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

00:00:00.000 Hey, everyone. Welcome to the Peter Atiyah drive. I'm your host, Peter Atiyah. The drive

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00:04:11.700 My guest this week is Dr. Jason Fung. Jason is a nephrologist in Toronto, Canada. Many of you

00:04:16.960 listening to this podcast probably already are at least familiar with him just for another reason

00:04:21.580 through social media or other channels. He's quite a vocal critic of the conventional approach

00:04:28.200 to treating type two diabetes. And he also has, in my experience, at least one of the most

00:04:34.280 significant clinical practices that utilizes fasting as a treatment for metabolic disease.

00:04:40.640 I've known Jason relatively informally for quite a while, but I've gotten to know him better in the

00:04:44.900 past year and was really looking forward to doing this interview because I certainly get asked a lot

00:04:50.240 of questions that I think Jason would have great insight into. He's the author of several books,

00:04:55.900 including The Obesity Code, The Diabetes Code, The Complete Guide to Fasting, and The Longevity Solution.

00:05:01.320 He's the co-founder of the Intensive Dietary Management Program. Jason graduated from the

00:05:07.340 University of Toronto and completed his residency at UCLA. In this episode, we talk about a lot. We

00:05:13.640 actually kick it off with a discussion I didn't plan to get into, but I thought it was really

00:05:17.640 interesting, and I hope you do as well, about evidence-based medicine and the difference between

00:05:22.100 taking two scientific disciplines, one of medicine and biology, the other of physics, and comparing

00:05:27.000 and contrasting some of the differences. I sort of make an argument around theoretical versus

00:05:31.660 experimentalists and things like that, and talk a little bit about nephrology. What took Jason into

00:05:36.580 that field, and why is being a nephrologist, a doctor who specializes in kidney disease, why does that

00:05:40.820 give him a quite unique insight into kind of the early indications of metabolic disease? And then we get

00:05:48.620 into the meat of this thing, which honestly, I think this is one of the most interesting discussions I've

00:05:52.480 ever had on insulin resistance. And you've listened to this podcast, you've heard me talk about that a

00:05:57.040 lot. And I think Jason's take on this, quite frankly, is probably the smartest thing I've heard.

00:06:01.960 Now, that doesn't mean that I necessarily agree with everything, and that doesn't mean that there

00:06:05.380 aren't holes in these arguments. But his explanation for why a concept of insulin resistance, which is

00:06:12.880 very difficult to explain when you try to parse it out into tissue-specific effects of insulin,

00:06:18.040 he has a much better explanation for this that clinically makes more sense and ultimately results

00:06:25.100 in a much more logical treatment plan. So once we go through this discussion of what people call

00:06:30.960 insulin resistance and come away with this idea of hyperinsulinemia, for which, by the way, he has a

00:06:36.020 great example using a suitcase that I'd never heard before, but I took the liberty of bolting onto it as

00:06:40.440 much as possible. So by the end of this, you might be sick of hearing about suitcases. And we talk a

00:06:44.240 little bit about NAFLD. And then we close the discussion. So if there's sort of a final part

00:06:49.300 of this, it's getting into the clinical stuff, the use of dietary restriction, including ketogenic

00:06:54.800 diets, carbohydrate restriction. But most of what we talk about pertains to fasting. And I think that

00:06:59.460 that's where a lot of people are going to be kind of interested. Jason has a very different approach to

00:07:03.120 fasting than I do in my practice. And I think that probably stems from the fact that I'm not treating

00:07:09.040 patients who are nearly as sick as Jason. So in that sense, he has to be a little bit more extreme

00:07:15.500 out of the gate. And to listen to some of the clinical wisdom that he brings to this is, even

00:07:21.080 for me, quite informative. So I hope you enjoy this discussion with Jason half as much as I did.

00:07:28.740 There's so many things I want to talk about with you. And I would say that you are among the three

00:07:33.660 people, top three certainly, that on social people are always saying, when are you going to

00:07:38.100 interview Jason? When are you going to interview Jason? And of course, we had planned to do this

00:07:41.900 in December in person. And that's when I had my whole dental calamity that required like tooth

00:07:49.320 extraction after secondary tooth extraction. So I never made it up. So anyway, I'm glad we could do

00:07:54.360 this. And I appreciate everyone's patience with this. But I guess the broader point is, I think people

00:07:58.700 are so interested in speaking because of all of the work you've done around fasting, insulin

00:08:04.320 resistance. And just overall, I mean, you're a clinician on the front lines. I mean, you know,

00:08:08.760 it's one thing to sort of pontificate on Twitter. It's quite another thing when you actually have to

00:08:12.220 show up in clinic and see hundreds of patients as you do.

