A New Paradigm of Insulin Resistance – T2D 13

posted in: Aetiology of Obesity, Insulin | 86

Our current paradigm of insulin resistance is that of a lock and key. Insulin is a hormone that acts upon a hormonal receptor on a cell surface in order to have an effect. InsulinReceptor

This is often referred to as lock and key model. The lock is the insulin receptor which keeps the gates to the cell closed. When the proper key (insulin) is inserted, then the gate opens to let glucose from the blood inside the cell. This glucose is then able to power the cell machinery.

Once you remove the key (insulin) then the gate closes back up and glucose in the blood is no longer able to go inside the cell.

What happens during the phenomenon of insulin resistance? Classically, we imagine that the lock and key no longer fit very well. The key (insulin) is able to open the lock (receptor) but only partially and not very well. As a result, the glucose is not able to pass through the gate normally.Insul Resistance

This results in lower than normal amounts of glucose inside the cell. The glucose, which is now blocked by the closed gate, piles up outside the cell in the blood, which we can detect as elevated blood sugar and make the clinical diagnosis of type 2 diabetes.

This has also been described as a state of internal starvation since the cell has little glucose on the inside. The knee-jerk reaction is for the body to increase production of insulin (key). Since each key works less well than previously, the body over-produces the number of keys to make sure that enough glucose goes into the cells. A nice neat theory.

The problem, really, is that this paradigm does not really fit reality. First, is the problem the insulin, or the insulin receptor? Well, it’s really quite easy these days to look at the structure of insulin and the structure of the insulin receptor of insulin resistance patients. You simply isolate the insulin or some cells and check their structure with fancy molecular tools. It immediately becomes clear that there is nothing wrong with either the insulin or the receptor. So what’s the deal?

The only remaining possibility is that there is something that is gumming up the system. Some kind of blocker that interferes with mechanism of the lock and key. But what? There’s all kinds of theories. Inflammation. Oxidative Stress. Advance glycation End Products. All the usual buzzwords that come out when doctors have really no idea. With this model, we have no real friggin’ idea what caused the insulin resistance. Without understanding what causes IR, we have no chance of treating it.Lustig1

Then there’s the central paradox of hepatic insulin resistance. Let me explain. Insulin has two major actions on the liver. Remember that insulin goes up when you eat. It tells the body to stop producing glucose in the liver (gluconeogenesis) because there is lots of glucose coming in from the stomach (food). This is mediated through the FOX01 pathway.

The second major action in the liver is to increase the production of fat (De Novo Lipogeneis (DNL)). This is to deal with the incoming flood of glucose that the body can’t use right way. This is mediated through the SREBP-1c pathway.

So, if the liver becomes insulin resistant, then the effect of insulin should drop for both of these actions. That is, the liver should continue to make glucose, and stop making fat. But that’s only the case for gluconeogenesis. That is, during insulin resistance, the liver continues to make new glucose as expected. But DNL (making new fat) continues and actually increases. So insulin’s effect on DNL is not blunted but accelerated!

What the hell?

How in seven hells can this insulin resistant liver selectively be resistant to one effect of insulin yet accelerate the effect of the other? In the very same cell, in response to the very same levels of insulin, with the very same insulin receptor? That seems crazy. The same cell is insulin resistance and insulin super-sensitive at the same time!

JapaneseSubway2How can we explain this paradox?

We need a new paradigm of insulin resistance that better fits the facts. In fact, we can think of insulin resistance as an overflow phenomenon, instead of a lock and key one. All we really know about insulin resistance is that it is much more difficult to move glucose into an ‘insulin resistant’ cell than a normal one.

But this does not necessarily mean that the door is jammed. Instead, perhaps the cell is already overflowing with glucose and therefore more glucose cannot go in.

Imagine the cell to be a subway car. When the door opens, the passengers on the outside (glucose in the blood) march in a nice orderly manner into the empty subway car (cell). Normally, it doesn’t really require much of a push to get this glucose into the cell (insulin gives the push).

But during insulin resistance, the problem is not that the door does not open. The problem, instead is that the subway car (cell) is already overflowing with passengers (glucose). Now the glucose outside the cell simply can’t get in and is left crowded on the platform.

Insulin tries to push the glucose into the cell like the Japanese Subway Pushers, but they simply can’t do it because it’s full. So, it looks like the cell is resistant to the effects of the insulin, but really the problem is that the cell is already overflowing. So, the knee jerk reaction is to manufacture more insulin (pushers) to help push glucose into the cell. Which works, but only for a while.

So, the cell is not in a state of ‘internal starvation’. Instead, the cell is overflowing with glucose. Glucose starts spilling out into the blood, which looks like gluconeogenesis has not been stopped which is consistent with insulin resistance. However, the Insulin and its Receptor are fine; they are simply overwhelmed by exogenous glucose ‘toxicity’.

But what happens to fat production?

In the classic model of insulin resistance, the paradox was that DNL was enhanced, not decreased which looked a lot like heightened insulin sensitivity instead of resistance. But in the overflow model, the DNL would be enhanced because the cell is trying to rid itself of the excess glucose by producing extra fat. The cell is overflowing and not in an ‘internal starvation’ mode.

