The Peter Attia Drive - #59 - Jason Fung, M.D.: Fasting as a potent antidote to obesity, insulin resistance, type 2 diabetes, and the many symptoms of metabolic illness

Episode Date: June 24, 2019

In this episode, Jason Fung, nephrologist and best-selling author, shares his experiences utilizing an individualized approach to fasting to successfully treat thousands of overweight, metabolically ill, and diabetic patients, and why being a doctor who specializes in kidney disease gives him a unique insight into early indications of metabolic disease. We also have a great discussion on insulin resistance where Jason makes the case that we should actually think of hyperinsulinemia as the underlying problem. We also discuss the difference between time-restricted feeding, intermittent fasting, and dietary restriction (e.g., low-carb) and how they can be used to attack the root cause of T2D, metabolic syndrome, and obesity. We also have a fascinating discussion about the limitations of evidence-based medicine which leads to a conversation where we compare and contrast the scientific disciplines of medicine and biology to theoretical physics.    We discuss: Comparing scientific disciplines: Medicine and biology versus physics [7:25]; The limitations of evidence-based medicine [12:30]; Early signs of metabolic disease: How specializing kidney disease gives Jason a unique insight into early indications of illness [20:50] Insulin resistance, hyperinsulinemia, and the overflow paradigm [29:30]; Why the common treatments for type 2 diabetes seem to make things worse [42:30]; How hyperinsulinemia (not insulin resistance) drives metabolic syndrome [53:15]; Insulin and weight gain, and using fasting to empty the cells of glucose [59:30]; The two step process of developing type 2 diabetes and how they are both manifestations of hyperinsulinemia [1:03:15]; NAFLD and hyperinsulinemia: A vicious cycle [1:08:30]; Are the features and symptoms of diabetes actually protective? [1:12:15]; Is obesity causing insulin resistance or is it the other way around? [1:17:30]; What role does inflammation play in obesity? [1:21:45]; CVD and cancer: Diseases of too much growth? [1:27:30]; How to reduce proliferation with rapamycin, nutrition, exercise, fasting, and manipulating hormones [1:32:45]; Getting patients to fast: How Jason and Peter utilize fasting in their practice, and how their approach differs [1:40:15]; Comparing bariatric surgery to fasting as a treatment for type 2 diabetes [1:48:00]; Why people think that fasting is bad for you [1:55:15]; Time-restricted feeding and intermittent fasting: Defining terms, and how Jason applies them in his practice [1:58:30]; A fasting case study: A diabetic patient with a non-healing foot ulcer [2:04:00]; Keys to a successful fast [2:12:45]; Muscle loss during fasting, and why Jason isn’t worried  [2:24:45]; Will fasting help a healthy person live longer? [2:31:30]; Does fasting cause gallstones? [2:38:45]; and More. Learn more at www.PeterAttiaMD.com Connect with Peter on Facebook | Twitter | Instagram.

Hey everyone, welcome to the Peter Atia Drive. I'm your host, Peter Atia. The drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful top performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics at pteratia-md.com.

Hey everybody, welcome to this week's episode of The Drive. I'd like to take a couple of minutes to talk about why we don't run ads on this podcast and why instead we've chosen to rely entirely on listener support. If you're listening to this, you probably already know, but the two things I care most about, professionally, are how to live longer and how to live better. I have a complete fascination and obsession with this topic. I practice it professionally, and I've seen firsthand how access to information is basically all people

need to make better decisions and improve the quality of their lives. Curating and sharing this knowledge is not easy, and even before starting the podcast, that became clear to me. The sheer volume of material published in this space is overwhelming. I'm fortunate to have a great team that helps me continue learning and sharing this space is overwhelming. I'm fortunate to have a great team that helps me continue learning and sharing this information with you. To take one example, our show notes are in a league of their own. In fact, we now have a full-time person that is dedicated to producing those, and the feedback has mirrored this. So all of this raises a natural question, how will we continue to fund the work necessary to support this?

As you probably know, the tried and true way to do this is to sell ads, but after a lot of contemplation, that model just doesn't feel right to me for a few reasons. Now, the first and most important of these is trust. I'm not sure how you could trust me if I'm telling you about something when you know I'm being paid by the company that makes it to tell you about it. Another reason selling ads doesn't feel right to me is because I just know myself. I have a really hard time advocating for something that I'm not absolutely nuts for. So if I don't feel that way about something, I don't know how I can talk about it enthusiastically.

So instead of selling ads, I've chosen to do what a handful of others have proved can work over time, and that is to create a subscriber support model for my audience. This keeps my relationship with you, both simple and honest. If you value what I'm doing, you can become a member and support us at whatever level works for you. In exchange, you'll get the benefits above and beyond what's available for free. It's that simple. It's my goal to ensure that no matter what level you choose to support us at, you will

get back more than you give. So, for example, members will receive full access to the exclusive show notes, including other things that we plan to build upon, such as the downloadable transcripts for each episode. These are useful beyond just the podcast, especially given the technical nature of many of our shows. Members also get exclusive access to listen to and participate in the regular Ask Me Anything episodes. That means asking questions directly into the AMA portal and also getting to hear these podcasts when they come out. Lastly, and this is something I'm really excited about, I want my supporters to get the best deals possible on the products that I love. And as I said, we're not taking ad dollars from anyone, but instead what I'd like to do is work with companies

who make the products that I already love and would already talk about for free and have them pass savings on to you. Again the podcast will remain free to all, but my hope is that many of you will find enough value in one, the podcast itself, and two, the additional content exclusive for members to support us at a level that makes sense for you. I want to thank you for taking a moment to listen to this. If you learn from and find value in the content I produce, please consider supporting us directly by signing up for a monthly subscription. I guess this week is Dr. Jason Fung. Jason is a nephrologist in Toronto, Canada. Many of you listening to this podcast probably already

are at least familiar with him just for another reason through social media or other channels. He's quite a vocal critic of the conventional approach to treating type two diabetes. And he also has, in my experience, at least one of the most significant clinical practices that utilizes fasting as a treatment for metabolic disease. Don Jason, relatively informally for quite a while, but I've gotten to know him better in the past year and was really looking forward to doing this interview because I certainly get asked a lot of questions that I think Jason would have great insight into. He's the author of several books, including the OB City Code, the diabetes code, the complete guide to fasting, and the longevity solution.

He's the co-founder of the intensive dietary management program. Jason Graduate from the University of Toronto and completed his residency at UCLA. In this episode, we talk about a lot. We actually kick it off with a discussion. I didn't plan to get into, but I thought it was really interesting, and I hope you do as well about evidence-based medicine. You know, the difference between taking two scientific disciplines, one of medicine and biology, the other of physics and comparing and contrasting some of the differences I sort of make an argument around theoretical versus experimentalists and things like that. And talk a little bit about nephrology. What took Jason into that field and why is being a nephrologist, a doctor who specializes

in kidney disease? Why does that give him a quite unique insight into kind of the early indications of metabolic disease? And then we get into the meat of this thing, which honestly, I think this is one of the most interesting discussions I've ever had on insulin resistance. And you listen to this podcast, you've heard me talk about that a lot. And I think Jason's take on this quite frankly is probably the smartest thing I've heard. Now that doesn't mean that I necessarily agree with everything. And that doesn't mean that there aren't holes in these arguments, but his explanation for why a concept of insulin resistance,

which is very difficult to explain when you try to parse it out into tissue specific effects of insulin. He has a much better explanation for this that clinically makes more sense and ultimately results in a much more logical treatment plan. So, once we go through this discussion of what people call insulin resistance and come away with this idea of hyperinsulinemia, for which, by the way, he has a great example

using a suitcase that I'd never heard before, but I took the liberty of bolting onto it as much as possible. So, by the end of this, you might be sick of hearing about suitcases. And we talk a little bit about Natholde. And then we close the discussion. So if there's sort of a final part of this, it's getting into the clinical stuff, the use of dietary restriction, including ketogenic diets, carbohydrate restriction. But most of what we talk about pertains to fasting.

And I think that that's where a lot of people are going to be kind of interested. Jason has a very different approach to fasting than I do in my practice. And I think that probably stems from the fact that I'm not treating patients who are nearly as sick as Jason. So in that sense, he has to be a little bit more extreme out of the gate. And to listen to some of the clinical wisdom that he brings to this is even for me quite informative. So I hope you enjoy this discussion.

But Jason half as much as I did. There's so many things I want to talk about with you. And I would say that you are among the three people, top three, certainly that on social people are always saying, when are you going to interview Jason? When are you going to interview Jason? And of course, we had planned to do this in December in person. And that's when I had my whole dental calamity that required like tooth extraction after secondary tooth extraction.

I said, so I never made it up. So anyway, I'm glad we could do this and I appreciate everyone's patience with this. But I guess the broader point is I think people are so interested in speaking because of all the work you've done around fasting, insulin resistance, and just overall, I mean, you're a clinician on the front lines. I mean, you know, it's one thing to sort of pontificate on Twitter. It's quite another thing when you actually have to show up

and clinic and see hundreds of patients as you do. Thanks. I mean, I think that's one of the things that I think distinguishes me from some of the other people that are out there is that the stuff's got to work. Otherwise, it just ain't worth it right like you can talk all you want about this and that but if it doesn't change management then it doesn't interest me particularly because that's where I come from. And I think this is where a lot of people get sort of they see these academics and they say okay well they know everything about this well, they might know everything, but if it doesn't work on the front lines,

it's not worth anything. And I think this is an attitude I see, like, in physics, which is, I know you really look up to Richard Feynman as do I, but I actually love the whole story of, you know, Einstein and Neal's Boran, all that, because physics, to me, is sort of like, I love that, because the way they do science is so much better than we do in medicine. That is to say, for in this specific instance, for example, if you have all

these theories, they're great, but if they don't agree with experimental evidence, it ain't worth anything, right? And they say this in physics, but they don't say this in medicine, where it's like, okay, you think that eating lots of carbs is really good for you, right? You have this hypothesis that eating less fat and tons and tons of refined carbs is good for you. And that's a great theory. It all makes sense. And the same thing with calories, or it gets sounds like if you just cut calories, it

makes sense. But if your theory doesn't work, then it's not a good theory. And this is what they say in physics, which they don't say in medicine. And in medicine, it always like boggles my mind how these bad theories go round and round and round because they make sense. But nobody's actually put them to the test, or nobody's point out these things. It's the same with insulin resistance. I think actually, to me, the most important topic

is sort of insulin resistance, because again, that's what I deal with as a nephrologist. I see a lot of type two diabetes. That to me is completely sort of misunderstood and the way we think about insulin resistance is sort of totally wrong. And that's why we have the sort of mess that we have, I think.

Well, we're going to get to that for certain. I definitely like to build on what you've said. Yeah, there's a beautiful demonstration of what you described. It's a video from either Caltech or Cornell, I can't recall. So it was either right before he had left Cornell or after he had arrived at Caltech. We're fine men as at a blackboard. And he is explaining the scientific method in about his elegant way as you can, which is to basically say what you did, which is, this is the scientific method you make a guess.

You design an experiment to test the consequences of that guess. You do the experiment and if the output of that experiment aligns with your guess, the hypothesis turns out to be likely correct or more likely to be correct. And if it doesn't, you go back to the drawing board. And the simplicity with which one of the most brilliant physicists of the 20th century explains that is not lost on anyone who watches it. And I would agree with you completely.

I've gotten into trouble by saying this before, but I guess on your podcast, you can sort of say what you want. But I'm generally suspective people who have very, very strong points of view on things in biology or medicine who no longer interact with patients. It doesn't mean that they're wrong, but I'm generally suspect because of that, because the other thing is, biology is harder than physics.

The reality is, it's just a lot messier. And sometimes people ask me, you know, do you think you'll always see patients? And the answer is, yes, I think so, and I hope so, because they are kind of a humbling tool. Every time I think I've really got it figured out, I'll always meet a patient who proves me wrong, and they're obviously right and I'm wrong. And I think the other part about physics, which I love, is that the way they think about it is that there's, you know, a theory, like Newton has a theory, for example. And it explains a lot, and it's a great theory in everything.

But then there's these anomalies. And the anomalies are what drives sort of science forward, because you have to come up with a better theory that explains the anomalies. And if you come up with a better theory, they make these wild predictions, and if these wild predictions are true, you know this new theory can sort of supplant it. So the way Niels Bohr and the Quanta supplanted

sort of Einstein, even though he was brilliant. So the point is that that doesn't happen in medicine. In medicine, we have this super-laborious process of evidence-based medicine. We're instead of saying, hey, here's a theory that makes more sense, because it explains everything. What they do is they say every single point they go, where's the evidence? Where's the evidence? Where's the evidence? That's why nothing ever moves forward. I do the same thing in nephrology that I did 20 years ago when I was doing my training.

It's like, what was the last advance we had? It's like so from so long at work. Most of the advances in medicine, for example, come from aspirin, it counts for like 50% of the progress we've made. It's sort of ridiculous, whereas physics sort of moves at light speed because they don't demand this sort of evidence space. And I always say that evidence-based medicine is good if you know how to apply it, right? Because the whole point of evidence-based medicine is that it's not how to apply it, right? Because the whole point of

evidence-based medicine is that it's not a search for truth, it's a search for consensus, and it may or may not be true, but if you have a crazy theory and then you send it out to five people and they say, well it's crazy, it gets killed. So if you have like a theory, hey, the earth goes around the sun, not the sun goes around the earth, you send it to a consensus of peers, they say no, no, no, no, no. Clearly, the, you know, the sun revolves around the earth, that would never have made it through. So the evidence-based medicine is not everything.

Like, you have to understand where to apply it. And this is where I think we've gotten into so much trouble, is that every sort of advance moves glacial because we sort of demand that things have to have evidence. So something like fasting, for example, which I always get into trouble a lot too, right? Again, to tons of trouble for calories, everybody, it taxed me for all kinds of stuff. But fasting five years ago was the dumbest thing you could do, right? And I'm like, why?

Like it doesn't make any sense that it should be so bad, right? So I thought about it and I went through it and then I just brought it immediately to patients, right? Just treated hundreds and hundreds and hundreds of patients and the results, like amazing. And of course, if you don't eat, you're gonna lose weight. If you don't eat your diabetes, it's gonna get better, right? So it worked and that was the point. Like you gotta get to that point, it's going to get better, right? So it worked. And that was the point.

Like you got to get to that point where it's like, and then everybody says to me, Oh, where's the evidence? I'm like, why do I need evidence? Like people are getting better, right? I'm not a researcher, right? You can come up with the research, but just try it on people. Look at it. But all these people are saying, Oh, there's no evidence.

There's no evidence clearly. It's bad. And that's where everything just sort of bogs down. You get all these people who sort of demand that every sort of little step has to be based on consensus. The consensus moves so slowly that you can't move. You can't move like Einstein move. You can't make those sort of intuitive leaps forward. That always bothers me a lot. Well, it's sort of a problem. There is a distinction, right?

In physics, I think, broadly speaking, and again, physicists will sort of bristle at the simplicity with which I'm saying this. But you can generally divide the field into the experimentalists and the theorists. And that's what I think allows the step function changes in understanding. So Einstein's advances were theoretical. So the experimental evidence to support these things came after, but yes, many times the big steps forward come on the basis of theoretical propositions. And we don't really have that in medicine and biology.

We don't have experimentalists and theorists. I've thought a lot about this actually, and I didn't intend to go down that rabbit hole, but there's a whole separate podcast, by the way, on this topic, of how could you change biological research to take some of the advantages that we see in the physical sciences where you can create a symbiosis between the theorists and the experimentalists? The last thing I'll say on this point, by the way, that I agree with you is the real challenge of exclusively relying on evidence-based medicine is that framework is very good for certain problems.

It's actually quite good for problems that are rather acute for which the interventions to address them are rather simple and for which you will get an answer quickly. So in many ways, the pillar of evidence-based medicine is infectious disease. If you think about how much we have learned through evidence-based medicine with respect to the treatment of HIV and, frankly, most infections, it's remarkable. I mean, we've really got that dialed in.

But again, if you take a step back and look at those criteria, well, infections are quite acute, typically. Very easy and binary to measure progression. The interventions are simple. Take this medication. Don't take this medication. That's much more complicated than, well, I want you to exercise a certain way for this period of time where I want you to eat a certain diet for a certain period of time.

