What, exactly, is Insulin Resistance? – T2D 23

posted in: Health and Nutrition | 73

A New Paradigm of Insulin Resistance

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.

During 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.

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.

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.

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.

How 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.

73 Responses

  1. I think the problem over is that insulin by itself is oxidative for the cell, that makes by a down regulation system, that the cell protect itself of the oxidative status that it could damage it. So, it become insulin resistent, in a attemp to reduce the oxidative state that would lead to cell injury.

  2. Sudden onset of permanent insulin resistance in a very thin female adult during and post pregnancy. Why does it happen?

    • Anora, I’m not a doctor and I don’t play one on the internet, but thin people can be highly insulin resistant as well. It’s very possible that you were insulin resistant already–the pregnancy made it more noticeable.

      Take a look at the work of Joseph P. Kraft, M.D. http://www.thefatemperor.com/blog/2015/5/10/lchf-the-genius-of-dr-joseph-r-kraft-exposing-the-true-extent-of-diabetes Dr. Kraft had all of his patients tested for insulin resistance and found that only 20% of his entire patient population (more than 14,000 of them!) had normal blood glucose and glucose tolerance. So chances are the problems you are experiencing existed before your pregnancy, and perhaps you are fortunate that the pregnancy illuminated the problems before they became much worse.

    • Yeah, what Jan said! Also, isn’t it a known side effect of pregnancy for women to appear to be, in that short term, diabetic and that that resolves post delivery?

    • Anora, I have seen videos by Lustig about sugar, where he talks about the only two natural times where insulin resistance occurs naturally: puberty and pregnancy. These are times when the body wants to hoard as much energy as possible, so insulin resistance causes higher insulin which blocks leptin.

    • If the person is very thin, it may well be that there is no insulin excess, but rather, excessively LOW insulin levels. Measure insulin, fasting and after a reasonably carby meal (oatmeal for example) and measure antibodies relevant to Type 1 diabetes. Post-pregnancy is also a risky time for the development of autoimmunity. Consider also gluten sensitivity which can jack up glucose levels (when you consume wheat). Even better, find a doctor who understands that thin hyperglycemic people can have adult onset type 1, and knows what to do about that.

  3. LCHF and IF worked good for the first 3 weeks. FBS came down from 180 to 118. but when I started reducing the drugs, it again raised. when reduced the medication to 1/4 of what I was taking, the FBS raised to 200. I increased medication to 1/2 of original, it came down to 170, after2 months of starting LCHF.
    Is it OK? dawn phenominon?
    MY fasting insulin is only 3.81 mu/ml.
    should I make any changes in the diet or anything?

    • Three weeks? That’s it? I’ve been on low carb, then LC + IF, then IF + LC/ketogenic for three YEARS. And I still have blood sugar > 100 in the morning due to dawn effect. Give it some time, like a year.

      I recommend eating as much fat, particularly animal fat, as possible. Mix up your fasting: miss breakfast for most days; skip lunch also a few days a week; maybe eat breakfast sometimes; throw in some longer fasts.

      • sten bjorsell

        If you do “Mosely IF” with 500 calories each fasting day you may well need years ! Try one, then two days in a row every week water only fast, unless its urgent and you can get a doctor to supervise longer fasts. Then real results can be reaped in months instead of years. Insulin must come down significantly and stay down for LONG to reduce insulin resistance. GBP-patients get 5 days (!) supervised fast around their operation. Many if not most DB-2 patients would be permanently cured on such fast, and stay well eating LCHF after. In less than a week. Permanently! And when not fasting, no snacks. Max 3 meals per day. Each snack pushes up the insulin level and keeps it up when it really should fall between the meals. More fat in meals means less hunger between meals. Another reason food companies wants us to eat fat free meals. Hungry like pigs all the time.

        • Hey Sten! I finally caved and went back to an Atkins induction phase diet. Last four A1C’s have been 5.8, 6.0, 5.6, 5.5. But I am not budging weight wise. Off my low, which also was with intestines empty, I am up 10lbs. I have been under 20g total carbs for about a week at this point. My hands and feet are a tad on the cool side but not nearly freezing as they were when fasting. I did get the point where about 2am they’d be toasty but when I went to bed they were freezing, even with wool socks. I’d still like to know what my REE, TEE, RMR, BMR (whatever) actually is at this point.