00:08:15.540 Thanks. I mean, I think that's one of the things that I think distinguishes me from some of the other

00:08:21.340 people that are out there is that the stuff's got to work. Otherwise, it just ain't worth it, right?

00:08:26.400 Like you can talk all you want about this and that. But if it doesn't change management,

00:08:31.360 then it doesn't interest me particularly because that's where I come from. And I think this is

00:08:36.880 where a lot of people get sort of, they see these academics and they say, okay, well, they know

00:08:41.440 everything about this. It's like, well, they might know everything, but if it doesn't work on the

00:08:44.700 front lines, it's not worth anything. And I think this is an attitude I see like in physics, which is,

00:08:50.920 I know you really look up to Richard Feynman, as do I, but I actually love the whole story of,

00:08:57.020 you know, Einstein and Niels Bohr and all that because physics to me is sort of like, I love

00:09:02.860 that because the way they do science is so much better than we do in medicine. That is to say for

00:09:11.540 in this specific instance, for example, if you have all these theories, they're great, but if they don't

00:09:17.700 agree with experimental evidence, it ain't worth anything, right? And they say this in physics,

00:09:24.020 but they don't say this in medicine where it's like, okay, you think that, you know, eating lots

00:09:30.480 of carbs is really good for you, right? You have this hypothesis that eating less fat and tons and

00:09:35.720 tons of refined carbs is good for you. And that's a great theory. It all makes sense. And the same

00:09:40.260 thing with calories, right? It sounds like if you just cut calories, it makes sense. But if your theory

00:09:45.060 doesn't work, then it's not a good theory. And this is what they say in physics, which they don't say

00:09:51.180 in medicine. And in medicine, it always like boggles my mind how these bad theories go round

00:09:56.800 and round and round because they make sense, but nobody's actually put them to the test or nobody's

00:10:02.700 pointing out these things. And it's the same with insulin resistance. I think actually, to me, the

00:10:06.940 most important topic is sort of insulin resistance, because again, that's what I deal with as a

00:10:12.720 nephrologist. I see a lot of type 2 diabetes. That to me is completely sort of misunderstood. And the way

00:10:19.680 we think about insulin resistance is sort of totally wrong. And that's why we have the sort

00:10:25.400 of mess that we have, I think. Well, we're going to get to that for certain. I'd definitely like to

00:10:30.680 build on what you've said. Yeah, there's a beautiful demonstration of what you described. It's a video

00:10:35.940 from either Caltech or Cornell, I can't recall. So it was either right before he had left Cornell or

00:10:41.060 after he had arrived at Caltech, where Feynman is at a blackboard. And he is explaining the scientific

00:10:45.360 method in about as elegant a way as you can, which is to basically say what you did, which is this is

00:10:50.940 the scientific method. You make a guess, you design an experiment to test the consequences of that

00:10:55.840 guess, you do the experiment. And if the output of that experiment aligns with your guess, the hypothesis

00:11:01.920 turns out to be likely correct or more likely to be correct. And if it doesn't, you go back to the

00:11:06.000 drawing board. And the simplicity with which one of the most brilliant physicists of the 20th

00:11:10.020 century explains that is not lost on anyone who watches it. And I would agree with you

00:11:13.320 completely. I've gotten into trouble by saying this before, but I guess, I guess on your podcast,

00:11:17.300 you can sort of say what you want, but I'm generally suspect of people who have very,

00:11:23.640 very strong points of view on things in biology or medicine who no longer interact with patients.

00:11:31.320 Doesn't mean that they're wrong, but I'm generally suspect because of that, because the other thing

00:11:35.020 is biology is harder than physics. The reality is just a lot messier. And sometimes people ask me,

00:11:40.240 you know, do you think you'll always see patients? And the answer is yes, I think so. And I hope so

00:11:44.300 because they are kind of a humbling tool. Every time I think I've really got it figured out, I'll

00:11:50.380 always meet a patient who proves me wrong and they're obviously right. And I'm wrong.