And then the resolution can be to whatever metric it is, whether it be T cell count or amelioration of the clinical infection. That occurs really quickly. So you're right. I think evidence informed medicine is probably a better way to think about it. But yeah, someone like you is, you know, you're really on the forefront of using your best ethical judgment to say, look, I'm going to bring something to a patient population. The other thing I want to add, by the way, well, I'm on my soapbox that you helped me stand up onto,

is people are very quick to say, well, you don't have the evidence to support fasting for a patient with type two diabetes. And you can say, okay, that's true. So there is a risk that if this patient with type two diabetes goes on a fasting protocol, something bad could happen. But what people in medicine I find are very, I wouldn't even say quick to forget, I don't even think it registers, is what's the risk of not doing something? The risk of doing something is usually more in our forefront. It's that risk of not doing something that people often forget.

And if the risk of not doing something is stay the course slowly, slowly increase the amount of insulin this patient requires, slowly, slowly watch the micro and macroscopic vascular disease progress. Well, that risks actually, but that's a pretty bad risk. Well, that's absolutely true. And it's like, this is the point that I always made to patients is like, if you keep on doing what it is that most doctors do, including myself, right? I used to just give people tons and tons of insulin. I know what is going to happen and everybody acknowledges that if you'll just get worse over time and it was just sort of accepted and it's like, there's the risk of not doing anything, right? But if you suddenly change, you know, bring an invention like fasting or low carbohydrate diets, ketogenic diets, or whatever, there's a risk of doing it. Sure. We don't

know what the risks are, but we know the risk of not doing something. And that's the virtual certainty that you're going to in 10 years go on dialysis or something like that, right? And that's not an insignificant risk. It's actually a huge risk compared to doing fasting, which has been done for thousands of years. And I say, like, look, like the problem with evidence based medicine and consensus and stuff, look at what happened with the low carb guidelines. So as you know, a couple of days ago, the American Diabetes Association came out with sort of new guidelines and they said, hey, low carbohydrates pretty reasonable. It has the most evidence behind it.

It's like five years ago, they're persecuting dietitians for giving low carb advice. It's like, you know, the human body hasn't changed in the five years that it took for you to realize that, right? And that's where you're doing patients a real disservice by having the sort of expert opinions, guidelines, right, where people can't decide for themselves, like as a dietician, you can't decide for yourself that you want to be low-car because five years ago, they would have run you out and persecuted you, right, taken away your license. And today, like as of sort of two days ago, you're actually falling completely within American Diabetes

Association guidelines, right? So it's like, this is a big problem. The flip side, I guess that's progress, and we'll take it, right? I've said this before, it's sort of one of my little tongue and cheek comments, but you know, all facts have a half-life, and some of those half-lives can be quite short. But it is interesting to see this because it's been about 10 years that I've been paying attention to this, and these things typically do occur on five-year cycles, both through the ADA, the AHA, and then in the United

States, obviously the USDA. Also, I guess, in fact, gosh, it's hard to believe we're coming up to 2020. This time next year, we'll be dealing with a new set of dietary guidelines, which I don't want to think about. So, let's change gears for a moment. You're a nephrologist. So, for people listening, that means you specialized after doing your training in internal medicine, you then subspecialized to double down on one particular organ, a beautiful organ called the kidney, which gives us a little bit of a sense of,

like, what is it about the kidney that is so special? Because it is a pretty special organ. You know, in internal medicine, everybody sort of divides themselves into types, right? So in medical school, it's interesting because you have the jocks who go into orthopedics, right? And then you have the really sort of touchy-feely people and they go into the found medicine and pediatrics. And internal medicine generally attracts a lot of people who sort of like to think about things. And then within internal medicine, you have the sort of subdivision into the different types.

And generally, at least where I was going to school at the University of Toronto, the nephrologists were always the ones who like to think about things because that's all we could do. And we can do a lot about it, like you stick people on the alias and so on, but they like to think think about problems like puzzles, like electrolyte problems and stuff. So you have this low sodiums and low potassiums and what's happening in the kidneys because the kidneys do a lot in terms of homeostasis.

They keep track of you know they keep the sodium in check and you keep the proper amount of water and salt and potassium and calcium in the body. So it's fairly complex, but it's a specialty where people like to think as opposed to like GI, which was towards these sort of action oriented people who like to scope and, you know, snare things out and stuff. So that was really what attracted me to nephrology really was that that's sort of my my personality is I like to think about stuff I like to work out puzzles. I'm addicted to Sudoku. It's just something I love to do and it's just the way I am So that's sort of why I chose nephrology and I wound up doing it that at UCLA

I do enjoy it and when I say there's not a lot we can do what I mean is that up to a certain point kidney disease not a lot we can do. What I mean is that up to a certain point kidney disease, you can treat them, but there's really like two treatments, right? There's prednisone, then dialysis. And the last time we had a drug that actually slowed down progression of kidney disease was like the ACE inhibitors in the 80s, right? It's been a long time since things changed. And just now we have the SGLT2s for diabetic kidney disease. Before that, it's like nothing. So there wasn't a lot to do, but there's a lot to think about. So that's sort of what I liked about it. And the kidney... I mean, every organ is unique in its own way, but one of the things that

I recall being sort of blown away by in medical school was how smart the kidney was. You don't think of it as a particularly intelligent organ, you think of it as well. It's just a filter. But there was a very clever design and evolution, which said, rather than the kidney learning what is bad and figuring out a way to always get rid of things that are bad, it was the opposite. It was learn what is good. And when you throw everything out during the first pass of filtration, just learn to pull back the good

because the probability that the good things are gonna change is low. The probability that you'll see new bad things is high. And so I remember the nephrologist sort of standing there saying, look, it would be tempting to think that the kidney would operate like it's going into your sock drawer to pull out just the right sock but it doesn't it pulls out all of the socks and puts back the right ones and

That always sort of stuck with me one is a pretty interesting Statement of just how important it is to have that system working and the second thing is how small the organ is and yet What a high fraction of our circulating blood volume passes through it. And as you build on that, which gets to some of the stuff we're going to talk about today, why the kidney is such an early warning indicator of disease either through high blood pressure or high glucose. I mean, is it safe to say that somewhat argued that the eyes are generally the first place you can see evidence of that disease of either high blood pressure, high glucose, but the kidneys would probably come in pretty close as well, wouldn't they? Oh, yeah, absolutely. So the thing about the kidney is that they get like 20% of the entire circulation of the body.ulus, which is the sort of functional unit of the kidney is huge. So basically they take everything out and then sort of put it back in.

So that's why they can fine tune it. So well, but as a huge amount of fluid that goes through the kidney sort of all the time, even though a trickle comes out as urine, like it's filtering like 10 time more than that. So you might have a liter of urine a day, but you're filtering way more than that every single minute, truthfully. So it's an incredible system. And the reason that the eyes and the kidneys are such early warning indicators is that the eyes is the best

because you can actually directly visualize. It's the only place you can directly visualize the blood vessel, but the glomerulus, which is, you know, you have about a, but the glomerulus, which is, you know you have about a million of these glomeruli in the body, but they're basically a big bag of blood vessels. So if you're gonna have diseases of the blood vessel, which turns out to be where these metabolic diseases impact each other. So the heart disease and kidney disease, that comes later on. But there's so many blood vessels in the kidney that it gives you this sort of early warning. So the first thing you generally see in terms of diabetes or high blood pressure,

you start to see this protein that appears in the urine. So you can measure it, something called the albumin to creatinine ratio, and you can actually see it. So when you start to get increased urinary album in excretion, what you know is that there is damage to the vascular system just because the vascular tree is like so, so big there. And you can directly measure it. So if you were to go to your liver, for example,

there's nothing you can measure, right? So it's got a big vascular. So the lungs have a big vascular system, but you can't measure anything. Whereas the urine, you can actually directly measure it and the eyes you can directly see it. So that's why they come out so early. So increased urine-obligation actually a very, very strong correlation to heart disease, not because having a bit of urine is so bad, but it tells you that there's something bad going on in the blood vessels of the kidney, which tells you that something

bad is going on in the blood vessels of the body. So that's why looking directly into the eyes is useful and measuring the urine is very useful. Yeah, and because my skills for looking into patients' eyes are not good enough that I can reliably do that, I have in the past three years really started to pay much closer attention to cystatincy, creatinine, along with microalbumin, for exactly this reason, because it's sort of occurred to me in a momentary insight that if my interest is in longevity,

which means trying to figure out a way to get people to outlive what their expected time course is, well, one of the most important organs that gets neglected is the kidney. And if you are in your 40s, but you already have a glomerular filtration rate at 80% of what would be predicted, you have to fast forward a little bit and say, well, what's that going to look like when you're 80? The net implication to me has been

a much greater focus on blood pressure, even sort of stage one. So slightly elevated blood pressure that I think many physicians until recently probably just weren't thinking of as a significant enough problem. But once you do start looking at that micro-obumen and that cyst at and see, as a non-neforologist we get a little bit of a window of insight into your world. And there are a lot of people walking around. I mean, a staggering amount of people walking around who on the surface just based on their creatinine look pretty normal, but a slightly deeper look says, no, actually they're not normal. They are compromised. And it won't be clinically relevant

for 30 or 40 years, but that's going to be relevant. The thing is that there are no symptoms. So I see people all the time with diseases like I. Jane of Fridays, which is the most common sort of primary kidney disease in the world. And they will not know it and they will have lost sort of like 95% of their kidney function by the time I see them, just because they never knew they had a problem because they never checked it. It's very silent in that way.

You just don't know you have a problem unless you start looking for these things and that's why it's important to sort of keep an eye on the urine. It's so easy too, right? It's not invasive. Anybody can do it. Well, let's talk about this thing called insulin resistance because there's two broad, broad topics I want to explore with you today. And I can see no better way to approach them than in this order. Let's start with the problem statement and then let's start to talk about the treatment. So I will confess at the outset, Jason, that as it's been nine or 10 years that I've thought about this problem, I still have a hard time explaining to somebody.

Certainly if I only have the duration of an elevator ride, what insulin resistance is, because I get tempted to get into well, it means this thing in this type of tissue, but this thing in this type of tissue in blah blah. So let's not hold you to the standard if you've only got an elevator ride to explain it. But how would you explain it both to maybe a layperson, but then even at the level of nuance that we could sort of have a rigorous discussion about it. This is really what I think is the sort of most important problem in medicine, which is the metabolic syndrome and insulin resistance. The whole way that we sort of think about it, I think, is completely wrong.

I'll kind of step back and say, let's start with what we think is insulin resistance and taking this physics approach, what's wrong with it, what parts of it don't fit the sort of experimental evidence, if you will. So, when we talk about insulin resistance, and sort of, I'll just step back a bit and say, okay, what do we think about insulin resistance the way I was taught about insulin resistance, which I'll tell you, I think, is completely wrong. And probably you were taught the same thing, right?

So the way we think about insulin resistance is we think about it only in terms of the glucose, right? So insulin is a hormone, and when insulin goes up, it allows glucose from the blood to go into the cell. So we know that we know that glucose, for receptors go, it goes into the cell membrane, glucose goes in, and now the cell can use it. So the reason we call it insulin resistance

is because we know that there are normal levels of insulin, as opposed to type one, where there are low levels of insulin. There's normal levels of insulin, but the glucose is not going into the cell for some reason. And when you measure the blood glucose, for example, it's very high. And there's insulin around. So if insulin is around, why can't the glucose go into the cell? And this is why we say, hey, if there's insulin, then the cell must be resistant to the insulin.

This is insulin resistance. This is the sort of lock and key paradigm that we talk about. So insulin is a hormone that acts on the insulin receptor, which is on the cell surface. And the insulin receptor is like a gate. So there's a door, there's a lock. Insulin is like the key. So it opens the door, and therefore the glucose can go from the blood into the cell. The cell has energy to use. So we can measure insulin. We can also look at insulin receptors. You can sequence it. And you can tell there's actually nothing wrong with them.

So insulin receptors are completely normal. Insulin is completely normal. So what you say is that, well, there must be something that's gumming up the system. So like a piece of gum that's stuck in that lock, it's gumming up the things. You have a normal key. You have a normal lock.

But when you put the key in the lock, it doesn't really work. And then, therefore, the glucose can't get up the things. You have a normal key. You have a normal lock, but when you put the key in the lock It doesn't really work and then therefore the glucose can't get into the cell and the cell is now facing a Internal starvation and the internal starvation is why we give insulin to move the glucose into the cell and that's our current thinking or at least what I was taught, and what most people still think about insulin resistance, but it's almost completely incorrect. And there's no possible way can be correct because there's a central paradox of insulin resistance, which is that insulin has actually many, many different functions, only one of which is letting glucose into the cell. So for example, we know in the

liver that insulin is responsible for denovolipogenesis. That is if you have a lot of carbohydrates glucose, it will build it into glycogen. And that is working fine. If there's too much glucose after the glycogen is full, it's going to turn it into triglycerides or fat, and that is working fine. So, denovolipogenesis is working fine. Let's take a state of type 2 diabetes, which is we acknowledge as a high insulin resistance. How can it be that you have a liver cell which can't let in the glucose, so it's resistant to the insulin, yet the other effect of insulin,

which is denovolyphogenesis, is not only working fine, it's actually going over time, right? You can measure denovolyphogenesis and type two diabetes. It's super, super high. And what about the mitogenic effects of insulin? So insulin is a growth factor. You can measure it, for example, with large for gestational age babies.

And you say that a woman is insulin resistance, yet insulin is actually doing what it's supposed to do. It's actually stimulating a lot of growth. So there again, insulin is super sensitive or say testosterone. We know insulin has effect on testosterone and PCOS. And there is working, again, not just normally, like super high. So in the liver, you have this sort of central paradox where you say in the same tissue

to the same levels of insulin, you have both resistance and super sensitivity. Like, that's not really possible. It's the same cell, same thing, but they people call it selective insulin resistance. So that's sort of the central paradox of insulin resistance, and it doesn't really make any sense that this can be the way. And Jay's and I would just add an even simpler observation to that, which I've always struggled with, which is a very common phenotype of insulin resistance is adiposity, obesity, meaning obesity, which of course means the accumulation of fat in a fat cell. So a fat cell is getting bigger. Well, for a fat

cell to get larger, it needs to incorporate triglyceride, to incorporate triglyceride requires insulin, and to keep insulin in the fat cell requires insulin to prevent lipolysis. And so on the one hand you say, well, this patient is insulin resistant, we'll talk about which cells, you know, maybe the muscle is insulin resistant, but at the very least looking at the fat cell, it appears to be quite well insensitive to insulin, right?

Exactly. And it's the same thing with denovolipogenesis. And that this is why I say, we know that denovolipogenesis in this state of insulin resistance is taking sort of glucose and turning it to fat. And then the liver sort of exports this fat as VLDL and triglycerides. Well, the thing is that if you have internal starvation

of this liver cell, that is the glucose cannot get into this liver cell, how on earth is this liver going to package glucose and turn it into fat? Because we know that is happening, but where is this glucose? Like, it's taking glucose making it into fat, but you're telling me with this paradigm that no glucose is getting in, you're facing internal starvation. I mean, it's like making a brick wall with no bricks. It's just impossible. But yet, this is the paradigm that we face, this internal starvation paradigm.

And you look at the person, you look at a type one untreated type one diabetic, where there actually is no insulin. And they're like a stick. So if you have ever seen some pictures, these type one diabetics could not gain fat no matter how much they ate, then they, you know, they peed out all their glucose, then they died. That's not what it looks like in type two diabetes in insulin resistance because type two diabetes is a disease of too much insulin resistance. So there's no way that is possibly true. So what you have to come up with is a different sort of a new paradigm of thinking about what insulin resistance actually is. And this is one of the things that you know why I say physics always appeals to me because that's where you can come up with a new theory which explains all these sort of paradoxes much better. And that is that it's not a sort of underfill problem.

It's an overflow problem because there's two possible ways. So we say they're insulin resistant because the glucose does not go into the cell. That's the whole reason we say it's insulin resistance, locking key paradigm, the gate is closed. But there's actually two reasons why that glucose might not go into the cell, because either the door is closed or it's already too full. That is, if you have a cell that is already bursting to the seams with glucose, that glucose from the blood simply can't get in.