Why is this critically important? Because understanding this new paradigm will lead to the answer of how insulin resistance develops and what we can do about it. The problem does not lie with either insulin nor the insulin receptor. Both are normal. The problem is that the cell is completely stuffed full of glucose. So, what caused it? The answer then seems obvious – it’s a matter of too much glucose and too much insulin. In other words, it was the insulin itself that caused the insulin resistance. We don’t need to chase shadows looking for some mysterious cause of insulin resistance.

Once we understand that excessive glucose and excessive insulin is the cause of the insulin resistance, then we can now devise a rational treatment. Reduce insulin and reduce glucose. Once you reverse the insulin resistance, you cure the type 2 diabetes.

86 Responses

  1. Dirk Van Giel

    This is amazing! If cells are overflowing with glucose wouldn’t it be a great idea to start exercising and make sure the glucose in these cells are burned?

    • What a novel idea; reckon the doctors will ever catch on? Fasting works even better. What if we combined the two??? “What a wonderful world this would be”.

      • Are there any actual studies of fasting+exercising?

        • Bethany

          Krista Varady did a study that appears in the October 2013 edition of Clinical Nutrition about combining alternate day fasting with endurance exercise. She was specifically focusing on coronary heart disease risk factors, but did find that weight loss was greater in the fasting + exercise group vs. the just fasting group or just exercise group.

          As we would expect, just fasting had significantly more weight loss than just exercising. Keep in mind that this was her version of alternate day fasting, which includes up to 500 calories on “fasting” day and eating whatever you want on “feast” days.

          • I personally would find a day of 500 calorie eating difficult. I might be able to do it if I ate breakfast with 500 calories, but I couldn’t do it with 500 calories of dinner. I’d rather either eat ad libitum (feasting, I guess–eating whatever I want) at dinner or just skip dinner altogether.

            I personally think exercise is useless for losing weight, unless you exercise a ton (and then I think you’re changing your insulin response, which is the real cause of weight loss).

            Personally, by using low carb and fasting, I’ve lost weight and at the same time, I’ve reduced the amount of exercise I get.

          • David


            Hard to say exercise is useless. An hour of moderate effort on the elliptical or the treadmill burns 800+ calories for a 200 lbs man. At higher intensities, or weight training for that matter, you’re likely shifting your own bodies hormones, not just insulin.

      • MickiSue

        Great idea, if exercise didn’t tend to increase appetite, and if, on a SAD, that increased appetite didn’t trend to consuming more carbs, which then further stuff the cells…

  2. sten bjorsell

    Sounds great.
    Where are the studies showing that in DB-2 /insulin resistance cells are not starving of glucose (like they do in DB-1)?
    When it is clear that it is proven beyond doubt the classical method of insulin treatment of DB-2 is really dead. It
    would also explain why patients get worse and die sooner with more intensive insulin treatment, the outcome of various trials, the ACCORD trial that showed increased mortality with more insulin, for instance.

  3. This is a little bit against the spirit of this blog, but does anyone have an idea if it’s better to have dessert before or after the meal?

    • This is answered within the spirit of this blog –

      You should only eat dessert after the meal. You should also skip the meal. 🙂

    • I’ve been thinking it’s better to have dessert earlier in the day, then find a way to walk it off. For instance, we’re going on vacation soon and will likely have ice cream with the kids. We used to always have ice cream after dinner, but I’m thinking we should have it perhaps after lunch, then go do something (go hiking, walk on the beach, etc.) to use up the excess glucose. And, of course, fasting after returning from vacation works well too.

      • It all hinges on what you mean by dessert. If it involves sugar and floury baked goods then the answer is NO DESSERT FOR YOU.

        • Never having another dessert is unlikely and impractical as a suggestion.

          • He didn’t say no dessert he said no sugar laden dessert. I think a lifetime without such things is easy if it means you solve your health issues

          • I have dessert A LOT. I’m just saying.

          • I started having recognizable symptoms of alzheimer. Going keto with zero carbohydrates became much easier and very practical.

    • Though I love Steve’s reply, I also remembered another blog that might actually have an answer at least by logical extension: https://intensivedietarymanagement.com/circadian-rhytms-fasting-17/

      For instance:
      “Now, this does not necessarily mean that you must eat a large meal as soon as you wake up. But it means that perhaps eating a large meal in the evening (after the sun goes down) may cause a much larger rise in insulin than eating that same meal during daylight hours.”