00:11:54.020 And I think the other part about physics, which I love is that the way they think about it is that

00:12:00.600 there's, you know, a theory like Newton has a theory, for example, and it explains a lot. It's a

00:12:06.100 great theory and everything. But then there's these anomalies and the anomalies are what drives

00:12:12.040 sort of science forward because you have to come up with a better theory that explains the anomalies.

00:12:18.720 And if you come up with a better theory, they make these wild predictions. And if these wild

00:12:22.720 predictions are true, you know, this new theory can sort of supplant it. So the way Niels Bohr and

00:12:27.760 the quanta supplanted sort of Einstein, even though he was brilliant. So the point is that that doesn't

00:12:33.100 happen in medicine. In medicine, we have this super laborious process of evidence-based medicine

00:12:38.520 where instead of saying, hey, here's a theory that makes more sense because it explains everything.

00:12:43.280 What they do is they say every single point, they go, where's the evidence? Where's the evidence?

00:12:47.380 Where's the evidence? So that's why nothing ever moves forward. Like I do the same thing in

00:12:51.980 nephrology that I did 20 years ago when I was doing my training. It's like, what was the last advance

00:12:57.800 we had, right? It's, it's like, so from so long it were like most of the advances in medicine,

00:13:04.660 for example, come from like aspirin. It counts for like 50% of the progress we've made. It's sort

00:13:10.820 of ridiculous. Whereas physics sort of moves, you know, at light speed because they don't demand this

00:13:17.100 sort of evidence-based. And I always say that, you know, evidence-based medicine is good if you know

00:13:22.460 how to apply it, right? Because the whole point of evidence-based medicine is that it's not a search

00:13:27.900 for truth. It's a search for consensus. And it may or may not be true, but if you have a crazy theory

00:13:34.300 and then you send it out to five people and they say, well, it's crazy, it gets killed. So if you

00:13:39.700 have like a theory, hey, the earth goes around the sun, not the sun goes around the earth. You send it to

00:13:45.260 a consensus of peers. They say, no, no, no, no. Clearly the, you know, the, the sun revolves around the

00:13:50.480 earth. That would never have made it through. So the evidence-based medicine is not everything.

00:13:54.980 Like you have to understand where to apply it. And this is where I think we've gotten into so much

00:14:00.840 trouble is that every sort of advance moves glacially because we sort of demand that things have to

00:14:09.560 have evidence. So something like fasting, for example, which I always get into trouble a lot

00:14:14.580 too, right? I get into tons of trouble for calories. Everybody attacks me for all kinds of stuff,

00:14:19.420 but fasting five years ago was the dumbest thing you could do. Right. And I'm like, why? Like,

00:14:25.220 it doesn't make any sense that it should be so bad. Right. So I thought about it and I went through

00:14:31.480 it and then I just brought it immediately to patients, right? Just treated hundreds and hundreds

00:14:35.740 and hundreds of patients. And the results like amazing. And of course, if you don't eat, you're

00:14:40.060 going to lose weight. If you don't eat, your diabetes is going to get better. Right. So it worked.

00:14:44.060 And that was the point. Like, you got to get to that point where it's like, and then everybody

00:14:48.280 says to me, oh, where's the evidence? I'm like, why do I need evidence? Like people are getting

00:14:53.820 better. Right. I'm not a researcher. Right. You can come up with the research, but just try it on

00:14:59.240 people. Look at it. But all these people were saying, oh, there's no evidence. There's no evidence.

00:15:03.080 Clearly, it's bad. And that's where everything just sort of bogs down. You get all these people

00:15:08.980 who sort of demand that every sort of little step has to be based on consensus. The consensus

00:15:16.480 moves so slowly that you can't move. You can't move like Einstein moved. You can't make those

00:15:21.520 sort of intuitive leaps forward. That always bothers me a lot.

00:15:27.120 Well, it's sort of a problem. There is a distinction, right? In physics, I think,

00:15:30.460 broadly speaking, and again, physicists will sort of bristle at the simplicity with which I'm saying

00:15:35.040 this, but you can generally divide the field into the experimentalists and the theorists.