So this is a totally different paradigm than this sort of internal starvation paradigm because it's an overflow paradigm, but it solves the problem of the central paradox, that is, why is this liver cell making so much new fat from glucose? Because it's jammed full of fat. The glucose from the outside cannot go in,

but the liver cell is so busy trying to make new fat, the novolyphogenesis that is just shoving it out the door, but there's too much going in. So the problem is not insulin resistance per se. The problem is hyperinsulinemia. That is, in the first place, it was all this insulin that put all this glucose into the cell, but you're putting so much into the cell that it's too full. I use an analogy.

Like, suppose you have a suitcase and you're putting your shirts in your suitcase, which is fine, and your wife says, here, put these shirts in, you put it in, that's fine. And then at some point, your wife says, here, put these two shirts into your suitcase, but you don't put them in. Well, why don't you put those two t-shirts, last two t-shirts into your suitcase? Either the suitcase doesn't open or it's just full. There's two possibilities and they're completely different. Or to extend on that analogy, you could say, well, you're just not listening to your wife. What you're basically saying is look, the conventional view here is when your wife said,

put these two shirts in your suitcase the last two times, you just decided, I don't want to, you know, I don't want to do that. Exactly. But what if there's another approach? What if you're fully well and willing to put those last two t-shirts in the suitcase? But when you open up the suitcase, there is simply no more room. The output looks the same, excess shirts outside of the suitcase, right? But the reason could be entirely different. Exactly, but the implications are huge because the thing

is that if it's just the fact that you're not listening to your wife and you're not putting the t-shirts in, then the solution is for somebody to grab those two t-shirts and just shove them in. Right? And that's what we did with type 2 diabetes because we said the glucose can't get into the cell. What we need to do is give you exogenous insulin. Sometimes huge doses of exogenous insulin so that we can shove the glucose, ram it down

the throats of the cell. That's for some reason not listening to us. But if it's an overflow paradigm, the implication is completely different because the solution is to get rid of the sum of the stuff that's in your suitcase. So if you bring it back to insulin resistance or hyperinsulinemia, then the solution to trying to get rid of this so-called insulin resistance

is not giving more insulin because that was the problem in the first place, putting those shirts in the suitcase. That was the problem in the first place. So putting more in is not the solution. The solution is to get rid of it. So the solution is to empty that cell of glucose. That's the whole solution, which is a totally different paradigm than what we've been taught, right?

Because we use sulfonol, you're reas we use insulin. Based on just trying to shove more glucose into this already filled cell. And it solves the problem, it explains the paradox of, I'll tell you the whole thing, it actually goes much further. But it solves the problem of this central paradox of why it's making testosterone, why the insulin effect is so high, right? Why do you get PCOS, why do you get the mitogenic effects of insulin, the growth effects of

insulin because you know that insulin is a growth factor, it has huge implications for cancer, for example. So breast cancer, colon cancer, very insulin sensitive, much higher rates in type two diabetes and obesity. So you're getting the cancer causing effects of the insulin, but yet you're saying people are insulin resistance, the fat, and the whole thing, it solves the problem of why you're having continued

denovolipogenesis, even in the face of this so-called resistance, because you actually have too much. It's not just a theoretical thing. It actually has huge implications for the treatment, because your treatment now has to be getting rid of the sugar, getting the insulin down. So let's pause for a moment and talk about the treatment. I want to just sort of synthesize this for the listener, because what you're suggesting is quite radical. Let's be honest, right? The conventional view is going back to your analogy, which I love, by the way, is that after your wife asking you enough times to put more t-shirts in, you stop doing it.

And the consensus view is you just stop doing it for some reason. You're not sensitive enough to her request. You're being an insensitive guy. Look, that's an easy thing to understand. You're just an insensitive guy. Well, that's an easy thing to understand. You're just an insensitive guy. Well, the current approach is your wife walks over and opens the suitcase and gets a few of her friends and your friends to help jam those t-shirts in there.

Because if you had enough people and you could put enough weight on the t-shirts, you could probably sneak a few more in, right? In other words, if you had more insulin or another analogy would be she yells louder is probably a more in, right? In other words, if you had more insulin or another analogy would be she yells louder, it's probably a better analogy, right? So if her polite request is insulin, then raising her voice is more insulin,

then yelling and screaming, and then by the end she's gonna like, take your favorite football and throw it at your head, and at that point, you're mainlining insulin into the patient. Let's talk a little bit about some of the other drugs, because most of the approaches to type 2 diabetes pharmacologically are not actually aimed at reducing glucose. Metformin is one of the very few drugs you mentioned the SGL2 and SGL2 inhibitors, which I want

to come back to. So we'll carve out the ones that actually lower glucose, but most of them are trying to amplify the noise. So walk us through the classes of those drugs. So we have the sulfonolureas, which stimulate insulin, and there's insulin, which stimulates insulin, and the DPP4s, for example, which are also similar in terms of the increased insulin. This is more than incretons, but they increase insulin basically. So the classic response of the older class of medication, so I'm going to leave, so metformin, I'm going to leave a psych, because that's actually a totally different thing.

SGLT2 is the sort of newest class, but the old ones are all about increasing insulin, so that's your wife screaming louder at you to shove more shirts in. And this is the thing. So if you do that, so say you give somebody a sifano urea and you start shoving more, you know, your wife starts yelling at you. So you start shoving more t-shirts. And at first, you can do it. But as you keep doing that, the problem just keeps getting worse and worse.

Because at first it's a little full, then it's a lot too full. And then what happens? Well, even if she's yelling at you really loud, you still can't put any more. And because you've now, you're just way over over the limit. So this is what happened in the body. Because look, if we look at the way we treated type 2 diabetes, sort of 20 years ago, it was to give sulfonolureas, then insulin, then more insulin, then more insulin. You're just

shoving more shirts into that suitcase. And the cell is getting more and more glucose, and it's getting more and more full. As it gets more and more full, the insulin resistance gets worse and worse. So what do you do? You keep going up, you keep going up. And guess what? That's exactly what happened. But if you think about it, if you to have a patient who 10 years ago was on one drug, and now they're on huge doses of insulin, that diabetes never got better. The sugars might have gotten better, right? But the actual disease itself of type two diabetes never got better. It only got worse. And that's the reason we say it's chronic and progressive because the treatment was completely incorrect. We did the wrong thing.

We kept putting more shirts in when we should have been taking shirts out. We kept putting more glucose into the liver, which is what insulin does, right? Instead of taking all that glucose out of the liver, it was the wrong thing. That's why people got worse. That's why we could never show any benefit to tight glucose control in type 2 diabetes. That's why the accord, the advance, the VADT, and all those trials failed because they're working on this incorrect paradigm of insulin resistance. This is the lock and key paradigm. So now we have a drug class, which is something completely different.

So this is the SGLT2. Before you go to that, Jason, I'll just add another point to this, because I know I discussed this with Jake Kushner several months ago, but it's important to revisit this in case folks either be forgotten that or didn't listen to it. I want to emphasize what you just said a second ago because you said it's sort of like, yeah, we all know this, but it's such an important point, right? When diabetes trials are using glycemia as their endpoint, meaning how low can you get

the hemoglobin A1C, how quote unquote tightly can you control the glucose, they do seem to have some benefits. Anything that is macrovascular does seem to get a little bit better. So where glucose at high levels causes problems, those things seem to get a little bit better. But where glucose at modest levels in the presence of high insulin, sorry, at the micro, I said macro, I meant microvascular, but the opposite is not true. So by taking someone's average

glucose from 200 down to 150, that would be considered a huge win in a diabetes trial if you took their glucose from 200 down to 150, and that benefit might show up in their kidneys. But if you had to double the amount of insulin you gave them to do that, it turns out at the macrovascular level, for example, heart and brain, they don't get any better. In fact, they might get worse. I remember the first time I sort of saw that about three years ago. It was a big aha moment, which is why aren't they getting better?

And that's sort of when I began to think about hyperinsulinemia itself. I mean, maybe it was longer than that, but not that long ago, right? It was like hyperinsulinemia itself is problematic if you normalize for glycemic levels. Yeah, because this is the thing that it's not the blood glucose per se. It's the whole body glucose, because if you think about this overflow paradigm now, if you take this glucose that's in the blood and simply shove it into the liver, have you done anything good for this patient? The answer is no because you're just covering up the problem. So you take insulin and your sugars are amazing, right? They're normal. But you

shoved all this sugar into your liver. What happens when you stop taking the insulin? All the sugar comes rushing back out of your liver and your sugar goes high. So you actually have to keep taking it to keep it bottled up. All you've done is you've covered up the problem. You never made it better because it's like taking garbage and throwing it under your sink. You can pretend that your kitchen is nice and clean, but it's going to start to smell. And that's the problem. It's the whole body glucose, moving the glucose from one compartment of the body, which

is the blood, to another compartment, which is the liver. So you move the glucose from where you could see it, into somewhere where you couldn't see it. That doesn't do your body any good. And that was the real lesson of the Accord Advanced VADT. That was 2008. Those were actually the trials that started me down this whole thinking that what we're doing is actually completely incorrect.

Because if you remember, for 2008, I've been doing this for like 18 years or 17 years. And that was what we always thought, right? You get the blood glucose low enough or normalize it. You're gonna see huge benefits, but we didn't. We didn't see any benefits at all. And that was a huge paradigm shift because these all came in 2008. And yet nobody wanted to propose a new theory of,

what is insulin resistance and how are you treating it and why are we so wrong? We just kept doing what we kept doing. We just said, well, maybe it's the hypoglycemia. It's like, come on, that's stupid. They weren't getting a lot of hypoglycemia. But what they had to understand at that point, which nobody ever did, was that this paradigm of lock-and-key internal starvation is completely the wrong way to think about it. Therefore, you're using the wrong treatments. You're using treatments that are actually going to make it worse, not better. And when you actually get rid of the glucose, so this gets me back to SGLT2s.

So the SGLT2s are a new class of drug. And what they do is they actually make you pee out the sugar. So it blocks the receptor on the kidneys where you're actually absorbing the glucose. And you you pee out the sugar. So it blocks the receptor on the kidneys where you're actually absorbing the glucose and you actually pee out the sugar. So you get side effect, you get tons of side effects, you get like urine infections and yeast infections and for some reason you get ketoacidosis too. But the point is that if you look at the trials they're actually quite consistent, you actually get a huge, huge protective effect from the SGLT2s.

That is, for the first time in decades, we have a drug that actually protects against kidney disease. So reduce the risk of kidney disease by about 25%. And reduce the risk of heart disease, which we've never seen before in any class of antidiabetic drug, because what we're doing now is we're actually getting rid of the garbage, we're getting rid of the glucose, we're emptying out that suitcase. So the amount of lowering of blood sugar was super unimpressive in all of these trials.

So there's like five or six trials now. Every single one of these trials shows end organ protection with almost no benefit to your blood sugar. Like A1C would drop like point three or point four. Like nothing, it was terrible for the blood sugar, but the end points were incredible. Why? Because you're actually getting rid of the actual problem. You're emptying out the body of this glucose, which is what was making them sick in the first place, as opposed to simply moving it around.

And that, I think, is the explanation as to why SGLT2s are so, so effective for organ protection, which we never saw before. Because now, you're actually treating the underlying problem of too much whole body glucose as opposed to too much glucose in the blood. You know, it's a totally different dynamic. Like if your whole body has too much sodium versus

just the blood has too much sodium, it's a totally different problem, right? If your whole body has too much sodium, you get edema. If your just your blood has too much sodium, you have hyperinatremia, two totally separate problems. Same thing here. If you blood glucose is high and your whole body glucose is high, totally separate problems. Now we're actually addressing the underlying reason. Let's consider, we're going to go to this in detail, so we don't have to go deep now

on it, but just listening to the way you're describing it, it seems that another way to provide benefit, which clinically seems to work quite well, is exercise, because the more one would exercise, the more one would increase a different reservoir outside of the liver, which is actually a larger reservoir, and one that can't put its glucose back into circulation, which is the muscle.

So as I listen to you describe this, it's not inconsistent with this clinical observation, which is you take a person with type two diabetes who is not exercising at all, who is sedentary, and even if you make no change to their nutrition, exercising them quite vigorously for an hour a day is actually going to have a benefit independent of anything else. Now, the idea here would be how many of these things can you combine them?

So what is the magnitude of that benefit? There is a benefit, for sure. I mean, all the studies we've done on exercise are beneficial, but it's much less efficient than attacking the diet. Just because liver is really the key to type 2 diabetes, the fatty liver, and all that sort of thing, and you really can't exercise your liver. You can burn off a lot of this glucose with exercise, but compared to the amount that you put in on a daily basis, it's a lot more work than to simply not eat, for example. So in terms of efficiency, it's just less efficient, but clearly there is a benefit to exercise.

And it's the same thing. You're really just trying to empty out all this glucose from the system. The other thing is that what always strikes me is sort of funny, is that it's not really just about the diabetes. It actually affects more than that because it actually goes into the entire metabolic syndrome

because if you think about it, metabolic syndrome is a constellation of five things. If you take the ATP definition, it's the increased blood glucose, which we've talked about, but also abdominal obesity, high triglycerides, low HDL, and high blood pressure. If you think about it, hyperinsulinemia plays a role in the same thing because what happens of course is that if you have this overflow paradigm, this liver is now busy exporting out tons and tons of the fat, right? It's got too much glucose because of too much insulin, so it's too much glucose, too much insulin.

So therefore the liver is jam-packed and it wants to get rid of all this extra fat. So it's actually putting out tons of triglycerides. So that's why you get hyper triglyceridemia. And then, of course, as triglycerides go up, we know that HDL goes down. So HDL goes down. As you're exporting out all of this fat, this fat goes into all kinds of places where it's not supposed to go. Into the pancreas, into the omen, and you get this abdominal obesity. Not because of dietary fat, because remember dietary fat doesn't go into the liver. It goes

into the chylo-microns, which goes into the blood vessels, which is just taken out by the adipocytes. Never goes into the liver., which is just taken out by the adipocytes. Never goes into the liver. It's the fact that the liver is pouring out all this new fat that gets taken up in all the organs around it. So you get fatty pancreas, for example, which I wanted to talk about in a second. But that's abdominal obesity. And we know that insulin has an effect on blood pressure because insulin causes reabsorption of sodium at the site

of the proximal tubule. So now, hyperinsulinemia, too much insulin, is really what is behind abdominal obesity, high blood glucose, high blood pressure, low HDL, and hypertriclisoridemia. That's the metabolic syndrome. The whole syndrome is not a syndrome of insulin resistance. It's a syndrome of hyperinsulinemia. And that's a way better way to think about it because if the problem is hyperinsulinemia, then the solution is completely obvious. Insulin's high? How are we gonna lower it? Right? It's no different than hey if your thyroid is too high

you want to lower it. If your thyroid is too low you want to give some. Well that's not so hard to understand. But think about type 2 diabetes for a second. Type 2 diabetes we know that insulin levels are high. So why did we think it would get better by giving more insulin. We totally misunderstand the problem. Yeah, I had a mentor who trained as an endocrinologist, but now focuses exclusively on type two diabetes and obesity. He said the exact same thing, which is we have to he doesn't like the term insulin resistance for the same reason you don't, which is he says it's not consistent with the way we think about under chronology.

In under chronology, we think about hyper and hypophil in the blank. And yeah, he uses the example thyroid, right? And he's like, look, if you have two little thyroid hormone, we give you more. If you hypothyroid, we give you more. And type one diabetes is that analogy. If you have too much thyroid hormone, we don't give you more of it. We treat you in a way that reduces the effect of it and sometimes that means taking out part of the thyroid and all these other things. It's funny. I think part of the

reason I think people struggle with this is the endocrine system is easier to replace than to shut down. Hyper-cortisolemia is another great example, right? When you have patients whose cortisol levels are unmeasurable, an extreme example of that would be someone in an adesonian crisis. You know, we're pretty good at giving more cortisol. But when you have people with hypercordisolemia, which unfortunately comes hand in hand with hyperinsolemia, there's no pill to lower hypercortisolemia. Exactly. And this is the same problem we had. That is type one diabetes, which is two little insulin. Hey, it was great. Just give more insulin. But we had type two diabetes, which is too much insulin. There's no drug like SGLD2 for a little bit. But before that,

there's no drug. So then we just gave the same thing, right? It's so ridiculous, just like giving a hyperthyroid patient, hey, give them some alphiroxin, right? It's like, that's going to make it worse, but we did the same thing, and we watched these people get worse. We gave them insulin and what happened? They all gained like 30 pounds. Like every single study showed that, the DCCT showed that, right? They just gained weight and they became hyperinsulinemic. We have type ones who actually became hyperinsulinemic. You start out taking 20 units, 15 units a day when you're a kid, and then by the time you're 45, you're taking like 60 units a day.