      Since reading that I have made decisions not to eat (former type II off meds for a year now after 6 months intermittent fasting in 2015, still do it for maintenance and will do for the rest of my happy healthy life) because of the hour.
      Also I agree that for some of us (read me) psychologically is it impossible to think we’ll never have another dessert (indeed that is one reason I am convinced that IF has such a high long term success rate, delaying satisfaction is doable, feeling deprived is defeating –if you find it exhilarating then we do not have the same psychological make up).
      So if you are going to do the deed on a feasting day, then chances are it is better to do it closer to midday than dusk, and maybe even better if it is sunny out? 😉

  4. Wow! I’ve studied this for years. I’ve taught my students about the lock and key model and this seems to be such a better understanding. I’ve been reading your work and watching your videos since I stumbled across it on the internet. I used to think I was studying diabetes for my brother who has suffered with it for years. Then, long story short, I found out I had it. I cured myself by eliminating all foods that quickly turn to sugar. I have noticed over the years that when I eliminate sugar, my triglycerides fall precipitately. So, the old teaching that fat is bad for you and grain is good for you should be rapidly loosing ground. But, guess what my brother and I are still being told by doctors? That is right; cut down on the fats… I had a VA intern actually get mad at me because I refused to take statins. I also told him I would not take the diabetes medications.

    • Carol Kushner

      My diabetes Type II is also cured using intermittant fasting and for the”eating days” I use the recipes on diet doctor.com. I take no medication for diabetes and I have stopped taking my statin — my only prescription now is for a blood thinner (Apixaban) and I also take Vitamin D. I still have weight to lose so I will continue with this regime until I’ve lost the excess weight and then I will be one happy girl!! My blood sugars have been perfectly normal for three weeks without diabetes meds (gliclazide — I never took insulin). This is a truly revolutionary approach — the rest of the world needs to catch up. Thank you Dr. Fung for making this information available to patients (and their doctors) in such a clear way. You deserve a big medical prize for this.

  5. Michael

    Interesting theory. One thing that it doesn’t explain though is the fact that many T2D:s on LCHF still need some medication. Why is that If there is no structural problem with their insuline receptors?

    • You can be LCHF and still have high-enough insulin levels. Protein has about half the insulin-raising effect of carbs, so if you eat enough protein you raise insulin. If you’re already insulin resistant it may not take too much of a rise in insulin to prevent your fat cells from releasing energy. LCHF does not recommend as much fat as a ketogenic diet, which for clinical treatment purposes is about 90% calories from fat. Basically, have a little salad and bacon bits with your glass of olive oil. (Okay, 300 calories of spinach is a boat-load of spinach). When I did “lazy keto” i was eating 3 times a day, and probably too much protein, so I didn’t lose much weight. Now I lick butter and drink an ounce of olive oil with some sea salt.

  6. Nancy J

    Could there be a different mechanism for liver cells vs. peripheral cells, or do you think one mechanism can explain both?

  7. This is a great explanation! When cells get crammed with glucose for a long time, what happens? Fermentation starts. You got cancer! This fits so well to everything else, it must be right. What an astonishing logic you have, Dr Fung!

  8. Joan Day

    Dr Fung–you are just fabulous–you can explain things so well. I love the example of the subway train–many of your followers as you know are not PHD.s , scientist/researchers, or Drs. –we the “common people” , patients, and internet fans, so enjoy your blog, and words of wisdom, that we can understand. [because of the way you explain things.] You are an amazing teacher, and healer. You have helped so many people, you may never really know how many–I for one, will be forever grateful. I found you after an article in the Toronto Star, near the end of January 2015. Thank you for all you do. I have so many friends that have type 2, and i am always talking about you–sooner or later , when they decide they want help, and change–they will know your name. As my weight comes off, and my health improves, when they ask what are you eating, doing–i say google “Jason Fung”. so please keep these blogs coming–

    • rick mccarthy

      Great post. Dr. Fung’s the best. I’m enjoying the heck out his book. Thanks Doctor.

  9. Reaction rates very much depend on the concentration of the reactants. If you get too much product, then things slow down or even reverse. This is all basic physical chemistry and I wonder if there is a lot of research going on to study the chemical pathways in detail and determine where the backups are occurring. It certainly would provide a basis for your theoretical explanation, and would be a lot more satisfying than the lock and key model.

  10. Okay then if I have so much stored sugar in my cells why can’t it be used properly for energy? Why the lethargy? I have believed it was because the sugar couldn’t ‘get in’ Now I am confused again…

    • Think of molasses or honey inside your cells…

    • Diana- Sonja here. I totally agree with you. pls scan down ~10, and see what I wrote! something more is going on.

    • Check out Wikipedia for “autophagy”. Autophagy is a natural process where damaged and tired proteins and organelles inside your cells are broken down and recycled for parts. When insulin and amino acid levels are high enough they inhibit autophagy. It’s like never taking the trash out of your house even while you’re regularly buying groceries. As things pile up inside the cell they get in the way of other healthy cell functions. We need to stop eating proteins and carbs for a period of time in order to allow autophagy to occur. (It’s my understanding that eating fat will not stop autophagy.)

  11. Is there any way to develop a test or study that could prove this hypothesis correct and the original hypothesis wrong? Sort of like swallowing bacteria and getting an ulcer to prove that (some) ulcers are caused by bacteria?