00:15:39.420 And that's what I think allows the step function changes and understanding. So Einstein's advances

00:15:45.700 were theoretical. So the experimental evidence to support these things came after, but yes,

00:15:50.720 many times the big steps forward come on the basis of theoretical propositions. And we don't really

00:15:57.660 have that in medicine and biology. We don't have experimentalists and theorists. I've thought a lot

00:16:03.260 about this actually, and I didn't intend to go down that rabbit hole, but there's a whole separate

00:16:07.400 podcast, by the way, on this topic of how could you change biological research to take some of the

00:16:13.880 advantages that we see in the physical sciences where you can create a symbiosis between the theorists

00:16:19.960 and the experimentalists. The last thing I'll say on this point, by the way, that I agree with you is

00:16:24.080 the real challenge of exclusively relying on evidence-based medicine is that framework is very good for

00:16:32.180 certain problems. It's actually quite good for problems that are rather acute, for which the

00:16:39.340 interventions to address them are rather simple, and for which you will get an answer quickly. So in many

00:16:46.540 ways, the pillar of evidence-based medicine is infectious disease. If you think about how much we have

00:16:52.900 learned through evidence-based medicine with respect to the treatment of HIV and frankly, most infections,

00:17:00.180 it's remarkable. I mean, we've really got that dialed in. But again, if you take a step back and

00:17:05.040 look at those criteria, well, infections are quite acute typically, very easy and binary to measure

00:17:11.880 progression. The interventions are simple. Take this medication, don't take this medication.

00:17:16.520 That's much more complicated than, well, I want you to exercise a certain way for this period of time,

00:17:21.480 or I want you to eat a certain diet for a certain period of time. And then the resolution can be

00:17:25.580 to whatever metric it is, whether it be T-cell count or amelioration of the clinical infection,

00:17:29.780 that occurs really quickly. So you're right. I mean, I think evidence-informed medicine is probably a

00:17:35.840 better way to think about it. But yeah, someone like you is, you know, you're really on the forefront

00:17:41.520 of using your best ethical judgment to say, look, I'm going to bring something to a patient population.

00:17:47.020 The other thing I want to add, by the way, while I'm on my soapbox that you helped me

00:17:51.100 stand up onto, is people are very quick to say, well, you don't have the evidence to support

00:17:56.600 fasting for a patient with type 2 diabetes. And you can say, okay, that's true. So there is a risk

00:18:02.240 that if this patient with type 2 diabetes goes on a fasting protocol, something bad could happen.

00:18:07.520 But what people in medicine I find are very, I wouldn't even say quick to forget, I don't even

00:18:12.300 think it registers, is what's the risk of not doing something? The risk of doing something is

00:18:17.820 usually more in our forefront. It's that risk of not doing something that people often forget.

00:18:23.200 And if the risk of not doing something is stay the course, slowly, slowly increase the amount of

00:18:29.100 insulin this patient requires, slowly, slowly watch the micro and macroscopic vascular disease progress,

00:18:35.840 well, that risk's actually, that's a pretty bad risk.

00:18:38.360 Well, that's absolutely true. And it's like, this is the point that I always made to patients. It's

00:18:42.980 like, if you keep on doing what it is that most doctors do, including myself, right? I used to just

00:18:49.180 give people tons and tons of insulin. I know what is going to happen. And everybody acknowledges that

00:18:54.080 you'll just get worse over time. And it was just sort of accepted. And it's like, there's the risk of not

00:18:59.600 doing anything, right? But if you suddenly change, you know, bring an intervention like fasting or low

00:19:05.200 carbohydrate diets, ketogenic diets, or whatever, there's a risk of doing it. Sure, we don't know

00:19:10.460 what the risks are. But you know, the risk of not doing something. And that's the virtual certainty

00:19:14.960 that you're going to in 10 years, go on dialysis or something like that, right? And that's not an

00:19:20.140 insignificant risk. It's actually a huge risk compared to doing fasting, which has been done

00:19:25.100 for 1000s of years. And I always say like, look, like the problem with evidence based medicine and

00:19:29.900 consensus and stuff. Look at look at what happened with the low carb guidelines. So as you know, a couple

00:19:34.940 days ago, the American Diabetes Association came out with sort of new guidelines. And they said, hey,

00:19:41.040 low carbohydrates, pretty reasonable. It has the most evidence behind it. It's like five years ago,

00:19:46.500 they're persecuting dieticians for giving low carb advice, right? It's like, you know, the human body

00:19:52.440 hasn't changed in the five years that it took for you to realize that, right? And that's where you're

00:19:57.340 doing patients a real disservice by having these sort of expert opinions, guidelines, right, where

00:20:06.100 people can't decide for themselves. Like, as a dietician, you can't decide for yourself that you want to

00:20:11.400 be low carb, because five years ago, they would have run you out and persecuted you, right, taken away

00:20:16.560 your license. And today, like as of sort of two days ago, you're actually falling completely within

00:20:23.160 American Diabetes Association guidelines, right? So it's like, this is a big problem.

