to suction blood out of people before it can cause illness. In medieval times, of course, leeches were used. 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 are inflammation, oxidative stress, free radicals and all the other typical answers.

Gunshots, knife wounds, and shrapnel all cause bleeding, the body’s non-specific response. Those are root causes. When you get shot, you bleed. But the problem is the gunshot, not the bleeding. The blood is a marker for the disease, rather than the disease itself.

Fever is another example of a non-specific response to infection and injury. Fever is a good marker for infection. When we find a fever, there is often an underlying infection. But the fever did not cause the infection. Bacteria or viruses are the underlying cause.

Inflammation, oxidative stress and free radicals are not the cause

The same logic applies to inflammation, oxidative stress and free radicals. Something is causing injury, which stimulates inflammation, oxidative stress and free radical formation, which are all the body’s non-specific response. The problem is whatever caused injury, not the inflammation, oxidative stress and inflammation, which is simply markers of disease.

If inflammation were actually the root cause of heart disease, for example, then anti-inflammatory medications, such as prednisone or non-steroidal anti-inflammatories would be effective in reducing heart disease. But they are not beneficial at all. They are only useful for those diseases where excess inflammation is truly the root cause, such as asthma, rheumatoid arthritis, or lupus.

The exact same logic applies to oxidative stress, which is a marker of disease, but not a causal factor. Some underlying injury is causing the oxidative stress, which needs to be treated. This is the reason why antioxidant therapy is so startlingly ineffective. Vitamin C, or E or N-acetylcysteine or other antioxidant therapies, when tested rigorously, fail to prevent disease.

Saying that, “Insulin resistance is caused by inflammation” is like saying, “gunshot wounds are caused by bleeding”. Not useful. However, inflammation, bleeding and fever are all useful markers of disease and treatment efficacy. They mark the presence of the disease. If the fever breaks, then the treatment (antibiotic) is highly likely to be effective. Inflammatory markers can also be good markers for the effectiveness of treatment. If insulin therapy decreases inflammation, then this is likely an effective treatment. Sadly, it does not.

Without understanding the root cause of insulin resistance, we have no hope of properly treating it. This lock and key model with ‘internal starvation’ is a nice story but cannot explain many of the phenomena observed in type 2 diabetes. In particular, it fails to explain the central paradox of insulin resistance.

The central paradox

Recall that insulin normally goes up when you eat. Insulin acts predominantly in the liver to help store incoming food energy. Insulin instructs the liver to do two things.

  1. Stop making new glucose from its stores
  2. Switch to storage mode to produce glycogen. When full, produce new fat via De Novo Lipogenesis (DNL)

In a state of high insulin resistance, such as type 2 diabetes, both actions of insulin should be simultaneously blunted. This certainly hold true for the first action of insulin. Insulin yells at the liver to stop making new glucose, but the liver continues to pump it out. Glucose spills out into the blood, provoking the body to increase insulin levels.

In an insulin resistant state, the second action of insulin should also be blunted, but is paradoxically enhanced. Using the old lock and key paradigm, the insulin resistant liver does not allow glucose through the gate leading to ‘internal starvation’. In this circumstance, the liver cannot create new fat and DNL should shut down. But in fact, DNL not only continues and actually increases. So insulin’s effect is not blunted but accelerated!

In fact, there is so much new fat being generated, that there is nowhere to put it. This leads to excess accumulation of fat inside the liver, where there normally should be none. Liver fat should be low, not high. But type 2 diabetes is strongly associated with excessive fat accumulation in the liver.

How can the liver selectively resist one of insulin’s effect of insulin yet accelerate the other? This happens in the very same cell, in response to the very same levels of insulin, with the very same insulin receptor. This makes no sense whatsoever. Insulin sensitivity is reduced and enhanced at the exact same time and in the exact same place!

Despite decades of ongoing research and millions of dollars, all the world’s top researchers were still stumped by this central paradox of insulin resistance. Research papers were written. Different hypotheses were proposed, but all failed because the old ‘lock and key’ paradigm of insulin resistance with internal starvation was incorrect. Like a house built on a crumbling foundation, the entire underlying premise of treatment of type 2 diabetes disintegrated.