Why? You developed insulin resistance. And yet you had no insulin in your body in the first place 20 years ago, right? Because we thought that giving more insulin was good, but we didn't realize that, hey, too much insulin is just as bad as too little insulin, or worse, and in this case. And the funny part about it is that we actually know a lot about biochemically how this sort of overflow paradigm works. So if you look at the glycolidic cycle and the TCA cycle, for example, you have glucose

which undergoes glycosis to pyruvate and pyruvate goes through pyruvate oxidation into acetyl CoA, which undergoes the stochastic cycle, which gives you citrate and gives you ATP, which again, we know feeds back in blocks like calluses. Like, okay, well, you have glucose, it goes into the cell, it goes undergoes citric acid cycle, you get lots of ATP, you get lots of citric acid, feeds back, blocks like calluses, which means the glucose can't go in.

It's like, okay, we worked out the whole biochemistry of how this is overflow paradigm is supposed to work. We actually teach it to like high school students that, hey, if you're feeding in way too much of this stuff into the TCA cycle, there's a feedback, there's a negative feedback loop and almost every biochemical reaction does this, right? In biology, if you start stimulating stuff, you actually have something that's going to block it. TCA cycle is no different. ATP is going to block glycolysis, which is going to block that glucose so you don't overload the system.

That's what's happening. Glucos can't go in anymore. This is such an important point because then you can say, okay, hyperinsulinemia, which is actually too much glucose, too much insulin, is going to feed back and not let the glucose into the cell, which is why the glucose stays outside and you have this so-called insulin resistance, but the key is to empty out the cell of glucose. How are you going to do that? Well, low carbohydrate diets, intermittent fasting. There's no more potent way to lower insulin than to fast. I mean, we're going to come to this in a moment, but I get such a kick out of watching people argue back and forth

about whether carbohydrate restriction versus fat restriction is better at lowering insulin. My experience is that carbohydrate restriction does a better job than fat restriction. But I feel like sitting on the sideline saying, hey guys, there's another tool over here. You've both sort of forgotten that's like infinitely more potent. Eat nothing and watch what happens to insulin levels. And this is what we did. We just said, okay, don't eat anything.

You've got to clear out this glucose. You've got too much glucose in your cell. Clear it out. The easiest way to do that is eat nothing. Then you're going to force your body to start using some of this fuel, right? And the first place it's going to pull it out of is this fatty liver.

Oh, by the way, the fatty liver. So of course, it is driven by this denovolipogenesis, which is why, again, we see this huge correlation between fatty liver, which is a huge problem, by the way. It's actually causing a ton of cirrhosis these days. And type 2 diabetes, because it's actually part of the same problem. But exactly, you're completely ignoring your most effective tool, which is intermittent fasting. As soon as we did that, we saw tons of people just reverse their type 2 diabetes, which

gets me to my next point, which is the type 2 diabetes. Everybody forgets that this is actually a two-step process. You don't develop type 2 diabetes just with insulin resistance. It's actually two things. You need one is insulin resistance, or hyperinsulinemia, which isn't much better name. And then two, you need beta cell failure because what happens is, and this is where the old paradigm was completely wrong again. So we said, okay, well, you have insulin resistance, your body responds by increasing the amount of insulin. So we know that happens. So you get hyperinsulinemia. And and then eventually the pancreas is just so tired of making all

this insulin that it atrophies and it fails. And that's beta-cell failure. That's when you actually see the blood glucose go way up. And this whole process takes like 10 years or so. So the rising insulin resistance is met with hyperinsulinemia, which keeps the blood glucose normal. And it keeps it normal for a long time at the expense of hyperinsulinemia. And this is precisely what Kraft said. You can figure it out much earlier if you look at insulin levels as opposed to blood glucose levels. But the point is that now you have to hypothesize

that there's two completely separate things going on. One is insulin resistance and two is beta cell failure. And they're totally separate. And again, it doesn't make any sense. There's too many experimental points that don't line up. One, we know that if you're going to say type two diabetics, their beta cells have failed. Well, we know that's not true because virtually all type two diabetics are reversible. If you do bariatric surgery, if you look at the studies, like 80%

90% of those type two diabetics, they actually get off all their meds. They actually reverse their type two diabetes. So if you said that the beta cell just failed, then you're wrong Because even the most severe type 2 diabetes reverse we have three year olds So the youngest person in the world to get type 2 diabetes was three years old You're gonna hypothesize that this three year old pancreas Has failed has atrophy like that's clearly wrong and the other thing is that you have to say if has atrophy, like that's clearly wrong. And the other thing is that you have to say, if these two things go hand in hand,

why is it that you only see beta cell failure in this case of insulin resistance? And never anywhere else. Like how does that even work? Like they go together, one goes with the other all the time and exclusively with each other. So this is the point, but you'd have to say that there's two separate things going on, but if you think about the sort of overflow paradigm, again, it explains this paradox very

easily because what happens is that, and this is where, you know, if you look at a lot of the work on the twin cycles hypothesis fits in, is that you're filling up your liver with all this glucose, hyperinsulinemia, you've got too much glucose in your liver, your liver starts making fat and pumping it out. Then, one of the organs that accumulates in is the pancreas. So now you've got fatty pancreas. And that is the problem, is that your pancreas is not failed. Your pancreas is just clogged with fat. And you can measure these in an MRI and whatever, and you can see that all these people who have type 2 diabetes actually have big fatty pancreas as well. And as you simply get them to fast with a counterpoint study, which was done by Royce Taylor and so on, they showed

that the type 2 diabetes was reversible because you simply unclog the fat. But now the fatty liver is responsible for the insulin resistance or hyperinsulinemia. And the fatty pancreas is responsible for the beta failure so they're both manifestations of the same thing. They're both manifestations of hyperinsulinemia. And that explains why it's not two defects of type 2 diabetes. It's actually a single defect and why it's a reversible problem.

So again, this hypothesis fits the anomalies so much better than everything else. And if you look at fructose, for example, it's like, why is fructose so bad? And it's like, well, it doesn't have any glycemic effect. It really doesn't have that much of an insulin effect, but causes law of this fatty liver. All that fructose goes into the liver. It's turned into fat through normal lipogenesis. And now that's all part of the same pathogenesis,

the fatty liver, the hyperinsulinemia. So it explains everything about how this disease of type 2 diabetes, more than just hyperinsulinemia or insulin resistance, it explains how that all kind of comes about. It sort of fits a lot better. And this is what I mean. That's why I like the physics model, which is like, okay, we have a theory now, which now fits the facts so much better than the old lock and key model. And therefore, you have to adopt it and say, what are the treatments that come out of

this that are going to be more effective? There are actually two separate things I want to ask about. The first one is, do you see a way that Naferl D is causal towards hyperinsulinemia, and separately where hyperinsulinemia is causal to Naferldi, the literature is really not clear on this, and you could just say, well, let's just dismiss the literature out of hand, but clinically these things are so tightly wound, and I've never really done the clinical experiment to tackle one without the other. So it's a very common presentation is hyperinsulinemia that you describe. And I also am a big fan of Joseph Kraft. And actually I would credit it to Naji Torbe, who was one of my mentors, the endocrinologist

I referred to, who really got me to think of it as hyperinsulinemia as the endocrine condition. And his view was, look, the oral glucose tolerance test with frequent sampling is our best tool because long before glucose levels get out of whack, you're going to see inappropriate amounts of hyperinsulinemia early on. But nevertheless, the common presentation is patient has hyperinsulinemia,

whether or without normal glucose levels, their hemoglobin A1C is often completely normal. Their ALT is high, much higher than we would like it to see, though not so high that people would get alarmed by it. And if you really felt like doing it and you were resource unconstrained, you could get an ultrasound of the liver and you would almost assuredly see the accumulation of fat. Well, with that patient, we take a treatment plan that addresses both the naffel-dee resolved, the LFTs within a very short period of time normalized, and so too does the hyperinsulinemia.

And so I've never tried to disentangle if the high level of insulin is really pushing the fat accumulation in the liver or the other way around. Although, of course, you could argue that there's different scenarios, right? If you put somebody on a very high fructose diet that wasn't necessarily overly abundant in glucose, it might actually be that the Nafoldi drives the hyperinsulinemia versus a diet that is too high in carbohydrates for the individual, such that it's the hyperinsulinemia

that ultimately leads to what? Help me think through the arrow of causation in the other direction. Well, I think it does both, right? So you have those studies by Hevel from 2009, where he took people and gave them a lot of fructose, right? So the experiment was great. They took people, two groups of people,

one they gave sort of coolade that was sweet with glucose and one that they gave coolade sweetened with fructose. And then they actually looked for insulin resistance and so on. And what they found was that when you gave a lot of fructose, people got type 2 diabetes. You could measure the oral glucose tolerance test

and they actually became diabetic. So, what you see is that the fructose, which is metabolized in the liver, is causing this fat accumulation specifically in the liver, and that is going to cause hyperinsulinemia, right? Because the liver is full of, you know, all this excess fat. Now, you're trying to shove all this glucose into this fatty liver cell, and the liver is like, no, I can't take anymore. So I'm going to be resistant to this. So as it gets resistant, the blood glucose goes up, and the body starts to have to make more insulin to sort of

get rid of this other situation, which is, hey, there's too much glucose in the body. So I think the arrow of causation goes both ways, which means it's sort of a vicious cycle, each is making the other worse. So you have to take care of the problem. So when you take care of one, you sort of take care of both. And I always say that what's interesting is to look at this way of thinking, and then if you think about it, if you take it sort of one step further, what you see is that the obesity, the insulin resistance and the type 2 diabetes, which is the fatty pancreas as well, is they're actually not detrimental, they're actually protective, they're actually mechanisms of protection against the problem. So,

for example, let's take obesity. So I say, okay, so let's think about this one step at a time. Suppose you have houses on a street, and insulin, every day you take a little bit of sugar, so a bit of glucose, and insulin comes by and knocks on the door and gives you a little, you know, a bit of glucose. And you say thank you, and you use it for energy, and everything's great. Now all of a sudden, you start taking a lot of glucose.

So insulin comes by, and instead of giving you a little cup of glucose it gives you a big barrel of glucose. And it's starting to like too much, right? But you take it because you're supposed to. But eventually, you know, your house fills up with all this glucose. So after a while, the glucose keeps coming in. And insulin keeps giving you a big barrelful that you can't use every single day, and now your house is full.

So what are you going to do? Well, you're going to stop taking that glucose. So that's insulin resistance. So that's not actually, that's protective. It's protecting itself from the effect of too much glucose. That's what the fatty liver is doing. It's protecting itself from too much glucose.

It says, hey, hey, I can't take any more of this. So what happens, of course, is the insulin's like, oh, I got to get rid of this glucose, right? I can't have it hanging around. I'm going to lose my job. So it gets more insulin and starts battering down the door and just shoving in all this glucose. Not that glucose is bad, but there's just too much of it. So it just keeps shoveling in. So then you're overcoming that protective response. The obesity, which is the filling up of your house, was actually trying to protect yourself against this excessive insulin resistance.

And we see actually evidence of that in the lipodistrophies. So I don't know if you saw that paper a few years ago about lipodistrophies. So you had these people that actually had no fat. And you think, okay, if they're so thin, if they're so skinny, they must have no insulin resistance. They had the worst insulin resistance you've ever seen, like off the charts. They wrote about it in the New York Times. Yeah, this is the thing that sort of explains that paradigm, which is if you are truly insulin resistant, and you at least buy the argument that that's a global term, you know,

meaning one cell is insulin resistant, they all are. Well, then yes, you should be the leanest individual on the face of the earth because your at a post tissue does not have the ability to integrate or assimilate this signal that says, one, bring triglyceride in and two, halt the process of lipolysis. The problem is not insulin resistance per se. It's actually the hyperinslenemia. So what your body is doing is taking all this fat and sort of storing it away. So it doesn't cause a problem, right?

So these people with the lipid distrophy, they couldn't store the fat. So what happens is that the fat stored up in their liver and they had the highest insulin resistance you've ever measured because it's really a protective mechanism. The fat is trying to suck away all this glucose so that it doesn't cause a problem. This is why obesity itself is actually a protective mechanism against hyperinsulinemia, against too much sugar.

So the ultimate problem is too much glucose and too much insulin. So then the next step is, okay, so now insulin sort of is way too much that insulin's got all his cousins out, you know, battering down your door, throwing in all this stuff and you can't take it anymore. So then what do you do? Well, you start to take some of these barrels

and you try and give it to like your friends and your family and so on, right? So this is what the liver does, right? It's got way too much fat sitting around. So it takes this fat and shovels it out the door as VLDL. And it goes into the other organs. So it goes into the pancreas. It goes into the liver.

It goes into your omentum. That's how you get the obesity. The abdominal obesity that you see. So now you've got obesity as a protective mechanism, and insulin resistance itself as a protective mechanism, because the cell is trying to protect itself from too much insulin, too much sugar. The last part is that you're throwing out all this glucose

into your pancreas, all this fat into your pancreas, your pancreas stops. It makes a lot of insulin, makes a lot of insulin, makes a lot of insulin, up onto a certain point, makes a lot of insulin up onto a certain point. Now it's all clogged up and it can't make the insulin. So what happens? Well, you start to pee out all this sugar, right? You get the polyurea, polydipsia, glycosuria.

Your body is actually trying to protect itself by peeing out all this sugar. So it's like, you have to look at it the other way. We think of all these responses, obesity, insulin resistance, and the beta-cell failure as pathologic. They're actually protective. It's a totally different thing. Your body is actually trying to protect yourself against the root cause of the problem, which

is too much insulin, too much glucose. So when you enhance that glycosuria with SGLT2s, guess what? You actually have a protective, like a hugely protective effect, because that's the protective mechanism against the root cause. When you actually give people more insulin, you actually keep all that inside than what happens again. And clinically, you actually keep all that inside than what happens to gain weight. And clinically you see this. Clinically the patients know it because you give them insulin, their blood sugars are

better, but then they gain weight. And as they gain weight, their diabetes gets worse. So you give them more insulin. And as you give them more insulin, they gain more weight. Do you think that adiposity per se, all things equal, is also driving the hyperinsulinemia. And if so, what is the mechanism? Or do you believe that the adiposity is a bystander of it? Because this is also an enormously difficult problem

to tease out in clinical trials. Because virtually any clinical trial that demonstrates an improvement in quote insulin resistance or more accurately a reduction in hyperinsulinemia is without exception to my knowledge accompanied by weight loss and a reduction in adiposity. And this too then drives a causal question, which is the adiposity driving the hyperinsulinemia? So let's for a moment posse it, that hyperinsulinemia is the way we will refer to this and we won't talk about insulin resistance because that term has really lost meaning in this context, that the

adiposity is driving the insulin resistance or the insulin resistance is driving the adiposity. I think it's more likely that the hyperinsulinemia is driving the obesity rather than the other way around. I mean, it's always hard to tease out, but you can look at, to me, it's always like, let's take sort of an experiment and see. So there is a great experiment a few years ago where they took people who were type 2 diabetic, and this is in the 90s. And they gave them love insulin. So from time zero to six months, they went from zero units of insulin to like 100 units of insulin, that blood sugars were great. And what happened?

Well, they gained like 20 pounds. And if you look at the number of calories that they were eating per day, it actually dropped by about 2, 300 calories per day. So what you see is that the only difference, because this was a randomized sort of trial, the only difference was the hyperinslenemia. That's what we changed. When we changed experimentally, the amount of insulin people were getting, because we're giving it to them, they gained weight. So to me, that is clearly a causal

relationship. We see this all the time, right? You prescribe insulin, people gain weight. You give sulfonolureus, which increases insulin, people gain weight, right? You give them S-G-L-T-2s, which make insulin drop, then you lose weight. And type one diabetics know it too, like they lose weight. So the arrow of causality is very easy to establish, going from hyperinsulinemia to obesity. And forgetting all the mechanism, all I'm saying is that when you give insulin, people gain weight. Every single time you give insulin, or raise it by sulfonolureus, or when you lower insulin with type 1 diabetes, they lose weight. And it doesn't forget about what you eat or whatever, like people say, oh, let's put equal

calories in that like, forget it, like, all I'm changing is the insulin. Then obesity goes up or down depending on what happens to the insulin. It's much harder to establish that causality, the other way around, right? You can, and they've done this with liposuction. So if you take a situation where you remove 20 pounds of fat, What happens?