  12. Zig Euner

    1) It’s still a form of “internal starvation”, though. If hepatic cells are chugging along conducting DNL, then that glucose is not being used for energy. And if they’re doing DNL, then they’re also not doing beta oxidation. So hepatic cells are using glucose for DNL, and not burning it for ATP, and also not burning fats. So they’re experiencing ATP starvation, and the rest of the body that relies on hepatic cells to provide energy substrates will also experience a degree of ATP starvation. So the hepatocytes engage in gluconeogenesis, because they’re getting the ATP starvation signal. What a confused muddle!
    2) To a commenter above, in living systems, reaction rates are also going to heavily depend on the enzyme(s) involved. Fortunately for life, the rates aren’t only dependent on concentration, otherwise we’d pretty much just be big piles of goo!
    3) It makes sense that insulin resistance would be controlled by substrates that depend on insulin: e.g., glucose. So glucose gets processed, ends up going down the electron transport chain. A few electrons do a reverse move through Complex I, which signals “hey, this mitochondrion has sufficient glucose/energy to process right now”. In aggregate, those signals from all the mitochondria in the cell = signaling “magic” = insulin resistance. That’s fine if the enzymatic machinery to metabolize fats and ketone bodies is in place (thus, physiologically appropriate insulin resistance). Sadly, for most of us, it is not, because when and what we eat keeps the main hormone controlling substrate ingress high: i.e., insulin (or pathological IR).
    4) Practically speaking, none of this matters insofar as treating the pathological IR goes. Cells are over-crowded; they need to become less crowded. How can that happen? Time spent using up the glucose crowding the cells, thus lowering glucose. Maybe the fastest way to do this is to fast, which of course is what this blog espouses.
    5) But it will still take time to ramp up production of the enzymes to handle beta oxidation. Fasting probably makes this happen a little quicker than eating say LCHF for most people, just because eating anything stimulates the release of at least a small amount of insulin. But the assembly of these enzymes will take how long it takes, under even ideal (read: low insulin) conditions. Hence, that adjustment period where I’m getting used to my fasting regimen and feel like I have no energy. (Also implicit further fasting support: if not doing an all out fast, eat as infrequently as possible. Nibbling/Snacking/”Eating” multiple times during the day will just keep the insulin spikes coming. So even if they’re lower, due to stopping eating processed crap, their frequency still means raised insulin levels throughout the day.)
    6) So now to come full circle, go back 100 years to treating diabetes (and epilepsy, and maybe other stuff?) by fasting patients. Reduce the glucose-overcrowding, enable better fat burning, et voila! Cured (or hopefully at least managed, depending on what the patient does after the fast)! And so here we are on your blog today. 🙂

    • Zig, thanks in particular for comment #1. I was specifically trying to work out the “internal starvation” aspect in my own mind. This is quite helpfull.

  13. I’m afraid in this case you are completely off.
    The reason why there seems to be a controversy in “selective hepatic insulin resistance” is because of focusing on only the liver. Metabolism is coordinated by an adipose-liver axis with regular modulation by the immune system. If something appears controversial in the liver, then the most likely explanation is that something else is happening in the adipose tissue. The whole “glucose needs insulin to enter cells” is a medical fallacy which has nothing to do with basic science. Yes, in hyperglycemic and hyperinsulinemic conditions (i.e. in disease) something like that happens, but not in normal physiology. Insulin’s single most important role in the body is to suppress lipolysis. This is that can switch between glucose and fat metabolism. How? Lipolysis delivers the major regulator at the rate limiting step of gluconeogenesis in the liver, namely to pyruvate-carboxylase. Whenever acetyl-CoA is low, GNG slows down. On the contrary, high Ac-CoA drives GNG, see diabetic hyperglycemia.
    It’s been quite clear from early last year (http://dx.doi.org/10.1016/j.cell.2015.01.012), but it was recently confirmed (http://dx.doi.org/10.1016/j.cmet.2016.04.022).
    If anybody wants to properly understand insulin resistance and the development of modern metabolic diseases rooted in it, start at the adipocyte. See also Scherer’s 2015 Baning lecture, recently published in Diabetes.

    • 12Kevin

      Regardless of the inherent limits of explicating complex interdependent functions, would you agree that nutrition systems (like periodic fasting) which lower insulin levels remain sound approaches to modern metabolic diseases? And/or, that tracking insulin levels is a good proxy for predicting current and future metabolic health?

      • @12Kevin
        Yes, maintaining adipose insulin sensitivity for feeding and their physiologic insulin resistance for fasting is crucial. Both a low insulin load diet and fasting help. No major disagreement in that part.

    • “Insulin’s single most important role in the body is to suppress lipolysis”
      This may be true, but because insulin first mission is to get rid ASAP of the excess of glucose in the bloodstream…because excess glucose is toxic. (so better the cells quit using fatty acids and start burning sugar NOW!!!)
      “Whenever acetyl-CoA is low, GNG slows down.”
      When GNG is activated (glucagon/insulin ratio), oxalacetate is diverted to glucose production. That results in an accumulation of Acetyl-CoA which drives ketone bodies synthesis. So when Acetyl-CoA is high may be because the Krebs cycle is lacking oxalacetate. So, “Whenever acetyl-CoA is low…”:Krebs cycle is running on sugar so GNG is not necessary.