It’s the insulin that causes insulin resistance

irparadigmsHow can we explain this apparent paradox? The vital clue is that insulin itself causes insulin resistance. The primary problem is not the insulin resistance, but the hyperinsulinemia.

Insulin resistance refers to the fact that for a given amount of insulin, it is more difficult to move glucose into the cell. But this does not necessarily mean that the gate is jammed. There are other possibilities why glucose cannot get into that resistant cell. Perhaps the glucose cannot enter the cell because it is already overflowing. The new paradigm of insulin resistance as an overflow phenomenon resolves the central paradox.

This changes EVERYTHING. If you believe the old ‘lock and key/ internal cellular starvation’ model, then the appropriate treatment is to increase insulin as much as needed to push that pesky glucose into the cell. That has been the way we have treated type 2 diabetes for the last 50 years. And it’s been a complete disaster. The ACCORD/ ADVANCE/ VADT/ TECOS/ SAVIOR/ ORIGIN randomized controlled trials all proved the failure of this paradigm.

However, if the ‘overflow’ paradigm is correct, then increasing insulin to push more glucose into an overflowing cell is EXACTLY wrong! This would only make diabetes worse. Which is EXACTLY what we see clinically. As we prescribe insulin to type 2 diabetes, patients don’t get better, they get worse. Their blood glucose is better, but they gain weight and they still develop all the complications – heart disease, stroke, kidney disease, blindness etc.

The correct treatment of the overflow paradigm is to empty out the BODY, not just the blood of the excessive glucose. How? LCHF and intermittent fasting. And guess what? That’s EXACTLY what we see clinically. As we start fasting type 2 diabetes patients, they lose weight, their medication requirements go down and eventually it reverses.

Jason Fung

Earlier: Insulin Causes Insulin Resistance



How to Reverse Type 2 Diabetes – The Quick Start Guide

How to Reverse Type 2 Diabetes

Top videos about type 2 diabetes


Top videos about insulin


Earlier with Dr. Jason Fung

Insulin Causes Insulin Resistance

Obesity – Solving the Two-Compartment Problem

Why Fasting Is More Effective Than Calorie Counting

Fasting and Cholesterol

The Calorie Debacle

Fasting and Growth Hormone

The Complete Guide to Fasting Is Finally Available!

How Does Fasting Affect Your Brain?

How to Renew Your Body: Fasting and Autophagy

Complications of Diabetes – A Disease Affecting All Organs

How Much Protein Should You Eat?

Practical Tips for Fasting

The Common Currency in Our Bodies Is Not Calories – Guess What It Is?

More with Dr. Fung

Dr. Fung has his own blog at intensivedietarymanagement.com. He is also active on Twitter.

His book The Obesity Code is available on Amazon.

The Obesity Code

His new book, The Complete Guide to Fasting is also available on Amazon.