And the answer is nothing. Right. Now, that study, if you're referring to the one that Sam Klein published in the New England Journal of Medicine, I love that because it's a great example. Of course, the pushback is yes, but that was only subcutaneous fat that was removed. We don't do liposuction on visceral fat. You know, on some level, I think this is a great theoretical question. It might not matter.

In other words, it doesn't change the clinical decision. It's an important question as we think mechanistically about what's happening, but it doesn't change what you do with a patient, which in the final analysis matters more than anything. But yes, until we can really do liposuction on visceral fat, which I personally think would just pose too much risk to justify, it's going to be very difficult to tease out the other direction.

But what about the role of inflammation? Because the other thing that seems to go hand in hand with hyperinsulinemia in patients is they also tend to be quite inflamed. And we can measure this non-specifically with things like C-reactive protein, Fibrinogen, Interlucons, we can even see cardiac specific forms of inflammation.

So for me, this is just a very non-scientific clinical observation, but I'm curious as to whether you've seen it. Yeah, in terms of inflammation, again, I look at it from an experimental standpoint. So if I think inflammation causes obesity, for example, then what happens when you decrease inflammation? Because we have anti-inflammatory medications.

What happens to obesity? Well, you can give NSAIDs and people don't lose weight. You can give prednisone, which is probably our most powerful anti-inflammatory. People don't lose weight. If you give all these antibodies, this antibody that, and there's all kinds of inflammatory IL-2 and TNF, and you have all these things. Other than if they get super nauseated, they lose weight, but if they don't get super nauseated, then they don't really lose weight. So, to me, that whole story, there might be a kernel of truth in that.

But to me, it doesn't really make a lot of sense. Like if you get a really bad infection, you know, some kind of inflammatory state. So inflammation goes way up. Rumatoid arthritis. Do you gain a lot of weight? It's like, yeah, don't really see it. As opposed to the consistency where you give insulin people gain weight, you take away insulin people lose weight.

To me that's a consistent causal relationship. Whereas inflammation, it's much less. I don't deny that there's a lot of important inflammatory mediators and stuff, but it's just not so simple that you can say more inflammation causes weight gain, less inflammation causes weight loss, therefore treat everybody with advill or something like that. Yeah, where I was gonna go was actually slightly more nuanced, which is again getting a little bit ahead of where we're gonna go because I want to start talking about some treatment ideas, but you take a hyperinsulinemic patient with no inflammation in

my limited experience, they tend to respond quite well to carbohydrate restriction and exercise. When I take patients who have significant hyperinsulinemia, but it's also coupled with inflammation, I don't find that they are as impacted by what I just said. And I find that those are the patients that initially got me to start exploring significant periods of fasting. Either significant 500 calories a day for five days, that type of fasting or you know, water only for three days, five days, that sort of thing. And again, not a very scientific organization or observation rather, these are small and clinical things that I see. But I wonder if A you've seen that and B if it suggests that inflammation can have a sort of negative synergy with

hyperinsulinemia. I think that there probably is something to that because there is, I mean for sure other hormones are involved, like we know for sure there are other hormones involved. So look at cortisol, for example. Inflammation's difficult because there's so many different mediators, right? You can have T&F, you can have IL-2, you can have all kinds of inflammatory mediators, endotoxin and stuff.

But there for sure other hormones that make it really are very important, like cortisol. So you give cortisol people gain weight, right? It's not as much as the insulin, but you give prednisone, and you know, we've all done it. You give prednisone, you gain weight. When you take away the prednisone, like they finish their course of prednisone,

that weight kinda goes back down. So we know that cortisol, for example, is a huge impact on body fatness. For example, we know the studies from sleep. If you get good sleep, you're more likely to be a good weight. If you're sleep deprived, for example, it's a stressful situation where cortisol is going to go up, then you're more likely to gain weight. So that's not an insulin thing. It's a cortisol thing. And we know for sure that sex hormones have to play a role somewhere in there as well because there are women who develop gestational diabetes. And they're insulin, they're diets, they don't change. The

difference is they got pregnant, right? And that's a difference in sex hormones. And somehow that impact, and I actually don't know how this works, but somehow it does impact the response of I'm not sure they're hyperinsulinemic either. I think there must be something completely different about that entire thing, but it's not as common, so I don't I don't think about it as much. Or girls and boys at puberty, for example, the difference of girls and boys is testosterone versus estrogen, for the most part, it's not an insulin difference. Yet girls who go through puberty have way more fat than boys.

You get more muscle. So we know that there are other hormones that clearly impact. So it's not just about insulin, but it's about cortisol, it's about sex hormones. And I think inflammation probably comes in there somewhere, but what to do about it, and it's a lot messier. Inflammation is a lot messier than thinking about cortisol, for example, where you can measure levels, and you can think about up or down.

Cortisol, for example, you have the too much, which is pushing disease, and what's the sort of hallmark, well obesity. And then you can get too little, too little cortisol is Addison's disease, and what's the hallmark? Weight loss, right? So again, very, very clear. It's easy to measure inflammation. It's just so hard. It's just too many moving parts for me.

Yeah. I don't know. I think this whole thing is too hard for me. But let's talk a little bit also about the role of hyperinsulinemia, specifically on the vascular system. What is it about hyperinsulinemia and the endothelium or the capillaries that seems to wreak havoc beyond what tends to accompany late stages of it,

which is hyperglycemia, which of course has significant damage mechanically on the microvascular system. But what about, like for example, why would hyperinsulinemia exacerbate coronary artery disease absent abnormal glucose levels, or even once corrected for lipid levels? Which, you know, that observation exists, right? You can take patients that have the same lipid levels, the same glucose levels, but the hyperinsulinemic patient is going to have worse cardiovascular disease.

Why is that? For that specifically, I don't know. I think that there's a lot more work because a lot of people still don't think about it as a disease of hyperinsulinemia. But I think of it generally in terms of two things. So I think about two things, like cardiovascular disease, a lot in cancer because those are actually the two top killers of Americans is CV disease and cancer. And they're both to me diseases of too much growth. That is everybody thinks growth is

good, but growth in adults is generally bad. Like you don't want to grow. Once you reach adult size, your liver doesn't grow, your kidney doesn't grow, you shouldn't be growing. And if you are growing, it's generally bad. So if you gain weight, you're your obesity gain fat, that's a disease of too much growth. If you have big fat, liver, that's too much growth. If you have all this excess protein in your brain that's blocking your signals, and that's Alzheimer's disease, that's bad.

And it's the same thing, cancer, disease of excessive growth. In the blood vessels, we know that there's excessive growth, right? It's not a matter. And this whole idea of fat or cholesterol clogging your arteries like a pipe. It's super like even when I was in medical school, we knew that was not the case. We know it's a response to injury. That's why you get it at bifurcation points, for example, and you get smooth muscle proliferation, and then the foam cells which go in,

and it's not clear whether the foam cells and all that is a response to the injury, but it's because of that whole cascade, that atherogenic cascade, it's a response to injury, but you get excess proliferation of certain things, including smooth muscle cells and so on. But to me, it's just the disease of too much growth. That's eventually building and lapped and closing off that artery. And this is where diseases of too much growth is linked very tightly to insulin, because insulin is a growth factor. I mean, this is one of the things

that is super exciting in cancer, I'll tell you, like the PEOPI3K thing because it directly links insulin which we all think about in terms of metabolism to growth. Every single time that you have a nutrient sensor like insulin like M-Tor like AMPK, but it's the same insulin the pathway that it goes through, which goes through P-I-3K and then like map K and AKT, is it influences growth, it increases growth. And that to me is one of the big problems with insulin all the time, is that you're telling your body to grow all the time when it really shouldn't be growing all the time.

So you actually have to decrease growth, if the problem is too much growth, you want less growth, and one of the things that you want to influence is insulin and mTOR. MTOR, I know you talk a lot about mTOR. It's the same, exactly the same. It's a nutrient sensor at heart. It's very sensitive to dietary protein. And what it does is if there's a lot of protein, you turn on all these cell proliferation signals when you have very little protein, what happens?

Atoffogy. It's like, oh, okay, so you have to realize that metabolism and growth are exactly the same thing, and it has even more implication for cancer, which is a disease of too much growth. So being obese, for example, it doesn't give you cancer, but it certainly increases your risk of breast and colon cancer by a whole lot. There are 13 cancers that are listed as obesity-related, and we know that there's a very strong relationship between type 2 diabetes, even without the obesity, but because they're hyperinsulinemic. There's a very strong relationship between type 2 diabetes and breast cancer, for example.

So to me, those are all diseases of excessive growth, and therefore you have to start looking at growth pathways, which actually are the exact same as metabolic pathways, which is insulin, mTOR, AMPK, which is important, of course, for metformin, and then all of a sudden you see, hey, all of these times that you can decrease nutrient sensors, that is, decrease emTOR, decrease insulin, increase AMKK, you're getting good effects for longevity. This is fascinating. Yeah, yeah. And it's so funny you say this, Jason.

So this past week I was in Boston and I was meeting with a number of folks. And one of the folks I was meeting with wrote a paper, the very interesting paper in 2006, I was not aware of it at the time. He wrote a theoretical paper, so it was a paper that got rejected by virtually every journal out there, but in 2006 he proposed theoretically that Rapamyson would be a great longevity drug. Now, today we'd say, well, that's obvious, but it's important to note that the first trial demonstrating the immense power of rapamycin to promote longevity was not published until 2009, three years after this paper was written. And what he said was, based on all of the evidence he had examined to date of the use of rapamycin, even in patients with transplant, its anti-proliferative properties alone speak to this.

And it's so funny to hear you say what you just said because he said the exact same thing. He said, think about it, Peter. Every chronic disease is some amount of hyper proliferation, hyper growth. And you have a drug here that, in the most elegant way, in the least toxic way, in the most specific way, targets one of the most important regulators of growth, his prediction was this is going to be the most important longevity drug there is. And, you know, I would agree with that.

In 2019, I think that there is no more promising agent than rapamycin for longevity. But again, it comes back to this growth thing. And to put another bow on what you said, it was certainly lost on me in medical school, how anabolic insulin is. And in fact, I remember learning many years later that bodybuilders used insulin.

And I remember thinking, oh, that's odd, I wonder why. And of course, after speaking to some bodybuilders, I got to learn, well, look, testosterone is anabolic, but insulin is even more anabolic. Now, you can't go overboard, and this is where these hormones are very sophisticated, because testosterone is very anabolic to muscle, which insulin is as well, but testosterone is very anabolic tomussel, which insulin is as well, but testosterone is catabolic to fat, whereas insulin is anabolic to fat and anabolic to muscle. Cortisol, just to bring it full circle, is the worst of both worlds. Hyper-cortisolemia is catabolic to muscle, while anabolic to fat. I usually end up drawing this picture for

patients on the whiteboard showing estrogen testosterone, cortisol, insulin, and then you draw a muscle cell, a fat cell. And it very quickly starts to paint the picture that says, this whole thing is just endocrinology. I mean, all of this comes down to how can you manipulate these hormones to the desired outcome? Nutrition being one tool, but exercise, the use of hormones themselves, of course, in cases where there's deficiencies being another way to do it. So it's a very interesting way to sort of frame this as the things that we care most about avoiding if you really look closely involved some measure of hyper proliferation and growth.

Yeah, because that's the chronic diseases today, because there's been a huge shift in the diseases that we treat. So if you go back 50 years, 100 years, you're talking about treatment of infectious diseases, hepatitis virus, pneumonia, and diarrhea, and all this sort of stuff. And we did great. We developed all these great drugs, antibiotics, antivirals, like really, really good stuff. And they haven't been as big a problem. Now we have a problem with resistance, of course, which is actually the same thing. Interestingly enough, I think there's a huge parallel between antibiotic resistance and insulin resistance. And in that, they're the same thing. Antibiotic resistance is not caused by some phantom things,

caused by using too much antibiotic. Insulin resistance is the same thing. It's caused by too much insulin. So you have almost the same thing where antibiotic resistance is caused by too much antibiotic. And we try and treat it by using even more antibiotics, to overcome that resistance, which is the dumbest thing you could do. In insulin, we have insulin resistance, we treat it with more insulin, which is what

causes it in the first place, and then things get worse, and we know and understand why. So you know that treating antibiotic resistance is about using less, same with insulin, the auto use less. But anyway, we shifted from treating these diseases, which are infectious diseases to these chronic diseases, but we never changed our paradigm of medicine, which is the paradigm was. You come into me as a doctor, I give you a pill and antibiotic, and you get better. Then people came in with these diseases, like diabetes and obesity, and the related

diseases of hyper proliferation, or I call them diseases of too much growth, cardiovascular disease and cancer. And all this other stuff too, like it's all about fibrosis, right, which in the end is just about revving the system too hard. But it's basically hyperproliferation, and then we said, let me give you a pill. It's like, that's totally the wrong thing, because you don't have that pill to decrease proliferation. Rapamycin might be one, but Rapamycin to me is limited because you've got not one problem.

You don't have one nutrient sensor. You have three nutrient sensors. You have insulin. You have mTOR and you have AMPK. It's a very sophisticated system. Look, insulin responds to dietary carbohydrates and dietary proteins. MTOR responds mostly to dietary protein. AMPK has actually, like, you know, measures the ATP, the AMPATP ratio. So it actually doesn't care what you eat.

It just cares about the cellular energy availability. So there are all three measuring different sort of things, and they all work on different timescale. So insulin goes up and down within minutes. It's gone within hours. MTOR is sort of up and down between 18 and 30 hours. And AMPK is sort of days to weeks. So you have such a sophisticated system

because you have three nutrient sensors that are giving you different information based on your diet and also based on your time scale. So your body actually gets such incredible information just by integrating which one is up and which one is down. But Rappemites only affects the one. Whereas some things like intermittent fasting is going to decrease your insulin, it's going to decrease your mTOR and increase your AMPK, which is all three things that you need to do in order to sort of decrease proliferation, because you know that all three of them insulin feeds into mTOR and AMPK also feeds in. They're

all part of that same thing. You're affecting three different parts of that pathway as opposed to one. And that is going to give you the best bang for your buck. And it's free and you can do it anytime you want. And it's like, oh, hey, they told people this 2,000 years ago, right? When all the religion said, oh, you should fast and you should do this and you should do that. Which is, to me, this sort of just incredible that, you know, it all comes sort of back to what we knew 2,000 years ago, which is that you know, it all comes sort of back to what we knew

two thousand years ago, which is that, hey, fasting every so often has incredible benefits because you're going to be able to affect those diseases of excessive growth. Let's pivot to this now. Let's talk about fasting. You and I are certainly two folks that are no strangers to this. Anyone who's been cared for by you, anyone who's been cared for by you or anyone who's been cared for by me pretty much is used to the same drumbeat, which is, I mean, I don't actually, I'd like to hear about how you do it. And our practice, you know, generally for the first year, we don't push too hard on the fasting thread, but boy, by the end of that first year and into their second year with

us, we're really having a hard discussion about this in some cases for patients that are resistant. Now, I have this sort of framework that I think about for fasting, which is you start out on this sort of crappy standard American diet. And how do you escape that gravitational pull of that horrible thing? And I'll be sensitive and call it the standard crappy diet, the Canadian crappy diet or whatever as well. They're comparable.

To me, the two easiest ways to help patients escape the gravitational pull of pure garbage is time restricted feeding and or some measure of dietary restriction. So the way that I explain that is time restricted feeding says ostensibly you don't restrict what a person eats. You just restrict when they, and nor do you restrict how much for that matter.