        • I’m doing LCHF diet and doing 42 hour intermittent fasting, only just started. Do I have to eat a certain amount on non fasting days or just enough to stop me being hungry. i am T2 Diabetic on no medication

    • 180 FBS on medication is a very progressed disease state. That will not resolve immediately. Either you’ve been hyperinsulinemic for a very long time or your beta cells are badly damaged. The more time you spend in a fasted state the more responsive your cells will become to insulin and the more rest you will give your beta cells, but make sure you don’t do this at the cost of not getting the nutrients you need or you are trading different ways of being unhealthy.

      As for the dawn effect, that is more pronounced the later in the day you eat your first meal. If you are a breakfast eater make sure to only have protein and fat at the start of the day.

      • My fasting insulin is 3.81 mu/ml only. As per Homa2 scale, beta cell function is 12.6% only. IR is 0.59 only. Sensitivity is 169%.
        I am diabetic for the last 10 years .
        I am on LCHF and skipping breakfast.

      • My fasting insulin is 3.81 mu/ml only. As per Homa2 scale, beta cell function is 12.6% only. IR is 0.59 only. Sensitivity is 169%.
        I am diabetic for the last 10 years .
        I am on LCHF and skipping breakfast. What further action to be done.

        • Today I checked my FBS. Came down from 209 to 139 mg/dL, within 13 days, keeping same level of medications (metformin 500+ glimepiride 1 mg).

          I am continuing LCHF and short term fasts. This give me hope.

  4. An excellent article and I’m a believer in the overflow hypothesis, but has much research been done to confirm or deny that theory?

  5. i’m told (by Tim Noakes, on youtube) that the liver can’t stop producing glucose. So, even after eating a lot of carbs the liver just continues to produce it’s background level of glucose. Raising glucoselevels even more! This is tested in baboons: https://www.youtube.com/watch?v=NxzOcaG9Yxo&index=28&list=PLKSq7Y3Wxy8V3aSzpluz6lyzGa3DfCrLe

    Does this support the “overflow” paradigm?

    • In the diabetic disease state beta cell release of insulin does not turn off alpha cell release of glucagon and so yes, the liver keeps releasing glucose. I suspect drugs will be coming out before too long targeting that instead of just pumping more insulin.

  6. This hypotheses sound so good, that I’d like to believe in it. However, there is type 3 diabetes, that is, Alzheimer’s disease, where brains are starving of glucose in spite of high blood sugar. It can even be monitored by a PET scan. How can that be explained?

  7. and maybe a fatty liver secretes massive amounts of baseline-glucose trying to become less fat?

  8. This study is not contradicting your hypotheses and puts insulins role in glucose metabolism into controlling liver gluconeogenesis only. So, kind of supports your theory. But even this can not explain the starving of brain of glucose in Alzheimer’s disease. I’m puzzled.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2129159/

    “It is generally assumed that this is because insulin increases glucose uptake into tissues. However, this is not the case and is just another metabolic legend arising from in vitro rat data. It has been shown that insulin at concentrations that are within the normal physiological range lowers blood glucose through inhibiting hepatic glucose production [21].”

    • Ari, you are correct in that many people with Alzheimer’s have either hyperglycemia, hyperinsulinemia, or both, and that a major driver of Alzheimer’s pathology is that neurons in certain regions of the brain become unable to harness energy from glucose. Despite a high presence of glucose and/or insulin in the periphery (outside the brain and central nervous system), these neurons are not taking in and metabolizing glucose. Dr. Stephen Cunnane has some excellent papers on this (focusing on the use of ketones as an alternative neuronal fuel precisely because these cells no longer take up and metabolize glucose properly).
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937039/ (Full text)
      https://www.ncbi.nlm.nih.gov/pubmed/26766547 (Abstract only)

      • Hi Amy and thanks for those links! I know, that ketone bodies do not need insulin to enter the cell (brain or other) and glucose doesn’t need it either (as was found in that study I linked) – which supports this overflow paradigm.