      • @Martin
        It is the role of a healthy adipose tissue to remove excess glucose from the bloodstream. It is done without much intervention by insulin. As we all (should) know by now, diabetes is not really about glucose take up, but rather disregulated hepatic glucose production (HGP). Above linked studies played a major role in our understanding how HGP goes wrong, and it happens in adipose tissue. Adipose insulin resistance when feeding is really bad.
        GNG is running continuously, there is no such thing as “not necessary”. The rate varies by a great extent, and Ac-CoA availability (determined mainly by beta oxidation) limits or pushes it. So yes, oxaloacetate availability determines the ratio between gluconeogenesis and ketogenesis. That’s where glucogenic amino acids come into the picture, i.e. how protein availability modifies GNG:KG ratio. Higher protein in the diet results in lower ketone levels, but protein is not enough to completely blunt ketogenesis. Bodybuilders in a ketogenic diet rarely measure higher tan 0.5-0.7 mmol ketones, but moderate protein consumers can go above 1 without longer fasts.

  14. Thanks Doc! This article offers a new paradigm which potentially clarifies so much for me. Since my diagnosis of T2D in 2008, I’ve been an avid researcher on the subject. My own research took me naturally into a Paleo type diet of my own devising. About a year later, I discovered Robb Wolf and numerous others in the ancestral/LCHF health movement, which really helped me to dial things in and leverage that knowledge in my own research and self-experimentation. About two weeks ago, I discovered your interview on Robb Wolf’s pod cast. I’ve been ravenously consuming all of your articles and videos ever since. I rarely comment on blogs but, after reading this one, I just had to say Thank you!

  15. I hope Dr. Fung does an indepth study on statins since I know first hand that my husband’s glucose bloodwork was fine but one year on statin (lipitor) his glucose was 116-prediabetic. I’m tired of a cardiologist just wanting to treat one problem but has no regard that his prescription is creating another life threatening illness. Hmmm, lower cholesterol or give a patient diabetes??? Watch “Sunday Housecalls” on Fox cable and see Dr. Samadi’s response!! I agree with his advice. I hope Dr. Fung addresses this issue head-on. Specifically about statins and diabetes. Thank you !

    • sten bjorsell

      You do not need indepth studies ! Just google: pfizer sued lipitor causing diabetes 2, and you find that 1000’s of people are in the same seat as your HB. Please also show prints of the articles to your cardiology geniuses, as many of them rarely get new information from others than statin/meds salesmen. The problem for Pfizer is that they knew this long before they later had to warn people about it. The serious crime is in knowing to cause harm and pushing on with sales saying nothing.

  16. I love this analogy! It makes much more sense than the lock and key idea. I’ve been on the metro in Moscow, Russia. There were no pushers that I recall, but one day, during rush hour, we were packed in so tight that I was lifted off the floor part of the time. To think I’ve done this to my cells…it’s no wonder sometimes I hurt for no apparent reason!

  17. Sonja M Discher

    I just CAN’T agree with this idea that the cell is overloaded with glucose! I have forever noted that for years I have NO energy! by this new idea, I SHOULD have excess energy! But let me tell you , THAT is NEVER true. before I had the diagnosis I always complained that it seemed like I just could not get any energy into my muscles, and I was a dancer, cheerleader and weighed 102# !! . IF the cells had so much glucose, you’d think a diabetic would be CRAZY with ENERGY. THAT is NEVER TRUE!! anyother DiABETICS agree about having NO ENERGY???!!

    • I have no energy either! Been that way for years. Back when I was 30, my 80-year old grandma had more energy than I had! … However when I fast my energy goes up. I am not obese but I am insulin resistant.

    • Could it be related to excess glucose induced inflammation? I agree that on high carb (more energy) I felt lousy. There are lots of articles out there that explain how bad oils and sugar cause inflammation. Just thinking “out loud”…

      • I don’t know how to put a link in right here but paleo leap has a great article about inflammation posted today…

    • If part of your cell making energy involved moving material from one side of the cell to the other, how well would it be able to move that material if it was packed in tight? If you made energy by walking from one end of the subway car to the other, and the amount of energy you created was determined by how fast you moved, how fast would you be able to move if the subway car was so full they needed “pushers” to get you into the car?

    • Burgundy

      Sonja; I’ve been pondering this too. I’m beginning to think the problem gumming up the works is oxygen deprivation. Lack of cellular oxygen is possibly slowing down the metabolism mechanism and causing the backup of glucose into the bloodstream.

      T2Ds breath more than normal and also have more acidic urine, possibly due to low cellular oxygen levels? Hyperventilating (breathing too much) causes less oxygen to enter the cell (due to the Bohr effect), maybe we diabetics also have an oxygen resistance problem where the cell membrane is inefficient at allowing the transport of oxygen into the cell?

      Maybe fasting also reverses the hyperventilating too, does anyone know of this happening? I’ve also seen something about polyunsaturated fatty-acids possibly reducing oxygen transport in the blood (and increasing hypertension),possibly also causing hyperventilating? I’d love to hear anyone else’s ideas along these lines.