But you just put a feeding window on and you say, look, for 16 or 18 hours a day, you'll consume nothing, and you will eat ad libidum in the remainder of that period of time, and you contrast that with dietary restriction, which we've already alluded to. Carbohydrate restriction is a form of dietary restriction. And it can come within without caloric restriction, but the simplest way to execute it would be to say, look, no restriction on when you eat, no restriction on how much you eat, you just can't eat these foods. And that's sort of where the majority of the diet wars live is, are you a vegetarian, are you vegan, are you on a low fat diet, a Mediterranean diet, a paleo diet, a low carb diet, a ketogenic diet, they're all forms

of dietary restriction. And to my knowledge, I'm not aware of one of them that is not significantly better than just being on the standard American diet. So that speaks probably less to their individual efficacy and more to the abject misery metabolically that is being exerted on people. Before we get into fasting, let's get everybody really dialed in on those two things. Timestricted feeding, plus or minus dietary restriction. How do you visit those two things before we get into fasting? I focus a lot more on the fasting. So I've always said, yeah, it comes down to the when you eat and what you eat. And this was the thing that I sort of pointed out years ago, like three, four years ago,

which the everybody focuses so hard on the what to eat and nobody talks like ever about the when to eat. That is, there is a sort of consensus. It was never intentional that we should eat all the time, right? You should eat six or eight times a day. You should graze through it the day. And you know, there's all sorts of reasons that were made up to suggest why we should eat all the time, right? You should eat six or eight times a day. You should graze through it the day. And, you know, there's all sorts of reasons that were made up to suggest why we should be eating six times a day.

But there was never any science, right? So, you know, if you ever look back and say, hey, where did we get this idea that we should eat six or eight times a day? And it's like from nowhere, somebody made it up. It stuck, and that was about it, right? It didn't, there was no studies. There was no randomized control trials,

there's nothing. Somebody just thought it was a great idea. And a few years ago, I said the same thing, which is that, hey, we're sort of missing half of the problem, because if it's two problems, when to eat and what to eat, and you're nobody's talking about when to eat, then you're not gonna succeed no matter what you do.

And that this is why there's this sort of diet wars. I wasn't that interested in getting into that. I was like, Marl, hey, let's look at this whole other problem. So, what we do generally is start with that because it's a lot easier to change the frequency as opposed to what it is they're actually eating and this just comes from experience. So, the first thing I did when I started really focusing in on diet was trying to change people's diet. But I did it from a clinical standpoint. That is, I'm not seeing one person sort of for an hour or every week. I have a clinical practice, which means

you get like 10 minutes, like every three months. So it has to be something that is sort of easy to understand and super effective as opposed to sort of counting carbohydrates or something, which takes a long time to explain to somebody and then explain why eating fats, not that bad for you and so on, I needed something that was sort of much more efficient in that way. And that's why we started using fast and quite a lot because it's something that people start of understood. You can explain it within the 10 minutes and then you can follow up with them and see if they're eating and they know sort of what it means to be fasting as opposed to some of these people who

really didn't have any idea what a low carb diet really meant. And that was the issue. Tell the story again. I remember last year you were telling me a funny story about and I don't remember what the ethnicity was Tell the story again. I remember last year you were telling me a funny story about, and I don't remember what the ethnicity was and the point was not to poke fun at one ethnicity or other. It was just like within this culture, to say, don't eat carbs meant, oh, okay, well, I won't eat bread or pasta, but I'm still going to eat lots of noodles and lots of this and lots of that. And they came back in and you said, how is the carbohydrate restriction going?

And they said, oh, it's fantastic, Dr. Fung, I'm doing so well. Great. What are you eating? And it was like all carbs. It was just different carbs. And that was, I remember you describing it, that being sort of an aha moment of culturally, it can be very difficult to get people to restrict carbohydrates. Yeah, because it's their traditional food. So it have a lot of Asians, so both East Asians and South Asians. And of course, the diet is based on rice and rice noodles and you know, for the South Asians is rice again. So there's a lot of cultural difficulty, which is why it was very difficult to sort of push too hard on it. You can't if you if you make enough of an

effort. And I think that message anyway is getting across that eating all these carbs are are not great for you. These refined carbs, but the point was that you have to still come up with something. This is where the practical experience sort of comes in. Like you can't just say, okay, well, I'm just going to stick with carb restriction, right? I'm going to put these Chinese and Filipino and South Asian tree-lank and people on no rice, no noodles, ketogenic diet. They might say yes, but they actually won't do anything to, you know, to follow it because it's just so difficult, right? Their culture is like that. They've been eating this way for 70 years, and it's very hard

for them to change, and their family eats like this. So it's like, what are you going to do? As opposed to fasting, which to me was a much simpler idea that was already embedded in every culture. So you talk to Muslims about and they're all like, ah, I know what you're talking about. You talk to Catholics and you talk to Jewish people like they go, ah, this is or Greek Orthodox or whatever and they're all like, ah, and the Buddhist were like, aha. So it was way easier just from a practical standpoint. That was where I started using it. And then I saw it like these crazy, like crazy good results. It was like insane. So we wrote a case report that was published in BMJ case reports.

It was three patients who had like sort of 20 to 25 years of type two diabetes and like five years of insulin on big big doses of insulin We told them about low carb diets, but you know, we don't spend a lot of time But we put on a 24 hours of fasting three times a week It's just like a one meal a day right nothing too strenuous or anything We got off all their insulin like between five and 18 days It was ridiculous how quickly they responded. And years later, we still have people who are like non-diabetic.

They went from 20 years of diabetes to non-diabetic and have maintained it for the last six years. Right, it was ridiculous how good. Like I just couldn't believe the results that we were getting. And that's when we were like, okay, well that's tell people and let's start writing about it and all this sort of stuff. And it took ages to get that. It took like two, three years to get that case series published by the way.

You alluded to bariatric surgery earlier. And about five years ago, I was involved in an effort to do a clinical trial to try to tease apart the observation you alluded to, which was that when you take a patient with type 2 diabetes who undergoes bariatric surgery, at the time I believe this was true primarily for the Ruan-Y gastric bypass. So for the listener, that's a surgical procedure where the part of the bowel that comes out of the stomach, which is called the jajunum, is the first part after the duodenum, you cut a piece and then reattach it as a piece of a Y and then bring it up such that you are basically bypassing not just significant parts of the volume of the stomach as a

reservoir, but also the initial part of the duodenum and the jajunum. The observation was the following. You do this operation on a patient. Within about 10 days, they haven't lost a meaningful amount of weight, but all of a sudden they don't need insulin anymore. And very quickly, their diabetes resolves. In fact, I believe we are still at a point, although this may be changing, where the only treatment that is viewed by an insurance company to actually reverse type 2 diabetes is bariatric surgery.

So the question we were trying to ask was, how would you design a clinical trial to parse out how much of that is due to the change in the internal architecture? Is there something problematic about the duodenum of that patient? How much of that is due to the change in the nutrition of the patient, because a patient who undergoes a gastric bypass has to make significant changes in their nutrition?

And how much of that is due to the perioperative period of caloric restriction? So what's your take on those patients, which, again, pretty profound results, again, not that profound, I think, when you consider them in the context of what we now talk about with what fasting can do, but what's your take on that? My take is that the fasting does everything. So you can actually get, I think, exactly the same results if you simply didn't feed them for 14 days or something like that. Because the thing is that when we

do this for people, when you put people on a 7 or 14 day fast, we see this. We don't do it a lot because generally they're older, so we want to be a little bit more sort of regimented. And there's also these cases of late nonset type one and so on. But you actually see exactly the same thing where the diabetes complete result. And the thing about it is that you can understand it perfectly by understanding

this sort of overflow paradigm, because what you're doing, of course, is dropping insulin levels very low. And then you're forcing the body after the first 24 hours like a gene runs out. So now you're going into a period where your body is going to have to metabolize fat for energy. So the first place it's going to start pulling it out of is going to be the internal organs because it's right there. The liver is going to be the first place that it's going to start pulling the fat out of. And if you look at Royce Taylor's data, what you see is that the liver fat starts to go

down right away. The insulin resistance starts to go down right away because that's the problem, right? It's this big fatty liver which you can't shove anymore glucose in. That's what insulin resistance is. As this big fatty liver goes down, just like I'mying your suitcase, the insulin resistance starts to melt away. And slower, because he showed this incredible data, which looked at pancreatic function with ultra-low diet. It wasn't fasting, but it was an ultra-low calorie diet. You can start to see that the pancreatic fat starts to go down because the body's not pumping out.

Your liver's not pumping out fat and dumping it in your pancreas. And as you get rid of that pancreatic fat, you're unclogging the pancreas, and you're producing enough insulin that you don't get the hyperglycemia anymore. Your glucose isn't that high because now you're at a stage where insulin production is going to go up because they measured that in Royce Taylor's counterpoint study, the one from UK, and you can see that the first phase insulin response starts to go up. It takes a few weeks, but that's exactly what you see clinically. That is, before you lose the weight, which is all a lot of sort of subcutaneous fat,

you're getting rid of the visceral fat, the fat around the organs, which is the heart of the matter. The insulin resistance is fatty liver, the beta-cell failure is fatty pancreas. You're getting rid of that first, and that's why that diabetes goes away so quickly before you see significant weight loss. So the whole pathophysiology makes sense to me, and to me I call it medical bariatrics. Fasting is what I call medical bariatrics. You get all the benefits of bariatric surgery without doing any surgery,

because you can get almost everything the same. Like, obviously, it's a lot more, you know, you have to do it. The compliance with bariatric surgery is easier than the compliance with fasting. I guess for me, I don't know, I still entertain the notion that there may be more than one way to skin this cat,

and that I think bariatric surgery is probably a great example of putting three things in place. I've actually seen data that look at making no change to a patient other than altering the morphology of the duodenum and that improves type 2 diabetes, which again, if you bypass the duodenum, you would bypass what that problem is there. Because the thing with the bariatric surgery patients is they're not fasting for that long, right? They're going to have fasted for 12 to 18 hours before surgery.

And nowadays those patients are dripping in liquids that are caloric even the day of or the day after surgery. So they might have a 24 hour fast, but there's no question that their caloric intake is lower during that first three or four days. But remember that you've got the malabsorption too, right? So the root on Y is both restrictive and malabsorptive, right? That is not only do strict, restrict how much they can eat. The amount they eat doesn't all get absorbed.

That's right, a dumping syndrome and so on. I agree with you. That's a good point. It's hard to do it based on just how much they're eating. Technically, we don't know how much they're absorbing. I like your term, which is like, let's just refer to this as medical bariatrics, and it's super potent. When you have purely restrictive things like lap ban, it's like, boy, those things didn't work at all.

We thought they'd be great lap bands, purely restrictive, easy to put in and so on. And it's like, yeah, you look at the numbers of people and they're just dropping. You know, my friend who is a surgeon says, yeah, you know, he used to put in lots of lap bands. He says, now the most common procedure I do is removal of lap bands because everybody wants to get rid of them because they the pure restrictions didn't work. So they're dripping in, they're drinking sodas and they're drinking milkshakes and stuff, and they're not getting the malabsorbative part, which is that rule on why, and therefore that was the problem. But I agree with you, I'm not against bariatric surgery.

I just think that as a sort of solution for everybody, it's a much more difficult problem because there's a lot of expenses, there's a lot of expertise, as opposed to the sort of easy thing, which is, hey, everybody can do fasting. It's just a matter of spreading knowledge and making it easy, right? It's not that people can't fast. It's that people tell them they shouldn't fast, right? Like if you go and look at Ramadan or something like that, right? People can fast. If it's the norm or lent or the orthodox, if you look at what the norm is, people can follow

that. It's just that the norm is so far off, we tell our kids, oh, hey, you got to have a snack. You got to have, you know, you have kids, right? It's like after school is a snack, like you get a, you know, the other day I got a thing home saying, oh, your son is going on a trip, but don't worry, we're going to give him lots of snacks. I'm like, oh, like why? Why did you need to do that, right? Or, you know, you send your kids to play soccer, right, I do, right, I did, and that they don't anymore. And it's like, somehow, everybody thinks

that between the halves of soccer, the parents were taking turns bringing snacks. It's like you don't need to give juice and cookies in between halves of soccer. Just let them play the game, the game is fun, right? But it's this culture where it says, you must eat all the time. This skipping breakfast is perfect example.

Oh, as soon as you get up, you gotta start putting muffins in your mouth. Otherwise, you're gonna die, right? You're gonna die of heart attack. Like, what the hell? Did you see the publication a couple of weeks ago that suggested that people who skipped breakfast had a higher cardiac mortality. Yeah, that's what I was referring to. It's like, oh my god.

What's your explanation for that study? I'm sure you've been asked about it a dozen times. Because these nutritional epidemiology studies are so dangerous, right? It's because those people, if you tell everybody that you have to eat breakfast, then you're going to select a group of people who don't listen to you, right? And they're going to eat breakfast, then you're going to select a group of people who don't listen to you, right? And they're gonna be on healthier. They're on healthier in a lot of ways you can't measure. You can measure smoking, you can measure this,

but there's so many things that you can't measure that are going to influence why those people who skip breakfast are more likely to have heart attacks. That association may exist, but it's not causal. And that's the thing, right? It's a correlation, not a causation, and it's a very dangerous assumption to say that, hey, you can eat breakfast and now prevent heart attacks, because that's what gets out into the press. Put a muffin in your mouth as soon as you wake up and you'll have less heart disease. That's not

what the study shows, but that's the implication that always comes out in the press. My issue with these studies, some of you are as I suppose, is that there's a non-healthy user bias to a lot of these. So one of the more obvious examples of the studies that suggest that diet sodas are, you know, worse for you than sodas. But of course, it misses a very obvious or clear thing that, you know, I might be missing which is who are the patients who are going to disproportionately consume diet sodas? Certainly, a subset of them might be people who are more health conscious and say, well,

if I want a soda, I'd rather it be diet than not. But it's more often that people who are being told, look, you can't have a regular soda, and so therefore you're selecting for less healthy patients. That is my interpretation of that study. Now, while we're on that topic, do you think there are clinical benefits from a 16-8, just to use that example, time restricted feeding pattern? So if you said to a patient who came in to see you, I want you to only eat between noon and 8 pm, nothing outside of that, but you don't make any other change.

Do you see them get better? We do. So, I think that you would do better if you fix what they eat inside that eight hours, too. But, if you take their diet and just squish it into eight hours, I think that like we see people get better, like we see people change a lot because as I said, we did sort of one meal a day where we squished it even further.

And those people basically, they didn't even change their diet that much. We talked to them about it, but we didn't focus a lot on it. And if you actually probably were to ask them, my guess is their diet didn't change a huge amount. But just by squishing the time that you're eating, you're sort of forcing people away. And I think part of the issue is that in the old days,

like in the 70s, what you had was a fairly lengthy fasting period anyway. That's why you have the term breakfast, right? So you eat dinner at 6 p.m. and you eat breakfast at 8 p.m. And it's 14 hours of fasting as your baseline, right? And that's every day without even thinking about it. Now it's kind of spread, right? Satch and Panda has done all these studies of how long people actually eat. And it's like,

you know, constantly the minute they wake up to the mini-guitpads, almost 15 hours a day that people are eating. I think that's gotten so bad that when you squish it back to a normal sort of 16, 8 sort of thing, because 14 hours and 16 hours, like 14 hours was sort of baseline in the 70s and 16s just a little bit. but because it's gotten so bad when you squish it back into that, we do see a lot of people who benefit just from that one intervention alone. And, you know, to me, it's always about practicalities. That is, is it easier? So if you have people, for example, say, two strategies.

One is counting carbs, which I think can work versus counting the number of hours that you don't eat. It's like it's so much easier to tell people between 12 and 8 is you're eating window, everything else, don't eat versus look at everything that you eat in the day, try and calculate how many carbs it is and add it up so that you have some arbitrary less than, right, less than 120, less than 50, less than 20. It's so difficult, whether you're counting calories or whether you're counting carbohydrates or doing macros, right?