        The study you linked, did not completely answer the dilemma of this overflow paradigm – if glucose is found plentiful in plasma and overflows other cells of the body, then how is it possible, that at the same time it does not reach braincells? Is the only explanation, that BBB cells become insulin resistant and do not pass glucose in sufficient quantities thru? At least that would explain the situation.

        The other option is, that insulin does not reach the brain because of BBBs insulin resistance (see Figure 1: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191295/figure/F1/ ) and areas of brain, where glucose needs insulin to enter braincells (via GLUT4), start to wither. “Surprisingly, in cerebellar membranes, GLUT-4 was present in significant amounts and its expression was insulin-dependent (103). In addition, the trafficking of GLUT-4 to the plasma membrane was modulated in the cerebellum, cortex, and hippocampus under conditions that increased plasma insulin levels (104), such as after peripheral glucose administration.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191295/

        Is it one or the other or still some other explanation? I don’t know, but would like to find out the exact mechanism, which causes this. It might also support this overflow paradigm.

        • Christopher Hamilton

          We don’t see alzheimer’s in young patients. I wonder if those cells are being “burnt out” during the person’s younger years because of the excessive glucose in the blood stream? It might be that the outer cell walls were not designed to swim through sugar constantly and the glucose becomes toxic to the outer cell walls and, after a lifetime of near constant exposure, the cell’s ability to repair itself becomes sufficiently compromised to the point that it can no longer repair itself from the toxic environment. I’m soaking in Epsom salts in the bathtub right now so I am on my phone and research is difficult, maybe see if there is any correlation between Alzheimer’s disease and hyperinsulonemia(sp?) in youth or adulthood?

  9. This is a really interesting post. But I am confused on this point: is not insulin resistance usually demonstrated with a glucose tolerance test in a fasted state? If the paradigm you propose is correct, shouldn’t the test fail to show resistance because the test is administered after the liver’s glycogen is depleted? Or is the fasting window for the test usually insufficient to demonstrate insulin sensitivity when the body is emptied?

  10. Theories, studies and data abound. For me I figure why not try LCHF and IF? If it doesn’t work medications will still be there.

  11. How can this be tested and proven in a laboratory?

    • Look for and view the presentation by Dr Roy Taylor called “Reversing the Irreversible”. He shows baseline, 1 week, and 8 week results of what appears to be glucose tolerance / blood insulin data. Outstanding presentation.

  12. I do not believe that there will be many good research studies done on insulin as long is big pharma is in control. Money talks. Why would they want to kill the goose that laid the golden egg? The Canadian Diabetes Association is in cahoots with big pharma. I remember a number of years ago, when they posted an article saying that sugar is safe, because its glycemic index score was lower than white bread. They never reply to my emails asking why they are not promoting a low carb diet.

    Not only in politics, but also in our daily lives, we seem to be living in a “fact free” world. Daniel Moynihan, former US Senator once said, “everyone is entitled to their own opinion, but not their own facts”. That does not seem to be true anymore in almost any field. Like the old saying “might makes right” those whose money controls the research and those whose money controls the media now seem to “own the truth”.

    It is only because of brave and persistent mavericks like Dr. Jason Fung and others, who choose independent means of spreading information through youtube, podcasts and blogs. it is up to us to help by also talking and writing about our positive experiences with IF and LCHF to move our society forward.

    The challenge, more and more for the average person is to educate her/himself, think critically, and use his/her power of discrimination to separate the real truth from skillfully fabricated misinformation: a more and more daunting task.

    • Excellent comment. Thank goodness for Dr. Fung and what he does to enable us to improve our health. He truly is a healing angel.

  13. A missing word in the fourth paragraph?

    “Since each key works efficiently, the body compensates by producing more keys than usual.”

    IIRC should read:

    Since each key works **less** efficiently, the body compensates by producing more keys than usual.