00:20:28.620 The flip side, I guess that's progress. And we'll take it, right? You know, I've said this before, it's sort of

00:20:32.340 one of my little tongue in cheek comments. But you know, all facts have a half life. And some of those half

00:20:37.420 lives can be quite short. But it is interesting to see this, because it's been about 10 years that I've been

00:20:41.640 paying attention to this. And these things typically do occur on five year cycles, both through the ADA,

00:20:46.820 the AHA, and then in the United States, obviously, the USDA also, I guess, in fact, gosh, it's hard to

00:20:51.620 believe we're coming up to 2020. This time next year, we'll be dealing with a new set of dietary

00:20:56.020 guidelines, which I don't want to think about. So let's change gears for a moment. You're a

00:21:00.560 nephrologist. So for people listening, that means you specialized after doing your training in internal

00:21:06.800 medicine, you then subspecialized to double down on one particular organ, a beautiful organ called

00:21:12.760 the kidney, which give us, you know, a little bit of a sense of like, what is it about the kidney that

00:21:17.220 is so special, because it is a pretty special organ? You know, in internal medicine, everybody

00:21:23.400 sort of divides themselves into types, right? So in medical school, it's interesting, because you have

00:21:29.520 the jocks who go into orthopedics, right? And then you have the really sort of touchy feely people,

00:21:34.480 and they go into family medicine and pediatrics. And internal medicine generally attracts a lot of

00:21:40.280 people who sort of like to think about things. And then within internal medicine, you have the sort of

00:21:45.420 subdivision into the different types. And generally, when at least when where I was going to school at

00:21:51.220 the University of Toronto, the nephrologists were always the ones who like to think about things,

00:21:56.620 because that's all we could do. We can do we couldn't do a lot about it, like, you know, you stick

00:22:01.460 people on dialysis, and so on. But they like to think about problems like puzzles, like electrolyte

00:22:07.740 problems and stuff. So you have this low sodiums and low potassiums and what's happening in the kidneys,

00:22:13.300 because the kidneys do a lot in terms of homeostasis, they keep track of, you know,

00:22:17.720 they keep the sodium in check, and you keep the proper amount of water and salt and potassium and

00:22:23.220 calcium in the body. So it's fairly complex, but it's a specialty where people like to think as

00:22:29.000 opposed to like GI, which was towards the sort of action oriented people who like to scope and,

00:22:33.800 you know, snare things out and stuff. So that was really what attracted me to nephrology,

00:22:40.900 really, was that that's sort of my my personality is I like to think about stuff. I like to work out

00:22:46.660 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

00:22:53.220 sort of why I chose nephrology. And I wound up doing it at UCLA. I do enjoy it. And when I say there's not

00:23:00.220 a lot we can do, what I mean is that up to a certain point, kidney disease, you can treat them,

00:23:06.400 but there's really like two treatments, right? There's prednisone, and then dialysis. And the

00:23:12.860 last time we had a drug that actually slowed down progression of kidney disease was like the ACE

00:23:18.860 inhibitors in the 80s, right? It's been a long time since things changed. And just now we have

00:23:24.520 the SGLT2s for diabetic kidney disease. Before that, it's like nothing. So there wasn't a lot to do,

00:23:30.020 but there's a lot to think about. So that's sort of what I liked about it.

00:23:33.260 And the kidney, I mean, every organ is unique in its own way, but one of the things that I

00:23:37.400 recall being sort of blown away by in medical school was how smart the kidney was. You don't

00:23:43.800 think of it as a particularly intelligent organ. You think of it as, well, it's just a filter,

00:23:46.940 but there was a very clever design in evolution, which said rather than the kidney learning what

00:23:54.940 is bad and figuring out a way to always get rid of things that are bad, it was the opposite.