It's just so difficult to do. It's so much easier to say things like only eat between this hour and this hour and don't eat anything that came in a box kind of thing, right? Those, to me, that's practical useful advice, as opposed to say, let's get your carbs from 55% to 40%. It's like, it's so difficult. It's just, and I'm not saying that it can't work. I think it can work. I just think it's so hard to implement when you're seeing patients sort of every few minutes, right? Like how are you going to do that from a practical standpoint, right? It's not feasible. I completely agree. I mean, I think there is no simpler instruction than when to eat and when not to

eat. And yeah, I think, you know, combining these things can often be incredibly potent. I don't know, I've seen mixed results on 16, eight truthfully. I've seen some patients who have really significant improvement. I've seen other patients experience no improvement whatsoever. We typically will push that window tighter 186, 222. Again, the tighter you push it, the more benefits you see, but I've really seen no substitute for what I call intermittent fasting. We use that terminology very distinctly. We reserve the term time restricted feeding for up to 24 hours of restriction, but we use the term intermittent fasting to describe what I think that term means, which is you

intermittently, periodically, i.e. fast. And fasting can be a complete reduction of calories, or it can be a hypochaloric fast. So you can consume somewhere between 20 and 40% of your normal cholera requirement for a period of time. Typically look at three to seven days and you repeat that cycle. What type of protocols do you use for intermittent fasting with your patients? We use all of them, so because we're predominantly clinical, we'll individualize. So the things we take into account is one, how severe is it? So severe type 2 diabetic on a huge amount of insulin, we're going to give a more stringent

schedule than somebody who's just sort of pre prediabetic and wants to sort of prevent it from getting into diabetes. So the other thing is how old they are and how willing they are to do it. So we see a lot of people who are in their 80s. We have people in their 80s doing like, you know, we had a lady who was like, I think she did 61 days, right? And she's not young, right? And we have people in their 80s.

Nothing. Yeah. That's what she said, although sometimes when you actually go into it, sometimes they have little things here and there. But she said she did 60 when we have lots of people who do long fast like that and they don't have any problems. We monitor them very closely though, but generally we don't do that. There's no point taking that much risk a lot of times.

She actually just felt good on it, so that's why she did it. But we don't usually push it long like that, but we will if we need to. But it depends on how quickly, so it's how severe is it, how old the patient is, and how urgent it is, because we have people who have a ton of disease, right? And we're like, if you don't get this diabetes fixed like right now, you're going to be in a world of trouble. So we had this guy, he's actually in his 40s. He had a non-healing diabetic foot ulcer for like a year, followed by a plastic surgeon. So he actually came into the hospital and I saw him because I was seeing him for his diabetic

foot infection, gave him antibiotics. I said, you know, your problem is not your foot. Your problem is your diabetes, right? Because, you know, the reason you have this foot ulcer is because of diabetes. You don't get foot ulcers if you is your diabetes, right? Because, you know, the reason you have this foot ulcer is because of diabetes. You don't get foot ulcers if you're not diabetic, right? Unless you have severe PVD or something, right? But the point is that if the diabetes was just causing your foot ulcer, you got to get rid of your diabetes. I talked to his dad because this guy was like in his 40s. And his dad was Greek orthodox. So his dad was like, oh yeah, let's do this. So

we put him on and we put him in fairly strict restriction. We started him, I think, on a week of fasting and then 36 hours, three times a week. And that also healed like within three weeks. It was like ridiculous how quick that thing just healed up. You led with a single week of fasting before cycling 36 hours weekly, or did you lead with the 36 hours? No, I started with the seven days, and then we did like 36 hours, because it was severe. Honestly, he was going to get his foot chopped off at some point. You're definitely more aggressive than I am because you're seeing much sicker patients.

I never lead off with water-only fasting for. Usually, what we do is we go, we push the windows of time restriction, which, as I said a moment ago, I'm not convinced there's huge benefit in time restriction. I think there's some benefit. I think the biggest benefit of time restricted feeding is the psychological one. It's breaking the cycle you just described earlier, which is people think intravenous access to food is essential for life. If they go more than two hours without a meal, the sky is going to fall. And so in many ways, time restricted feeding is just a way to prove to them that that is

total nonsense. I actually think that the long fast do exactly the same thing. Well, yes, yes, yes, but you can't, you can't lead. I mean, at least for me, I haven't tried leading off with that. Talk me through like that particular patient. So first of all, let's grant it that he now has agreed to try this. This is a patient who is not entering a fast the way I would enter a fast, which is I usually spend a week in ketosis before the fast, which means I'm showing up in a fast with a ketone

level of somewhere between 0.5 and one millimolar of beta hydroxybutyrate. I sail generally pretty easily into these fasts, not all the time. This is a guy who's got a respiratory quotient of one. He is a completely obligate glycogen consumer. He's probably not oxidized if fatty acid since guns and roses were popular. This is a guy who's going to be in for a world of hurt when you strip food away from him because within a few hours he's going to sense.

His liver will sense glycogen levels are low. It's time to eat. So how are you getting him through that? There's no easy way. We just tell him this is like going to sock for a week because you're not gonna feel that great You're gonna be hungry and all this sort of stuff It was the urgency and I'll tell you that people actually can do it You know quite a lot of people have we've done it on a number of people and most of the people as long as you warn them ahead of time

That it's gonna to be tough, they get through it. But the thing is, the psychological, if you've done a week, you know that 24 hours is like nothing. And you get into ketosis so fast, because that's the fastest way to get into ketosis, right? It's just too fast. There's no faster way you can do it than that. So it's not easy, but there's reasons why.

And that's why I say it's important that everything is individualized because I'd never do this to somebody who's like 40 and has an A1C of like 6.0. It's like why put the yourself through that, right? Do it gradually, you have no time restrictions. This is a guy who's actually coming into the hospital with diabetic foot ulcers that we're getting close to osteomyelitis, right? It's like it's a much different situation than not, right? I'm trying to make sure that somebody doesn't wind up, he doesn't wind up getting a bad infection and somebody wind up chopping his foot off, which is why I was super aggressive in that case.

I've heard stories of other people who have put patients on starting sort of 10-day fast and so on, so they don't all do well. They don't all get through it, but it's an option. That's all I'll say. And I hate to be prescriptive like, oh, you have to do this, you have to do this. And this is what seeing patients does to you. I find that the people who are super dogmatic

are the people who never see patients. Yeah, I can't agree with you more. Yeah, because patients always prove you're wrong. You think your stuff works Well, like 40% of your patients it doesn't work in right? So then I'm like I'm not very like oh you have to do this You have to do this because it's like yeah, I know it doesn't work like like carb restriction like some people It really does work well and some people it really doesn't work that well and the study show show the same thing, right? Chris Gardner's study. If you look at the display between low fat and low carb, some people do grade on a low fat diet and some people do terribly on a low fat diet. It's the same diet, same with a low carb. In general, the low carb people

do better. But when you look at the individual differences, and that's why people get on, get on Twitter and they they start talking about oh It's all about this or it's all this all this and then I like I know you don't treat people because if you actually treated people You'd never say stuff like that you'd never get on somebody about Taking the opposite position because you've been proven wrong so many like every day I'm proven wrong like something doesn't work and that's why I'm always like Let's do this see if it works if it doesn't work We're gonna adjust it and then if it works better than we're gonna keep doing that and we'll adjust it right and that's

That's where the kind of art of medicine comes in so you can start but to me I always tell people like there's two options when you do fasting You it's like going into a pool you can wait in or you can cannonball in right and It's like going into a pool, you can wait in or you can can in ballroom. And both are acceptable. One's a big shock to the system, but it works and the other is not as big a shock and it still works. For this particular patient, you know, that was one of the few, few times because most

of the time it's not that urgent that I did recommend, oh, you just got to do this. And his father was on board and he was on board and we monitored him super closely. We actually started him in hospital because he happened to be in hospital anyway, so I put him on clear fluids, right, and then just told him, don't take anything with sugar, just water. And he did very, very well. And I've done it to a few other people with diabetic foot ulcers as well because I considered that one of the more difficult.

That's something that you really have to take care of. I always think diabetic foot ulcers, to me, is fascinating because it's like, if you think about this overflow paradigm, it's like, why do diabetics get these infections that nobody else gets? Why do you get mu-cormychosis? Why do you osteomyelitis? Why do you get diabetic foot ulcers? You don't get foot ulcers from ischemic cardiomyopathy foot ulcer, right?

You don't get that. A schemic cardiomyopathy, you call mycosis. And it's like it's because what you're doing is you're putting all this sugar into the body. Then when the blood glucose goes up, you give them insulin to really jam that sugar into the body, right? And the body takes it and your liver gets all this sugar

and starts sending it all over the place. Pretty soon, your whole body is so full of sugar that everything just starts rotting. And that's why you get the kidney disease, that's why I get the eye disease. And that's why the bugs just love it because there's so much sugar and nutrients everywhere. So they get in your foot and they never go away.

Those foot ulcers never heal. You get these weird infections that you never see anywhere else. You get the, you know, the rashes, the incantosis and all that. It's just you got way too much sugar. It's all about the whole body sugar and not just the blood sugar. That's the real shift in thinking in paradigm that to me makes a lot of sense. And as soon as we're able to empty out all that sort of sugar, and I always use the analogy of a sugar bowl. We're just filling up the sugar bowl. You've got to empty that sugar bowl,

and then the sugar won't spill out. And that's why it works. And the fast thing is the same thing. So we'll individualize it. So based on all those sort of factors, like including what they want to do. You've got to talk to people and say, what are you willing to do? And a lot of people aren't willing to do a long fast, but a lot of people are actually

it's striking. What percentage of your patients are willing to do a water only fast for at least a period of three days? Right off the bat, because we offer this as a treatment to everybody. We don't say, okay, well, if you've never heard of it, it will still recommend it. And like 50% right off the bat won't do it any fasting at all, right? There's so like and grain. I had this discussion yesterday with a fellow. I told him, oh, he needs to fast. He was, he was developing, you know, prognoria and he was going into renal failure. And I said,

really, you need to fast. And he says, my endocrinologist says I can't fast no way. So it's like okay, that's it right there. So 50% of people won't fast for any period of time at all. Like not even like five hours, right? So it's changing. I think views on fasting are changing. But you can see like, you know, did you read that whole thing with Jack Dorsey? He gets on CNBC or whatever and everybody goes like crazy that, oh, he doesn't eat for 24 hours. It's like, what's the big deal? Like, why do you think we carry body fat, right? And it's like, look, he's looking good.

He feels good. What's the big deal? Why are you getting on him, right? But the idea is so ingrained that we have to eat, have to eat, have to eat, even to lose weight, we have to eat that. They won't do it. So if you take away the 50% who won't do it right off the bat, then you have people who will do it for a short period of time. And probably only about 20% might agree to like a longer fast, mostly. And it's not the physical side that actually

gets them. It's always the psychological side. The physical stuff is super easy to deal with. It's the psychological part that's really hard. That is when you're looking at somebody who's eating and you're trying to fast. It's like really hard, right? And yeah, you can do it once in a while, but if you do it sort of breakfast lunch dinner, breakfast lunch, that's the hard part. And that's where we focus a lot of our attention working on the psychological

How to set your environment up for success and coming up with different strategies for success and creating a supportive Community that's gonna help your success. That's the hard part because think about religions like Ramadan How do they all fast because people say oh, I could never fast It's like but you know that literally hundreds of millions of Muslims fast. It's like, it's because the environment is supportive. If all your friends are doing it and all your family, it's not fun, but it's not that difficult to actually do it. And that's the difference. And now we're recommending it for people who have no community. And that's what we're trying to create community of people who are accepting. And also that's part of the point of bringing it into the main stream. I wrote a couple of books about this, of course, and that's the point. If I wrote a couple of

articles that I sent to Jama or something to get peer reviewed, first of all the peer review would kill it. And then second of all, you'd get no traction whatsoever. And then you're not doing anybody any good because by making it sort of more out there, you make it more acceptable for people to talk about it and to accept it as a viable treatment. So let's go through some of that stuff.

So let's say that 40-year-old patient, first of all, appreciates the severity of what you've shared with him and his dad, which is, look, it's one thing to have diabetes, which you do, but you're actually in quite a late stage of this. If you're, I mean, I don't remember the literature on this, but from my days in surgical training, the five-year mortality once you have an amputation with type two diabetes is staggering. So I don't remember what it was, but it was so high that the point was, once you're getting a toe amputated

or a foot amputated or something like that, the probability you're going to be alive in five years is incredibly low. So I can be wrong on this, but I feel like the five-year mortality was something like 70%. So if you're in your 40s and you're already getting a diabetic ulcer

that's not healing, there's a non-zero chance. There's actually a significant chance you're not going to make it to your 50th birthday. So he says, I'm in. You mentioned something that I think can't be overstated, which is you have to be in a supportive environment. So if a patient tries to fast and they are surrounded by people, both their friends and family and also their other medical practitioners who are telling them this is a horrible idea.

Well, that's a recipe for failure. So now, let's posit that we've also got the support of the medical team and the friends and family. What are some of the other tricks and trades? I mean, one of the things that I hear a lot about is Peter, my sleep is really hard when I'm fasting. How do you address that? Yeah, that's a tough one one because they all can't sleep. There's not that much to do. We tell them

one to expect it. So it's one of the things is that if they know about it ahead of time, then they're much more accepting. So we say, look, you may have a lot of trouble going to sleep because people don't understand but the whole sympathetic nervous system and everything that's revved up, right? Nor adrenaline and all that stuff gets revved up. And a lot of people actually can't sleep and we say, well, you know what, if you find that, then you know, stay up, do some work and so on and don't worry about it, right? This is a temporary situation.

It's not going to last forever. We just want to make sure that everything gets better. And that patient, I don't think he had any sleep trouble, but we did warn him. So one of the things we do is we warn him ahead of time of all the potential problems. So it's like the book, what to expect when expecting, right? So it's not like it makes the symptoms any better, but it makes dealing with it a lot better. So we tell him, hey, look, you can have headaches.

Those will go away. You can have cramps. This is what to do. You can have diarrhea. This is what to do. You can have constipation. This is what to do. It's sleep is, you know, you can expect this. And you need to watch this in terms of your blood sugars

and so on. And this is what to do with your medications. And that patient, we actually, I think, has last anyone see that we saw, was like 5.9, which here is actually classified as non-diabetic, not even pre-diabetic. So we took them from a couple of medications and a non-healing diabetic ulcer to non-diabetic. Like within a couple of months, yeah, it took a little bit longer than somebody else. And everybody responds differently.

And even a couple years later, he's like non-diabetic, right? So it's like, that was the whole point. We miss, you know, in medicine, it's so difficult because we're so ingrained into these patterns of thinking that is, you have obesity, which causes type 2 diabetes, which causes a foot ulcer. So we get the plastic surgeon to divide the ulcer. It's like, that's the least important part. You need to get rid of the diabetes and get rid of the obesity, and then he will actually

get better. So warning people ahead of time is one thing that we do, and it doesn't make the problem any better, but it makes them deal with it. One, they trust you because they go, oh, hey, I got a headache for three days. And then it went away. So they know what you're doing, and that gives them confidence. And then just having that support. So he had his father, of course, who was going,

yes, yes, yes, you need to do this. And that came from his religion. So it was a good setup for that. Many times, we'll actually get the opposite, which is, what you're saying is that I'll get that patient actually get the opposite, which is what you're saying is that I'll get that patient. I'll say, this is what you need to do. The family says, oh, man, that's crazy.

And the family doctor says, oh, man, that's crazy. And the endocrinologist says, you must never do this. Then nothing changes, right? They have this and so on. My tip on this one, Jason, is that in anticipation of that sympathetic outflow, we recommend that patients take phosphatital serine with the fast in the evening, and that sort of calms down the adrenal glands. And then even just an oral over-the-counter GABA, unfortunately, it's becoming harder

to get centrally penetrating GABA over the counter, but even just peripheral GABA will sort of take down some of that sympathetic tone. So that coupled with some other sort of sleep supplements actually not only tends to help people sleep, but a number of people note that you can have some of the best sleep imaginable with those lower levels of glucose, higher levels of ketones. Now, what about electrolytes? How do you manage the electrolytes in particular sodium and magnesium during these longer fasts? There's nothing specifically we do, actually.