  14. Thanks Dr J. My daughter got her Fasting Insulin blood test result yesterday and it was 17. She is very concerned as she should be. She got all of the IDM blood tests and everything else was pretty good. I had mine done 6 months ago and it was 14. However following Megan’s and all of your IDM advice the next blood test read 4 and that was only 6 weeks later . Fasting really helped me lower mine.

    • Good that you have corrected the word in the sentence or it would mislead the people like us . Hence you have mentioned that the body compensates by producing more keys than usual. Is it the body or pancreas that compensates? I am asking this for my better understanding. I am still confused.

  15. […] Jason Fung skriver i Intensive Dietary Management. […]

  16. Let me say that I agree entirely with the article and I think we do need to spread the word more on intermittent fasting and low carb. Yes, we are in the midst of an obesity and diabetes epidemic which threatens to undo the entire health system.
    However, we should not confuse any of this with a cure all, in which case we become no better than charlatans. The human body is genetic, we are all wildly different from each other, and beyond a certain point we will age relentlessly. It’s a complex interplay of genetics and environment.
    The goal in public health should be to improve the environment factors as much as possible, but also to realize that these efforts are mostly in vain when up against a capital system whose openly stated goal is to produce as much junk and get it consumed by as many people as possible. 50 years and there is no victory against tobacco or alcohol much less the harder stuff, and you think you will have any victory against big agriculture and sugar?

    Fat chance.

  17. John Fackrell

    I was excited to read this article by Dr. Fung. As I was studying about diabetes. The standard insulin resistance model didn’t make sense to me. What did makes sense was that the cells are full they have had enough to eat and don’t want anymore. Which seems to be similar to Dr Fung overflow Theory.

  18. My first attempt at an all day fast was amazing. I began after breakfast and a reading of 14.2. The rest of the day was a fast..water and coffee (black) only.I tested at what should have been meal times, and it became progressively lower. I awakened at 2:00 AM and just out of curiosity, tested..6.1. I had a celery stick with peanut butter. Morning reading was 7.1, I did intermittent fasting for the rest of the week, with 0 bread and carb meals when I did eat, and decreased insulin to 15 Units from 30 with no major differences in the readings.
    Cheated last night with a large glazed Doughnut snack .My reading was 17.1 this morning. Reduced or 0 carbs are definitely necessary along with the fast.As in one of the videos by a client of Dr. fung, testing after every meal helps determine what to avoid.

  19. Nice post Jason

    You forget to mention the role of high intensity, glycolitically demanding activity like sprinting and intense strength training to use muscle (and liver) glycogen, thus creating storage for incoming glucose.

    I totally agree that IF and LCHF works great for improving insulin sensitivity, but so does exercise, if it’s well thought out and attacked with the right sort of intensity.

    There obviously then becomes a trade off between doing LCHF dogmatically and attempting glycolitically demanding exercise. They don’t go that well together 🙂

    How do you incorporate heavy resistance training into your practice with your insulin resistant patients?

    S

    • Great comment Stephan. My ‘lay person’ motivational construct is: keto is for the liver, exercise is for the muscles and fasting is for the brain. Simplistic, but I work best when things are simple.

      • Cool Jim, sounds like you’ve got it sussed. I do think that a complete approach is a good. A lot of folks who are very overweight just can’t do HIIT training, risk of injury / finding it to hard (lot’s of lean people do too btw), but intense resistance training, even with machines in a safe gym environment would be magical for many who need to find a way of depleting muscle glycogen more effectively and restoring some of those energy partitioning pathways that they seem to have lost along the way

  20. Joachim Overdick

    Interesting!

  21. Hi Jason and community

    I’m not a doctor . A . Nutritionist

    A friend called dr woodrow monte has a theory . That dietary methanol that at adh1 sites converts to formeldahyde
    Which modifies the insulin .

    Which then is not the key that fits the lock . Because if the cell lets the modified insulin into the cell . This may result in cell death .

    So we are left with glucose intolerance .
    Until you stop eating drinking dietary methanol . And wait for the damage to repair . If it can ??????