00:24:00.920 It was learn what is good. And when you throw everything out during the first passive filtration,

00:24:07.280 just learn to pull back the good because the probability that the good things are going to

00:24:11.540 change is low. The probability that you'll see new bad things is high. And so I remember the

00:24:16.420 nephrologist sort of standing there saying, look, it would be tempting to think that the kidney would

00:24:21.700 operate like it's going into your sock drawer to pull out just the right sock, but it doesn't.

00:24:26.560 It pulls out all of the socks and puts back the right ones. And that always sort of stuck

00:24:31.560 with me. One is a pretty interesting statement of just how important it is to have that system

00:24:36.200 working. And the second thing is how small the organ is and yet what a high fraction of

00:24:42.680 our circulating blood volume passes through it. And as you build on that, which gets to some

00:24:48.580 of the stuff we're going to talk about today, why the kidney is such an early warning indicator of

00:24:54.980 disease either through high blood pressure or high glucose. I mean, is it safe to say that some would

00:25:01.240 argue that the eyes are generally the first place you can see evidence of that disease of either high

00:25:06.420 blood pressure, high glucose, but the kidneys would probably come in pretty close as well, wouldn't

00:25:10.980 they? Oh yeah, absolutely. So the thing about the kidney is that they get like 20% of the entire

00:25:16.260 circulation of the body. So it's a huge amount of blood that goes through. And then the amount that

00:25:21.480 comes out through the glomerulus, which is the sort of functional unit of the kidney is huge. So

00:25:26.120 basically they take everything out and then sort of put it back in. So that's why they can fine tune

00:25:31.560 it so well. But there's a huge amount of fluid that goes through the kidney sort of all the time,

00:25:36.420 even though a trickle comes out as urine, like it's filtering like 10 times more than that. So you might

00:25:43.840 have a liter of urine a day, but you're filtering way more than that every single minute, truthfully.

00:25:49.060 So it's an incredible system. And the reason that the eyes and the kidneys are such early warning

00:25:54.580 indicators is that the eyes is the best because you can actually directly visualize. It's the only place

00:26:01.060 you can directly visualize the blood vessel. But the glomerulus, which is, you know, you have about a

00:26:06.360 million of these glomeruli in the body, but they're basically a big bag of blood vessels.

00:26:12.460 So if you're going to have diseases of the blood vessel, which turns out to be where these metabolic

00:26:18.500 diseases impact each other. So the heart disease and kidney disease that comes later on, but there's

00:26:24.660 so many blood vessels in the kidney that it gives you this sort of early warning. So the first thing

00:26:30.060 you generally see in terms of diabetes or high blood pressure, you start to see this protein that

00:26:35.040 appears in the urine. So you can measure it, something called the albumin to creatinine ratio,

00:26:39.800 and you can actually see it. So when you start to get increased urinary albumin excretion,

00:26:46.060 what you know is that there is damage to the vascular system just because the vascular tree

00:26:51.980 is like so, so big there and you can directly measure it. So if you were to go to your liver,

00:26:56.960 for example, there's nothing you can measure, right? So it's got a big vascular. So the lungs have a big

00:27:00.840 vascular system, but you can't measure anything. Whereas the urine, you can actually directly measure it

00:27:05.360 and the eyes, you can directly see it. So that's why they come out so early. So increased urine

00:27:10.120 albumin excretion is actually a very, very strong correlation to heart disease. Not because having a

00:27:15.800 bit of urine is so bad, but it tells you that there's something bad going on in the blood vessels

00:27:20.540 of the kidney, which tells you that something bad is going on in the blood vessels of the body.

00:27:25.160 So that's why looking directly into the eyes is useful and measuring the urine is very useful.

00:27:30.600 Yeah. And because my skills for looking into patients' eyes are not good enough that I can

00:27:35.640 reliably do that, I have in the past three years really started to pay much closer attention to

00:27:41.520 cystatin C creatinine along with microalbumin for exactly this reason, because it sort of occurred to

00:27:46.960 me in a momentary insight that if my interest is in longevity, which means trying to figure out a way

00:27:52.380 to get people to outlive what their expected time course is, one of the most important organs that

00:27:59.440 gets neglected is the kidney. And if you are in your forties, but you already have a glomerular

00:28:06.180 filtration rate at 80% of what would be predicted, you have to fast forward a little bit and say,

00:28:11.920 well, what's that going to look like when you're 80? The net implication to me has been a much greater

00:28:17.400 focus on blood pressure, even sort of stage one, so slightly elevated blood pressure that I think

00:28:23.420 many physicians until recently probably just weren't thinking of as a significant enough problem. But

00:28:28.520 once you do start looking at that microalbumin and that cystatin C, as a non-nephrologist,

00:28:34.260 we get a little bit of a window of insight into your world. And there are a lot of people walking

00:28:40.820 around. I mean, a staggering amount of people walking around who on the surface, just based on

00:28:45.120 their creatinine, look pretty normal. But a slightly deeper look says, no, actually they're not normal.