So, we monitor it very closely, of course. Magnesium is the one. So, everybody worries about sodium, and you can get some people who do get a bit sodium depleted. But if you're otherwise healthy, your kidneys should never get to that state, because there are people from the intersalt study, there are people that actually barely eat any salt at all and still survive fine. So your body should be able to reabsorb all the sodium it needs. Minesiums a bit more difficult because a lot of type 2 diabetics are depleted of magnesium to start. So we'll often recommend magnesium supplements and that's where a lot of the cramps and so on kicking. Some people do get a little dizzy and so on so that's

when we use the bone broth which is technically not a fast but it's like got calories and amino acids and stuff. But that's where we'll use bone broth for example where you can put a decent amount of salt in and take it and still feel well. We monitor the electrolytes more just because we want to make sure that nobody is getting into trouble, but I'll tell you that the number of times that I've actually had to intervene or tell somebody to stop, the fast because of electrolytes is like zero, I think I don't think I've ever had a case where the blood work came back and said, oh my god, they have to stop. There are some other things like if they get diarrhea, for example, and it can be fairly significant, then that might

play a role. But you know, when they get those, we tell them to stop. And we are always like, you know, we're always super cautious because we monitor them very closely. These are relatively sick patients, right? So they generally have a lot of medical issues, but we monitor them very closely. We give them very careful instructions that, hey, if you don't feel well, you need to stop right away. Don't even tell me, stop it, and then tell me, right? Because the point is that you can,

let's figure out what's going on, then if it's a solvable problem, then we can do it starting tomorrow, or we can do a totally different regimen shorter, fast more frequently. We're not stuck to this one thing or we can do ketogenic diets or we can do something else, right? There's all kinds of things that we can do without doing a long fast and some people actually hate the long fast and some people actually love the long fast. So we always say, don't get so rigid in your thinking that you have to push through. Like the one thing we tell people more than like, don't just push through because that's when you're going to get yourself into trouble. There's always tomorrow to start another fast if we figure out what's going on with this.

Don't you find it's helpful to explain what you're pushing through? I mean, for example, even if I fast for seven days, there is no day during that seven when I am not at least at one point quite hungry. Oh, yeah, the hunger, for sure. We always say you can be hungry, but make sure you're not like lethargic or something. I think it's important for patients to understand even seasoned fasters still get hungry. But what I find interesting in my wife who doesn't fast but is sort of interested in like why I do it, she can't believe it right, she can't believe that, you know,

I'll work long hard days and exercising to all that stuff while fasting and she's like, aren't you just starving? And I said truthfully, yes, every single day, I feel quite hungry at some point in the day, but it's never more hungry than on a regular day if I'm getting really hungry. Like, being hungry on the seventh day of a fast is not a more profound hunger. It's the anticipation of that that becomes problematic, which really speaks to the Shakespeare quote about, nothing is either good or bad, but thinking simply makes it so. The anticipation of that hunger seems to be a bigger problem. Maybe for your patients, it's less of

a concern because the highest priority is the amelioration of the diabetes. But do you spend much time thinking about how they can minimize muscle mass loss with the obvious loss of protein intake, or do you just say, look, it's so intermittent that we do this fasting that we're going to take whatever we have to take in the most catabolic sense and then deal with it on the back end. Or do you do anything specifically with respect to exercise? Nothing specifically, because again, I'm treating different populations, like I'm not treating bodybuilders, right? I'm treating 65-year-old women.

For them, it's like they don't even know how much muscle mass they have. And honestly, I'm not even sure. There is some protein loss, and I'm not sure that's a bad thing. I think that most people actually don't get a lot of muscle loss. You can get protein loss, which is connective tissue and skin. And this is one of the things that people always rag on me about. But this is clinical medicine. So I've treated thousands of people with fasting. And some have lost a lot of weight, like hundreds of pounds. And I've documented a few case studies in my blog and stuff. And one of the things that's very unusual about fasting

for weight loss, as opposed to weight loss for other things, is that we don't see the skin problems. Because skin is protein, like it's not fat, skin-connective tissue is protein. And you do go when you do the intermittent fasting, you do go through that period where you have gluconeogenesis and you're breaking down protein. That's the whole point of autophagy, for example.

It's breaking down protein. It's not fat, and I'm not sure that it's bad thing. So we actually get much less. I've never referred a patient for skin removal surgery and some people have lost like 150 pounds for years, right? And they actually don't notice the problem. Couple of my colleagues who I work with, and they've noticed the same thing,

that you don't have as many of the problems that you do with regular sort of weight loss, which is chronic calorie restriction, where you get these big flaps of skin that you have to go insurgically and take out. The question is, why doesn't your body get rid of them? Because it's superfluous. Your body shouldn't be keeping it around.

Your body should be getting rid of it. And it doesn't. Because you never went through this period where you're undergoing gluconeogenesis where you actually are breaking down protein. So do you get more muscle loss? There's been a couple of studies on alternate daily fasting, which really haven't shown increased muscle loss or lean loss.

I think that the protein loss is often confused and called muscle loss. To me, it makes no sense. Like, your body has a system, and I'm not talking the situation where you have 4% body fat, right? I'm talking about a situation where you have 30% or more body fat. It makes no sense that the body should store food energy as glycogen and body fat, but the minute you need to use it, you start burning muscle. Do we think our bodies are really just that stupid that they're going to do that? It's like storing firewood for the winter,

and then as soon as you need to use it, you chop up your sofa and throw it in the fire. Like who would do that? But we think that our bodies are just that stupid. Like I don't think their bodies are that stupid. I think that there's a period, which is fairly limited, during the fasting where you have gluconeogenesis, then you can see fat oxidation goes way up, right?

And Kevin Hall, I think, did some of these studies on what happens, and K-Hill, of course, did all those studies on what happens during actual starvation. You gotta remember that he was no wimp, right? These are like 60 days of fasting, right? Not like 16 hours. It was huge, and these people were not even overweight.

It was, you know. There are some studies that you just think, wow, how did they get away with that? There's before the days of the IRB. There's a great study. I don't know if you've seen this. There's two studies where they took people who were not even overweight. They fasted them for 60 days and gave them a big slug of insulin. It's like, why? It's like just to see what would happen. Well, no, no. I mean, that study was to actually see if the ketones were protective in the presence

of hypoglycemia. They injected those patients with insulin, took their glucose down to below one millimolar. These people just were walking around with it. Yeah, they did totally fine, provided they had enough BHB. That's an incredible. Yeah, it is incredible, but you'd never get that study done today. You'd get thrown out, like you'd get laughed at by the higher B. Like you're going to drop people's glucose to less than one. Like are you serious? Everybody now thinks if you don't eat for 24 hours, you can get seizures, right? But the point is that yes, it was for the ketones and stuff,

but it's a great study. Like, it's stuff that you just couldn't do these days, but the amount of proteins, so when you look at all the K-Hill studies and all the classic studies are fasting, that's a relatively limited period that you're actually burning, you've got the gluconeogenesis and you're burning protein,

which I actually think is a beneficial thing in the right situation where you have somebody with obesity and so on. And if you look at studies, like Nathal did a bunch of these studies where you have somebody with obesity and so on. And if you look at studies, like Natal did a bunch of these studies, and he tried to estimate how much excess protein somebody who is overweight has, like 20 to 50% more protein than a regular person. There's more skin, there's more muscle, there's more connective tissue,

there's blood vessels, there's all kinds of extra protein that goes along with being overweight. And that all needs to go if you're going to, if you're going to do it. So I'm not actually, I'm not actually worth it. Like so again, I've treated a few thousands of patients with type 2 diabetes. Remember, I'm not talking about the guy who has 4% body fat and is a body builder and can tell how much muscle he has based on how much he can live. I'm talking about the 65-year-old person with a lot of body fat and generally excess protein. In that case, the question is, how many patients have I had to stop because I was worried about

muscle loss? That would be like zero, right? In six years. And because I use it in a therapeutic manner, that is I'm not treating one person a week's worth of thing, right? It's like every person who comes in every 10 minutes, I'll say this is what you need to do, this is what you need to do.

So it's just part of my clinical practice. So it's like hundreds of patients a year and over six years, it's like thousands of patients. Like zero people had to stop because I was worried about muscle loss, right? So it's like, okay, tell me how that is going to be a big concern to me, right? And this is where again, it's like, people who don't fast, and people rag on me

all the time about this, right? It's like, oh, what about this, what about this? I'm like, okay, how many thousands of patients have you done this for? Try it on several thousand patients, and then come back to me and tell me if Muscle loss is the most important thing for this 65 year old 300 pound man on 150 units of insulin. It's a totally different situation. The last question because I know you've got to get back to clinic. We've taken you away from it.

Do you think there's a role for this type of fasting in people who are actually healthy, but looking to get benefit that goes beyond getting rid of a disease they don't have. In other words, if you take a person who's not hyperinsulinemic, i.e. insulin sensitive by these definitions, though, we made a pretty good case that everybody's insulin sensitive without a lepidistrophy. But you take a non-obeast, non-diabetic, non-naffled the insulin sensitive, non-hyperinsulinemic individual who's asking the question, will periodic fasts reduce my odds of chronic disease down the line?

How do you feel about that? Absolutely, yes, because look, the point of fasting is to lower insulin levels, right? So if you fast and you're healthy and you're not hyperinsulinemic, well, if you do periodic fasting, it doesn't have to be a long time or, you know, even that frequent, right? So if you look at the 70s, right? A typical person who is eating three meals a day, 14 hours of fasting every day, and then once a year maybe on Yom Kippur or during Lent or during Ramadan, they'll have a little bit longer fast. But there are times he's eating a lot too, right?

Christmas and all this sort of time. So that's just the balance, right? It's all about balance. This is the whole point is that you have to balance periods where you have going to take a lot of food like Christmas. You're eating, you're eating, you're eating, you're eating, you're eating. Now you want to balance that with, like, Lent, where you have going to take a lot of food like Christmas. You're eating, you're eating, you're eating, you're eating. Now you want to balance that with like lent, where you're just not going to eat a lot because that's what they told you to do. So this is what's going to happen is that you're going to drop your insulin levels periodically,

which will prevent you, right? It's going to clear out all that sugar every once in a while and then prevent you from getting diseases of hyperinsulinemia. So if you drop your insulin every so often, you're going to prevent yourself or lower your chance of getting diseases of hyperinslenemia, which are heart disease, stroke, cancer, Alzheimer's disease, type 2 diabetes obesity. Well that's the major risk of our current population.

So you want to lower your risk of getting those great. Like you're not going to lower your risk of getting pneumonia. Like you're going to lower your risk of these diseases of hypersylenemia. So for a healthy person, yes, I think fasting is very beneficial, but you don't have to do five days of fasting every month or something like that, right? You could do a little bit longer fasting once in a while and maybe not do some bedtime snacks and stuff. But you don't buy the argument then that, for example, Valtralongo's FMD, which is a type of intermittent fast.

I know you know what it is, but you know, listener might not. So, you know, this is one of literally a hundred different ways you could fast, but he would suggest that based on a certain set of macronutrients, you're consuming about 1000 calories, followed by 750 calories for four days, and that gives you a five-day cycle, and he talks about doing that quarterly, and would argue that there are actual longevity benefits, even in the non-diabetic or non-metabolically ill person. Again, I think for some

people that sounds really extreme. Personally, I don't think it's that extreme. In your patients, that doesn't seem extreme. It's actually fairly routine for a lot of people that we talk to, but again, it's a different patient population. For healthy people, I think that their, like, the data is just not there. So prevention of Alzheimer's, prevention of cancer, treatment of autoimmune diseases, for example, of altars talking about sometimes, I don't think that there's enough data to say yes or no. Like, could it work? Absolutely, it could work. I actually think that there's a good reason to think that these things will work to prevent a lot

of those diseases, like not necessarily. So of course, to me, all the diseases of excess of growth and hyperinsulinemia, to me, are clearly you're going to reduce your risk. But now you're talking about other diseases, like autoimmune diseases. And I think that there's good reason to think why they might work. But is there data to show it? Not really. Yeah, this gets back to the first point of, will we ever have evidence-based guidelines to support this? I think it's impossible, not improbable.

And therefore, we are stuck thinking about this through mechanistic lenses. Yeah, but see, the thing is that, again, people have it all wrong because people say, okay, so say they're talking about a five day fast once a quarter or something like that. Whether you do fasting, mimicking or regular fasting, let's say somebody says you should do five days of fasting once a quarter or once a year.

Okay, so the evidence-based medicine people are always way off because they say there is no evidence to suggest that five days of fasting once a year is beneficial. They're right, but they're completely wrong from a clinical perspective. Because there's also no evidence that five days of fasting a year and a person who's normal weighed and otherwise healthy is harmful to you. So now you have to say, what is the risk

of doing that five days of fasting? So five days, so in a year, you will eat three meals a day, one year you'll eat a thousand meals, for five days you're gonna make 15 meals out of a thousand. That's it. That's the extent of what you're doing. What is the risk of that? I'll tell you it's just about zero. Like, yeah, you're going to be hungry and stuff, but if you're otherwise healthy, the risk is very, very, very low. And then you say, what is the benefit? Well, there's not really any great evidence of benefit either. But because your risk is so low, your risk to reward ratio is pretty reasonable. Why wouldn't

you do it? That's the question because the risk is so low. Maybe there's no benefit. Maybe there is a benefit. I can't tell you, right? And it's the same for all drugs. You know that there's a certain number needed to treat. So a number needed to treat a 50 means that 49 out of 50 people simply do not benefit from that drug that you gave them. And it's going to be the same for fasting. There's going to be one person who benefits and 50 people who don't benefit. But the risk to reward, because when you give a drug, the risk starts getting so high that the risk to reward ratios, they don't make sense. But for something like fasting, missing 15 meals out of a thousand?

Yeah, it can make sense. And that's why all these sort of EBM's allits are all like, oh, there's no evidence, there's no evidence. It's like, you don't need evidence. It's assessing the risk and the reward and what clinically makes sense. To me, if I had, for example, some kind of autoimmune disease. So let's take this disease, rheumatoid arthritis, that there's no evidence that fasting is going to do anything

for, and Dr. Longo says, well, you can reset your immune system if you do seven days of fasting. What would I do? I would absolutely do it, as opposed to taking a bunch of toxic drugs like prednisone, like you've seen what prednisone does to people, why would I do seven days of fasting? The risk of that is zero.

Say I don't get any benefit from that. Then I don't have to do it ever again. But what happens if things get a lot better? I've just treated my own disease. The reward can be so high, but you don't have to guess at it. You can just at it. You can just do it.

Speaking of risk, there's some, in my opinion, kind of weak epidemiology suggesting that skipping breakfast will increase your risk of gallstones. How often are you seeing that in your practice? A lot of people have gallstones, so I don't see an increased risk, but on the other hand, it's going to be tough because the problem is that people who follow a low fat diet, of course, they're gallbladder. You don't need bile, right? You need bile to emulsify the fat, so therefore your gallbladder just sits around with all this stuff and you get sludge and so on. So I think the low fat diet can certainly predispose

you to stones. Then you start eating a higher fat diet and then it's squeezing out and you're getting stones. I don't see it clinically as a problem. I think what caused a lot of the problems was probably the lower fat diet because you're simply not getting the flow, the enter a hepatic flow. Like the bile supposed to come out. It's not supposed to sit there, but when you get rid of all the fat, it just sits there. That's just the balance. Our body makes it, sticks it in the gallbladder so that when you eat fat you can squirt a little bit of it out.

Now we think we're so much smarter than our body which has survived for millions of years that we're gonna eat zero fat and just have all this Stuff this sludge just sit in the gallbladder because you never took it out. Like how does that make sense to me? It makes no sense Well on that note we are at exactly the time when I know you need to get back to clinic. So I want to thank you greatly for your insights both at what I would say are hugely paradigm challenging level, especially as it pertains to insulin resistance and hyperinslenemia. And then also at the boots on the ground, clinical level, I know that very few people have the experience treating patients with fasting protocols for type two diabetes.

And I think you're doing fantastic work. So thank you very much for that. Thank you. You can find all of this information and more at pteratiamd.com forward slash podcast. There you'll find the show notes, readings, and links related to this episode. You can also find my blog at peteratiamd.com. Maybe the simplest thing to do is to sign up for my subjectively non-lame once a week email

where I'll update you on what I've been up to, the most interesting papers I've read, and all things related to longevity, science, performance, sleep, et cetera. On social, you can find me on Twitter, Instagram, and Facebook, all with the ID, Peter, ATIA, MD, but usually Twitter is the best way to reach me to share your questions and comments. Now for the obligatory disclaim. This podcast is for general informational purposes only and does not constitute the practice of medicine,

nursing, or other professional healthcare services, including the giving of medical advice. A note, no doctor-patient relationship is formed. The use of this information and the materials linked to the podcast is at the user's own risk. The content of this podcast is not intended to be a substitute for professional medical advice, diagnoses, or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition they have and should seek the assistance of their healthcare professionals for any such conditions.

Lastly, and perhaps most importantly, I take conflicts of interest very seriously for all of my disclosures. The companies I invest in and or advise, please visit peteratiamd.com-forward-slashabout. dot com forward slash about.