  22. This just isn’t going to fly. There is far too much clarity of thought and insightfulness for any conventional medical doctors to accept.

    (:->)

    Seriously, why is it so easy for a dummy like me to get this, and it seems so difficult for most medical doctors to get this? Is it because what Dr. Jason said back on September 8, 2016 in his article about continuing education for doctors: https://intensivedietarymanagement.com/big-pharma-behind-scenes/

  23. Wait a minute, I’ve got questions. First, why do the cells full of glucose not just burn it up? Second, how does the overflow paradigm explain why hyperinsulinemia causes the liver cells to reverse only one of the two processes they normally reverse when insulin is present?

  24. If the overflow theory is correct, then why do we become even more insulin resistant while in ketosis?

    • When the body senses there are no/ little incoming carbs, it starts sparing glucose for the cells that could not survive without it, like red blood cells and brain. It is a normal, reversible process that minimize glucose consumption by making muscle and fat non-responsive to insulin signalling. Eat carbs for a couple of days, and you will become more insulin sensitive than before starting keto.

  25. sten bjorsell

    Nate, good question. I suggest simple congestion is one potential reason for not allowing more glucose in. “Burning off” is a good idea but it hits the common problem “how to lift low a sluggish metabolism”, a separate big question!
    Higher insulin drives balance towards storage, opposed both by full cells and full liver. But cells are “one way streets” when it comes to glucose, while the liver is a “two way street”. I see no contradictions in the following explanation: When blood insulin levels exceed liver insulin resistance, there are two liver thresholds. First stop, no more glucose comes out, and at the 2nd higher stop, insulin is driving more glucose into the liver. **
    When it comes to making fat in the liver, this is the long term storage and escape route ! When liver is full of glycogen fats are made from it and it means the liver is making, storing and pumping out triglycerides into the blood stream, sometimes raising blood fat levels that in combination with already high glucose levels become really unhealthy, while getting fatter then reduces at least high blood fat levels to safer ones. All agree with the “cells are full” theory.
    More insulin at this stage would mean increase of liver size to hold the extra fat , like in natural fois gras, geese with very good internal insulin production gorging on sweet autumn fruit, enabling them to fill and enlarge these liver fuel tanks for long haul flights, while for us it results in worsened metabolic syndrome as we tend to do the same thing all around the year, not every autumn like the geese, the way the mechanisms evolved. That is what DB-2 is, a natural survival mechanism perverted to kill us due to constant feeding. IF is the answer, as Dr Fung has said !
    ** ( And when insulin drops (during nights typically), first no glucose is stored and then glucose is left out, resulting in dawn syndrome when it starts in the night).

    • Thanks, Sten. To me, this is such an interesting subject.

      So, the question as to what causes one’s metabolism to ramp up or down seems to me to be central to insulin resistance. That question brings up two more. How do some people become what is termed ‘skinny fat’. From my limited understanding that term means that a person is insulin resistant but does not look fat. Then another question, how does the body ramp up its metabolism when one eats less than 500 calories per day for a time, but then ramps it down when one eats say 1,000 calories per day?

      BTW, that different reaction to less than versus more than about 500 calories per day makes sense for when we were hunters/gathers. Way back when we survived on the food we had stored for cold winters, the slower metabolism could allow us to more or less hibernate until spring brought us more food. But less than 500 calories meant that we had better get out and find some food no matter what. To do that of course we would need to ramp up our metabolism.