  1. Georgia G
    Wow. The more I read what he has discovered, the more everything makes sense when it comes to patients who diabetes only worsens over time. We as healthcare providers tend to blame the patient but here we are just making their disease worse with the standard of care practice taught in school. Thank you for posting this. I'm a second year ARNP student in family practice. I have been fascinated with Dr. Fung, his articles/books and his stand he has taken for so many patients.
  2. Marianne G
    Oh, thank you Dr Fung and everyone at Diet Doctor! If only I had had this resource when my grandmother and mother were struggling with this horrible disease. Because of your work, there is hope that I will not follow them into blindness, dementia, amputations, heart failure, gastroparesis, neuropathy....... It makes me sick that the insulin they so depended on to keep them alive actually made them sicker and fatter and eventually killed them.
  3. Gianni
    Dr. Fung and Dietdoctor team, you are really brave people and responsible doctors. You have no idea the big impact you are making in the world. You are changing the world for the better because all these trues will widespread. Thank you!
  4. Victor
    Great article! However, overflow theory brings us right back to overeating and overeating brings us to calories counting as a method to avoid glucose overflow in the cell. Overflow paradigm is used often by the people who are against low carb diet. As for my taste, it is great concept since it also explains PIR well. But again it points to the idea that overeating is the problems, not carbs.
    Cheers, Victor
    Replies: #7, #13
  5. Aurora
    Is there any evidence supporting this theory at this point? Or any research in progress?
  6. Prof Ann Henderson
    I was newly diagnosed end of September. I went through the usual metaformin 'experiment', dropped it immediately and went onto a very low carb diet. I found immediately a drop in levels but it seemed to be the starving that did it. I wasn't intending to starve, I was just running on empty most of the time. After a week I had pain below the stomach which I thought was pancreas or liver and so I stepped up to half a bread roll a day. I was walking 6-10miles a day and running out of steam. The whole thing rapidly settled but I thought that's scared the hell out of the pancreas. I went in for my Hb test last week and I had reduced from 72 to 44. PLus my blood pressure had dropped from 145 to 120 and my weight by 1 stone to 10st. The answer is to run the tank on low and put up with it. I feel very healthy, I'm now doing very tough walking and eat my small low GI roll when I'm walking all day but nothing starchy when I'm not expecting to. I walk it off as I eat it. I had no choice, I couldn't take the tablets.I agree with the article on starving the sugar out of the system and the fat out of the liver.
  7. Diane
    Not really, I don't think. We are talking about too much glucose in the body. Where does the glucose come from? It comes from eating sugar and starch, not from eating calories. Eating sugar and starch also causes insulin to rise in response to the rising levels of glucose and that rising insulin also stimulates appetite making us want to eat more carbs. A vicious cycle of more carbs, more insulin, more insulin resistance.
  8. Tricia Bell
    So why is a high blood sugar so effectively
    lowered by administration of insulin? If the cells were already full of glucose then it would still have nowhere to go and blood sugar would remain high.
    Reply: #10
  9. Tim
    Weight gain means new cells...
  10. Apicius
    My guess is that there is always more room...just need greater force shoving it in. Like sending in the SWAT team.
  11. Tricia Bell
    Thanks Apicius,
    But Dr Fung says the cells are already overflowing with glucose. Cells control how much glucose enters so that there is not too much in the cell. Cells that don't have this control like in the eye, kidneys and nerves suffer the most damage as they really are struggling with the effect of intracellular hyperglycaemia, hence the symptoms of uncontrolled diabetes (kidney failure etc). I would just like to see more information, explanation and evidence about this theory
    Reply: #12
  12. Apicius
    I think you are very fortunate today. Dr Fung just posted an explanation of how insulin works under this condition on his website: https://intensivedietarymanagement.com/understanding-joseph-kraft-dia...

    Hope this helps :-)

  13. Angeh
    over flow part is completely right ... but not as explained .. but something blocks glucoliysis in cells and makes the cells overflow...
  14. Dinesh Prajapati
    Glucose is not increased by starch & sugar only but by all the carbohydrates we consume. I agree with comments #4. I am diabetic since last 20 years & I am also following the same to keep my BS levels under control.
  15. roger pointer
    "excess accumulation of fat inside the liver" Recently studies have found that excessive fat in the pancreas is an indicator of type 2 diabetes. Cause or effect: "A new study published in Diabetes Care by a team from Newcastle University, UK, found losing less than one gram of fat that is accumulating in the pancreas can reverse diabetes. It means blood glucose levels may go back to normal range if people lose their weight." Dr. Taylor said, “For people with type 2 diabetes, losing weight allows them to drain excess fat out of the pancreas and allows function to return to normal.”"
  16. Birgit
    Claims of anti-inflammatory effects of insulin
    How can this be compatible with increased inflammations in people with metabolic syndrome?
  17. Jennifer
    Regards Gianni,

    I totally agree 100% they seem to be challenging the conventional system, which I hold them all in high esteem for doing so which I am sure is not easy and no doubt gaining many raised eyebrows and other from Doctors who dont see to know how to treat or deal with the disease, and who seem to have it all wrong for far too long unfortunately, thankfully, the have a new wave of thinking and addressing focusing and targeting diabetes in a different way, to give hope for everyone with Diabetes at the the end of the day, and hopefully those doctors out there, who are stubborn, and treating Diabetes wrongly, should take a leaf out of their books, to ensure they start and take a new approach to methods and addressing diabetes differently than in the past.jenn

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