      • Anecdotally: my wife has a pulse oximeter. On a normal diet I am around 93-94 on oxygen saturation. While low carb of fasting I am at 98%. I also notice myself breathing slower and more shallow.

  18. Makes sense, thanks. However one question – if the cell is not in a state of ‘internal starvation’ why do those with IR get hungry? Thanks in advance!

    • Martin (above comment) says it’s like having molasses in our cells. That could make sense.

  19. It’s a sad state how medicine is more religious fanaticism than following the science. My cousin is T2 diabetic and her fasting glucose numbers were off the charts. I read almost every article here by that time and so I told her to switch her diet to LCHF and to intermittently fast. She has and her glucose numbers started to plummet from the first day. She’s also losing weight which I care little about but she is ecstatic about. She is so excited because she’s stopped taking her Metformin and yet her numbers are still low. She saw the doctor after a month and he was very proud because he assumed she was following his advice of eating mostly grains every 2-3 hours. When he found out she is eating once to twice a day and eating LCHF he berated her like a child. She asked him why should she follow his advice since by doing the exact opposite her numbers are getting better and as he put it “better than I’ve ever seen.” So clearly doing the opposite works because as he also said “no one who follows my plan has ever shown results this good so quickly.” Yet once he discovered it was not his advice she was following THAT is when he tells her to stop doing what’s working and start doing what he knows does not work. That should constitute a criminal act.

    • Wow that is just criminal!
      Hope she stays strong, and finds a new doctor!

      Jim MacK

  20. stephane

    So with that theory, cells would be crowded with glucose and the body would be still asking for more.
    But what in the first place is stuffing the cells with glucose they can’t process ?
    Why T2D patients report feeling lousy with no energy while their cells are full of fuel ?
    What if it were the mitochondrion machinery that is impaired ?
    What if the glucose to ATP conversion rate were poor, leading to ATP starvation which in turn drives fuel demand ?
    At the same time, the cells are not able to process fat because
    1 – They are crowded with glucose
    2 – Insulin signaling is high (fuel demand) preventing lipolysis

    So what is the mechanism by which the glucose processing gets impaired at the level of the mitochondrion ?
    These are my layman musings, feel free to comment and destroy them
    but I wonder if this hypothesis has already been investigated

    And Thanks dr. Fung for this excellent blog.

    • I was thinking along the same lines as you stephane. My own layman theory is flour fortification poisoning. France despite consuming 40% more flour than USA or UK has less obesity, diabetes. The only difference in the flour is it’s not fortified with iron and vitamins. Good luck finding gluten free foods in France as there is very little demand for it.
      Many diets tell us to omit wheat and very often people feel a lot better for doing so.
      The last time fortification was increased coincides with huge increases in obesity and diabetes which was in the early eighties.
      On the free the animal blog there are two lengthy posts regarding iron fortification and vitamin fortification and they make a lot of sense.

      • France also eats a lot more fat. Frois guas and cheese. Also their portions appear comically small to us Americans. Are there a lot of fat-free productd in France?

      • seebrina

        Don’t forget too that here in the US they have added Bromine to flour and bread products which is toxic and clogs the hormone receptors. Which translates to iodine receptors being clogged coupled with no iodine in the diet any longer. Iodine is used by every cell and hormone receptors. They should outlaw this as other countries have done . I think its a multi-layered problem along with insulin resistance.

    • “What if it were the mitochondrion machinery that is impaired ?
      What if the glucose to ATP conversion rate were poor, leading to ATP starvation which in turn drives fuel demand ?”
      I think those are very interesting questions!
      If glucose to ATP conversion were poor, it may be because it was not going all the way in the Krebs cycle (to CO2 and H2O(36 ATP)), but only to pyruvate and lactate(6-8ATP?)as it is when anaerobic work is done…
      That will give mitochondrion less work to do, wich will bring down her machinery capacity…
      Just a thought…

  21. Another EXCELLENT Blog…. I look forward to them like a kid at Christmas and am never disappointed! This is a bit off topic but has anyone had an increase or decrease in kidney stones on a LCHF diet. Just curious.

  22. Dr. Fung,
    I just finished reading your book and allow me to “thank you” for taking your time for spreading wisdom and hope to all of us that are seeking a common sense approach to control or reverse T2D. Also, thanks to the readers, whose shares their personal story and make positive contributions to this forum. Briefly, my personal account. I am 57 and 5 feet, 9 inches tall. Last November, I ended in the local hospital due to an acute case of blurred vision, serious dehydration, and few others ailments. The lab results confirmed my suspicion. Glucose: 433, A1C:11, Triglyceride: 605, GGT: 246. The diagnosed, T2D and fatty liver. At that time, my weight was 211 lbs. /96 Kg. The treatment consisted of insulin, metformin/2000 mg, Januvia 100 mg, and statin (dislike taking drugs). The doctor and the nutritionist lectured and warned me about the progressive trend of T2D. Basically, they handed me a death sentence.