      • sten bjorsell

        Hi Nate, agree it is an interesting subject. Jason Fung has written a lot of it in past posts and most of it makes good sense and much of it is supported by studies.
        We know that when we water only fast, metabolism ramps up to full speed. It is explained that without food, gradually only fat from the tissues become the dominating energy supply, which can be fully accessed once insulin drops sufficiently, a matter of fasting time alone. (Typically 3 days on water only, maybe 5+ for morbidly obese with huge livers!) If food intake before fasting is dominated by carbohydrates it may also take more days of hunger hardship. But on a fat dominated diet before fasting already lowerstarting insulin requires a lesser drop meaning shorter time of hunger. I heat LCHF and only first day is difficult when I do intermittent fasting. The “less than 500 calories per day” to maintain metabolism I doubt a lot. Better no food at all, else only fat. (If I start eat anything during a fast it becomes very difficult to continue fasting!) . And wIth any carbs and/or protein in the 500 calories, insulin is driven up which means that it becomes harder to access body fat reserves, irrespective of how large they are! The extra food means going into starvation mode = low metabolism due to the higher insulin from that extra (minimal!) food. But having a bullet proof coffee does not reduce metabolism, only making it necessary to fast longer if weight or metabolic syndrome loss is the objective.
        Yet reduced metabolism with little food to survive another winter makes sense in a slowly deteriorating (long winter) scenario. No contradiction! For us it is now a matter of understanding the different “gears”, making it “piece of cake” to reduce weight and restore insulin sensitivity, if it is the aim. Jason has put most of the explanations in the blog before and/or in his book(s).

        • Thanks for the comment. (Before I forget, I would suggest one small change. Instead of, “piece of cake” maybe it should be “slice of bacon”…) Anyway, yeah when we fast at the beginning of each month, we have two bowls of broth with some spinach each day of our fast. Also, I have some heavy cream in my morning tea. So, yeah I will try a water or maybe broth only fast. I’m can’t speak for Laura though.

          BTW, as I was reading Dr. Fung’s next post, it came to me that you cannot out run a bad diet. So, maybe that is why people with certain metabolisms cannot burn all of the glucose in their overflowing cells. And as a Type 1 diabetic I know how sluggish one can feel with high or even moderately high blood sugar. Another point is that with our fasts I have cut my insulin volume in half or even more.

  26. I would very much like to read Jason Fung’s thoughts about gestational diabetes and how it is linked (or not) to hormones. Why do I get low blood sugar (and intense sugar cravings that are, otherwise inexistent) the week before my periods? I feel like there’s a strong connexion between my hormone cycles and the way my body handles sugar levels and insulin.

  27. Hi Dr. Fung,

    I have a question about prolonged fasting….

    Is it okay/healthy/normal to see BUN drop below 3 mg/dL with a prolonged fast?

    Thank you!

  28. I started IF in 2013 after seeing the documentary report Eat, fast and live longer. I lost 40 pounds fasting 2x a week. I was not pre diabetic through testing but nearly obese. I changed jobs and found myself slowly gaining back 7-10 pounds. Sedentary business travel. Since then, (2 years ago) I have completely stalled. Tracking on MFP everyday, cultivating a low carb life style. Nothing. I suspect insulin resistance. Stress grazing the REAL reason. Understanding the macros ( I actually have a nutrition degree), I have also been convinced my calories need to be 300 a day below “normal”. When using conventional calculators I should eat 1300 per day to lose. I maintain my current wait at 1150 per day! I am really stumped on how to break this plateau! The goal I have set is NOT a vanity goal. How do I get these last 15 – 18 pounds off for good!! I finally understand what it feels like to be on the threshold of giving up. But I won’t!!! I’m 53, 5’7″ and 160 pounds. I do kundalini yoga regularly.

    • sten bjorsell

      Janette, you said it already: “stress grazing” is the real reason, one major at least. Look at the 2nd diagram on this page: https://intensivedietarymanagement.com/insulin-works-hormonal-obesity-vii/
      It shows resulting insulin peaks from snacking/grazing. Eat more often and before you know it it is closer to a straight line.

      Example: A forty-hour constant insulin infusion into a group of healthy young people caused 15 percent greater insulin resistance!!! A ninety-six-hour constant intravenous infusion of insulin reduced insulin sensitivity by 20 to 40 percent.
      From: https://intensivedietarymanagement.com/hyperinsulinemia-insulin-resistance-t2d-22/
      All hormones are naturally delivered in pulses to prevent resistance to build up! Opposite to the test above. Grazing or eating all the time is just the opposite to pulsing… But eating only 3 or fewer meals per day helps pulsing.
      And reducing calories further will only make you freeze also in the summer. Start with one whole day water fasting, or better night to morning day 2. Once a week. Increase fats. Stop grazing. Get bright light during the day to de-stress and sleep better. It works! If you can get it done , check your fasting insulin now and later. Target is below 5…..

      • Thank you!

      • Update: 2 weeks of 20/4. No snacking! LCHF macros pretty on target. Tracking macros on MFP so calories tracked. Averaging 800 but some days 1400 some days 600 just because I wasn’t hungry. I did not have the ability to check my A1C but I plan to.
        5 pound lost and dropped through the plateau by 1pound so far. I am eternally grateful that you and George Thomas below, took the time to encourage me. I’m going to get to that goal!

    • George Thomas

      “How do I get these last 15 – 18 pounds off for good!!”
      Don’t stress graze.

  29. sten bjorsell

    When it comes to the explanation that “cells are overfull of glucose” instead of the diabetes-1 explanation that the cells are starving, which we know for sure in that disease, I think it is correct in DB-2 especially if we take in consideration that glucose and oxygen isn’t the only “fuel” our cells require: High carbohydrate metabolism requires much more magnesium than a moderate carb diet, typically generally consumed before the obesity and diabetes-2 explosion started. And both diabetes-2 patients and pre-diabetics are proven to be generally low in cellular magnesium, in many studies! At the same time magnesium is also required to produce insulin, that we need more of with a higher % carbs in the diet. And magnesium is also important to detox us from minerals and toxic chemicals that are increasing in our foods today…. Sounds like a “perfect storm” making more people diabetic sooner! Yet reducing carbs alone will take us a good way back. If we are already sick we may however need more magnesium to relieve sore and hard muscles, cramps, calcified arteries and sometimes also arrhythmia, which all are among the longer term side effects longer term high carb fast carb consumption usually results in, maybe often via magnesium deficiency ! Over age 50/60 we need to address the magnesium shortages as well is what I mean.

  30. 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

  31. There is evidence, not just theory, that fat in the blood causes fat to build up in muscle cells which makes them insulin resistant … http://nutritionfacts.org/video/what-causes-insulin-resistance/

    Dietary fat also causes diabetes in the pancreas http://www.sciencedaily.com/releases/2011/08/110814141432.htm

    So I’m not sure how a LCHF fat diet can fix diabetes. Perhaps it reduces the symptoms but as soon as carbs return the symptoms return.

  32. Hello Dr. Fung from Czech Republic! I love your work! Can you give me an advice? Is it possible to restart this “bodyweight thermostat” after weight loss? Last year a lost about 15kg by counting calories and IF, but I have got hard time to maintain this new weight. I literally feel I can eat same amount of food, like I was 15kg heavier, so I eat less and Im hungry. I practise dinner-dinner IF, sometimes 48 hours IF, I do LC diet and I workout hard. I feel great, but Im gaining fat. You’re saying cutting calories is not an answer… Can this be example of insulin resistance? Thank you! I hope your methods will be known in our country someday too!

  33. Hi,
    I play the ketosis game. Check blood ketones occasionally. Today my ketones were 2.4 and my glucose was 107. All I had to eat today was a cowboy coffee 4 hours ago. and I ate dinner at 6 the previous day. I have had this occur multiple times. Is this unusual to have such a high glucose ? on no meds. last fasting insulin was 2. HgA1c has been 5.6 and not dropping for some reason. Thanks

  34. Guido Crocchi

    Dr. Jason Fung, I’m 67 years old, diabetic type2 from 46 years, taking 80 u of insulin per day and NASH since last 15 years, and I don’t get to reduce sugar ( ~170) nor insulin (~57).
    I’ve seen recently your approach for diabetic desease by reducing insuline resistance through LCH and intermitent fasting and I would like to try it.
    I live in Rio de Janeiro, Brasil, and would appreciate if you may have an indication for a doctor who follows your program.
    Thanks a lot.

  35. I would wonder his/everyone’s take on the studies showing different “resting” or natural insulin levels in people, i.e. even with fasting some people have a higher level of insulin naturally occurring in their body.