    In my quest to find alternatives solutions to deal with T2D, I conducted extensive research and became across Dr. Fung videos and lectures. I win the “lottery”. Since February, I have followed the intermittent fasting and (LC/HF) path and the outcome has been very positive. Fasting twice a week for 24 to 36 hours had transformed my body and mind 360 degrees. Self-experiment, I reduced the metformin dose from 2000 mg to 1000 mg and glucose level still hovering between 70’s to 90’s mg/dl. Now, I have stopped it altogether to see how T2D evolves in the incoming weeks and months. But, I still taking supplements like magnesium, krill oil, and turmeric.

    As today, A1C: 5.5 mg/dl, Glucose average in the last 3 months: 85 mg/dl (dropped statin, two months ago, due to the side effects), weight: 177 lbs./80 kg. (My old Army weight), Cycling 40-50 miles a week, running 2 miles twice a week, waistline reduce from 43 to 38 inches, BF reduce from 34% to 27%.

    What have I gained? “No more difficulties in lacing my shoes,” no more heartburn, high blood pressure is well controlled, no more lack of energy and aching body. Without any doubts, fasting has enriched my personal outlook to new levels and just the satisfaction to see my 40 size pants, replaced by size 34 in four months can only be described as pure enjoyment. I am not ready to claim victory yet. My personal commitment to my well-being must continue until the T2D is entirely reversed.


    • Congratulations Jochy, that’s a great story, you’ve dropped 34 lbs in 8 months if I’m following your timeline correctly, a steady rate of approximately ~1 lbs per week, and you’ve gone from size 40 to size 34 pants.

      Have you enjoyed changing your entire wardrobe? Somebody should work out, for fun, how the amount of food money saved by fasting compares to the amount of money spent on new pairs of pants 🙂

      • Good one David! LOL And congrats Jochy! My husband and I have done the same thing…. slow and steady wins the race.

    • Amazing JochyD. Good for you!

  23. I’ll right away snatch your rss as I can not to find your
    email subscription link or e-newsletter service.
    Do you’ve any? Please let me know so that I may subscribe.

  24. My understanding of this paradox is that you can’t think of the liver in isolation. Most cells, including fat cells and muscle cells (but NOT liver cells) require insulin to allow glucose to come inside the cell from the blood. When they become insulin resistant, they don’t take in their share of glucose, and blood glucose remains high, while the insulin resistant cells have low internal level of glucose. The “internal starvation”, which makes you hungry, in occurring in your non-liver cells. The high blood glucose flows into liver cells, which don’t require insulin for influx of glucose. The effect is that a disproportionate amount of glucose gets shunted into the liver while other cells are glucose deficient. This glucose overload in the liver is what stimulates fatty acid production.

  25. Burgundy

    So, a bit of overly simplified conjecture:

    a) insulin resistance is a red herring and doesn’t really exist;
    b) fatty acid metabolic pathway is stuck open at the cellular level, blocking conversion of glucose into ATP and using fatty acid synthesis instead;
    c) glucose backs-up into the bloodstream and causes insulin to go nuts and shoves it all into adipose tissue everywhere;
    d) fatty acid synthesis uses more oxygen without creating carbon dioxide creating oxygen starvation via the Bohr Effect and causing hyperventilation;
    e) fatty acid synthesis acidifies the body via lactic acid production and the low PH causes expulsion of acid via the urine in an attempt to maintain homeostasis;
    f) LCHF diet works because it uses the permanently open fatty acid metabolic pathway for energy and reduces the amount of glucose in circulation which has nowhere to go.

    So the elevated levels of free fatty acids in the blood, which is the case in diabetics, maybe the primary problem. Remove them, allow glucose to open up the pathway to the Krebs cycle and start oxidizing glucose instead of fat. Am I getting this right? If so, why do diabetics have a problem with free fatty acids?

  26. Barry W. |Justice

    Thank you Dr. Fung, for thinking! Few practitioners go beyond the readily accepted “studies” that have traditionally become the benchmark for our lack of success in the fight against diabetes, cancer and most other health issues. In a brain dead society where early diagnosis and drug treatments are trumpeted as successes you stand out as an example of how our thoughts and beliefs can transform us into sheep or elevate us! Thank you from the bottom of my heart for making the difference for the resistance! You have become the transformer.

  27. Barry W. |Justice

    Should read in the last sentence……….you have become the elevating force!

  28. […] why does this happen? The cells are already over-filled with glucose (see previous post – A New Paradigm, and Insulin Resistance is Good?). Like trying to blow air into an over-inflated balloon, it simply […]

  29. […] why does this happen? The cells are already over-filled with glucose (see previous post – A New Paradigm, and Insulin Resistance is Good?). Like trying to blow air into an over-inflated balloon, it simply […]

  30. “So, if the liver becomes insulin resistant, then the effect of insulin should drop for both of these actions. That is, the liver should continue to make glucose, and stop making fat”

    The two effects work in the opposite direction. The part of the GNG is true, the liver makes more fat because he thinks thats the insulin low but the liver should not stop making fat because low inuslin increase DNL. The liver feels low insulin and makes more fat, thats make sense.