  36. Jason,

    I recently heard the following talk from Chris Masterjohn: https://www.youtube.com/watch?v=N0XnXWM-92M

    He is not focused on Type 2 Diabetes but listening to his talk made me think of your theory of what constitutes Type 2 Diabetes. Masterjohn is focused, in the talk, on hydrogen peroxide and he talks about its ‘signalling’ effects, being the blocking of a cell’s absorption of glucose.

    I am wondering whether the focus on the insulin receptor might be wrong – in that you are right in saying that there is nothing wrong in a Type 2 Diabetic with the insulin receptors – however, there is a cellular ‘starvation mode’ caused by hydrogen peroxide?

    I have no idea about how to integrate what Masterjohn says about hydrogen peroxide’s role in ‘signalling’ allowance of glucose into a cell and your observation that insulin receptors are not damaged.

    Is my thought completely mis-placed? Or is hydrogen peroxide – and its causes – something that needs to be accounted for?

  37. Shannon Nelson

    I have PCOS and am morbidly obese. I recently bought and read Dr. Fungs new fasting book. I know I should be doing the protocol discussed in the book for the most obese. The 2 weeks fast plus the 42 hour fasts a week. But… I think I deal with food addiction (not even sugar or junk food addiction) and sometimes the urge to binge is like an addict. I wonder if you have any insight about that issue?

  38. Of course excess insulin causes insulin resistance. Peripheral insulin resistance isn’t really that noteworthy though. There are a lot of people who see this as a closed model, a given amount of glucose is in our blood, it should all be going into cells, it doesn’t, so that’s the problem. However, the problem isn’t that, it’s because too much glucose is being put into our blood in the first place, and this is due to insulin resistance, but not in the periphery, not in fat and muscle cells, but in the liver and pancreas.

    Insulin isn’t like a key to a lock, it’s a key to letting in more though, opening the floodgates so to speak. Insulin isn’t even required for glucose to get into cells quite well, as Dr, Unger proved by completely suppressing both insulin and glucagon and normal blood sugar was obtained. If you want more than that though you need insulin, but insulin’s main role is controlling endogenous glucose production, and this is the part that is broken with T2DM, and this is very well known.

    So it’s not that our peripheral cells don’t want glucose, they just don’t want this much of it, excessive amounts that is, the excessive amounts that is in our blood. That’s surely a good thing because they are already under higher levels of stress. I am very impressed with Dr. Fung as he’s one of the very few people out there that gets that peripheral insulin resistance is a good thing, although our alpha cells and our liver being deaf to it is not. This is a disease of oversupply, not under-demand, but we treat it medically as if it were the latter, so it’s no wonder standard treatments fail to treat us and only lead to a further progression of the disease.

  39. I dont uderstand how this theory can explain the ongoing GNG while the liver have insulin resistance . If the cell is overflowing with sugar why he keeps making new sugar? The internal starvation theory can explain it. Since the cell not feeling any sugar around he keep making more of it because he thinking that there is not enough sugar in the blood. But how the overflowing theory can explain it?

  40. Jason Libenswarm

    Professor Seyfried in his book “Cancer as a Metabolic Disease” Chaper 18, page 360 says:

    “Excessive or unrestricted KD (ketogenic diet) consumption can cause insulin resistance and hyperglycemia (9).”

    This (9) is:

    9. Zhou W, Mukherjee P, Kiebish MA, Markis WT, Mantis JG, Seyfried TN. The calorically
    restricted ketogenic diet, an effective alternative therapy for malignant brain cancer. Nutr Metab.
    2007;4:5. (you can find this here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1819381/

    Is this something to worry about?

  41. I have fasted for 24 hours twice now and both times and I swear my bones hurt quite badly throughout my entire body but my knees and fingers in particular.
    I felt very stiff and so I’m wondering if fastsing enhances or speeds up the effects of arthritis in any way??

    Should I be taking a supplement of some kind? Or just stop trying to fast?
    I certainly don’t want to speed up arthritis and I didn’t really feel anything like that before I tried the fasting.

    If anyone has advice, I’d greatly appreciate it. Thanks!

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