    If the theory of the overflow is true go ahead and measure it. Meanwhile I believe that the problem is in the receptor signal process.

  31. […] need to understand the new paradigm of insulin resistance to understand how insulin resistance, obesity, fatty liver, and fatty pancreas are actually all […]

  32. Ótima matéria, por isso que uma alimentação lowcarb é ideal pra pessoas que estão com esse problema, pois basta retirar o causador do problema

  33. Dr. Fung,

    I wonder if you are familiar with the paper linked below. It challenges the idea that insulin resistance is the primary driver of type 2 diabetes, and makes a case for beta cell dysfunction being the primary problem. Any thoughts?


    • Being a T2D since 2012, I have been under the assumption that my beta cells have diminished in productivity either by death or by dysfunction and, as such, cannot keep up with the demand I place upon my body with the foods I eat. As time progresses I have to inject more insulin unless I keep my food intake in moderation. I found that intermittent fasting has improved my body function and glucose regulation, but only if I maintain this fasting protocol. Any food intake increases my blood glucose. I take insulin and the glucose goes down. My thoughts are that if my body isn’t producing insulin as much as it used to, then I need to take insulin. What am I missing?

  34. Jay remi xax

    So I’m an MD and it took a second to understand this, but the root of the problem is hyperglycemia which is growing from the liver.
    -in order for cells to be overflowing with glucose there must be too much glucose in the cell which correctly tears down the lock and key model–in that instance the cells wouldn’t be full of glucose.
    – so why is there too much glucose in the bloodstream? It’s obviously not because the the glucose can’t get into the cells, because as you put it the cells are full.
    -therefore, it must be that the liver produces glucose when it shouldn’t (i.e. During meals) which supplies a double glucose load to the body making you persistently hyperglycemic.
    -secondly the excess glucose in the cells must alter their ability to process it exacerbating the problem in a self feeding cycle.
    – the fatty infiltration of the liver could then be a result of the liver trying its best to manage hyperglycemia through increased lipogenesis.
    -decompensation would then occur when this system cannot keep up with the demand.
    Can someone point out any holes in this theory?

  35. Matthew C. Wilson

    I don’t see how this new paradigm can support the discussion elsewhere that conceives of insulin resistance as time-dependent.

    If insulin resistance is an “overflow phenomenon,” i.e., “Insulin tries to push the glucose into the cell like the Japanese Subway Pushers, but they simply can’t do it because it’s full,” then how could resistance get worse over time? Once the cells are full, they don’t become even fuller. Instead, they cause overflow.

    Actually, if you think about it carefully, the new (overflow) paradigm more of less does away with the concept of resistance per se, replacing it with fullness and overflow. This has some advantages, because it solves the paradox discussed (gluconeogenesis and De Novo Lipogeneis during insulin “resistance”). However, it may raise some new problems of its own.

    For instance, if muscle and liver glycogen become partially depleted, then the cell wouldn’t be full anymore, and “resistance,” as well as glucose overflow, should be gone. However, this implication runs counter to common experience wherein symptoms of insulin resistance (stubborn fat) seem to persist even after significant depletion of muscle glycogen has occurred.

    Beyond this, as I mentioned above, how could “resistance” increase over time? Once the cells are “full” and the overflow phenomenon begins, the cells evidently don’t become fuller than full, because overflow is occurring.

    In order for “resistance” to increase in the new paradigm, it seems like something else must be added. In order to support the concept of increasing insulin resistance, there needs to be some mechanism that reduces the ability of the cells to upload glucose, even as the cells remain jammed full, causing glucose overflow.

    Short of returning to the lock-and-key model, it seems that you would either need to introduce cellular atrophy (cells getting smaller) or a reduction in the overall number of cells. It’s not clear how excess insulin would cause either or both of these things, but if it did, then the amount of glucose that could be uploaded would decrease over time, even though the cells remained full, causing overflow.

    The idea that cells are lost over time seems plausible. I have read, for example, that most people begin losing around 1 to 2 percent of their muscle mass per year, beginning around age 30. Maybe the same is true for liver cells as well. In any case, the point is, in order to reconcile the new paradigm (cellular fullness causes glucose overflow) with the idea of increasing insulin resistance, it seems that you need some mechanism whereby the overall amount of glucose uptake declines, despite the cells remaining jammed full.

  36. I have to admit that it took a while to grasp this but it does make sense (I have insulin resistance and read a lot about it but I have no prior scientific knowledge).

    However, it does bring up some questions especially regarding diet sodas and all artificial sweeteners and their impacts. I read that when you drink diet soda for instance, your brain thinks it’s real sugar and sends a message to the body to produce insulin…. What happens with that insulin according to this paradigm? Does it keep pushing all the real glucose it finds into the cell? Does it induce more fat production?…

    I’m guessing my question would be: what is the impact of diet sodas and artificial sweeteners on insulin resistance according to this new paradigm?

  37. […] esittää myös mielenkiintoisen uuden teorian insuliiniresistenssistä: hänen mukaansa myös T2-diabeetikon insuliinireseptorit toimivat normaalisti eivätkä ole […]

Leave a Reply