00:28:50.440 They are compromised. And it won't be clinically relevant for 30 or 40 years,

00:28:54.440 but that's going to be relevant. The thing is that there are no symptoms. So I see people all the

00:28:59.960 time with diseases like IgA nephritis, which is the most common sort of primary kidney disease in the

00:29:06.760 world. And they will not know it and they will have lost sort of like 95% of their kidney function

00:29:13.260 by the time I see them, just because they never knew they had a problem because they never checked it.

00:29:17.940 So it's very silent in that way. You just don't know you have a problem unless you start looking

00:29:23.260 for these things. And that's why it's important to sort of keep an eye on the urine. It's so easy

00:29:28.260 to write. It's non-invasive. Anybody can do it. Well, let's talk about this thing called insulin

00:29:34.740 resistance because there's two broad, broad topics I want to explore with you today. And I can see no

00:29:41.500 better way to approach them than in this order. Let's start with the problem statement and then let's

00:29:46.500 start to talk about the treatment. So I will confess at the outset, Jason, that as it's been

00:29:53.060 nine or 10 years that I've thought about this problem, I still have a hard time explaining to

00:29:58.800 somebody, certainly if I only have the duration of an elevator ride, what insulin resistance is

00:30:05.100 because I get tempted to get into, well, it means this thing in this type of tissue, but this thing

00:30:09.880 in this type of tissue and blah, blah, blah. So let's not hold you to the standard of you've only got an

00:30:14.040 elevator ride to explain it, but how would you explain it both to maybe a lay person, but then

00:30:20.740 even at the level of nuance that we could sort of have a rigorous discussion about it?

00:30:25.300 This is really what I think is the sort of most important problem in medicine, which is the metabolic

00:30:31.120 syndrome and insulin resistance. And the whole way that we sort of think about it, I think, is

00:30:37.460 completely wrong. I'll kind of step back and say, let's start with what we think is insulin resistance

00:30:43.300 and taking this physics approach. What's wrong with it? What parts of it don't fit the sort of

00:30:49.020 experimental evidence, if you will? So when we talk about insulin resistance and sort of, I'll just step

00:30:54.880 back a bit and say, okay, what do we think about insulin resistance the way I was taught about insulin

00:31:00.720 resistance, which I'll tell you, I think is completely wrong. And probably you were taught the same

00:31:04.760 thing, right? So the way we think about insulin resistance is we think about it only in terms of

00:31:09.960 the glucose, right? So insulin is a hormone. And when insulin goes up, it allows glucose from the

00:31:18.460 blood to go into the cell. So we know that. We know that GLUT4 receptors go, it goes into the cell

00:31:23.600 membrane, glucose goes in, and now the cell can use it. So the reason we call it insulin resistance is

00:31:29.420 because we know that there are normal levels of insulin as opposed to type 1 where there are low

00:31:34.980 levels of insulin. There's normal levels of insulin, but the glucose is not going into the cell for

00:31:39.140 some reason. And when you measure the blood glucose, for example, it's very high and there's insulin

00:31:44.980 around. So if insulin is around, why can't the glucose go into the cell? And this is why we say,

00:31:51.200 hey, if there's insulin, then the cell must be resistant to the insulin. This is insulin resistance.

00:31:57.780 This is the sort of lock and key paradigm that we talk about. So insulin is a hormone. It acts on the

00:32:04.500 insulin receptor, which is on the cell surface. And the insulin receptor is like a gate. So there's a

00:32:11.080 door, there's a lock. Insulin is like the key. So it opens the door and therefore the glucose can go

00:32:17.400 from the blood into the cell. The cell has energy to use. So we can measure insulin. We can also look at

00:32:24.580 insulin receptors. You can sequence it and you can tell there's actually nothing wrong with them. So

00:32:28.700 insulin receptors are completely normal. Insulin is completely normal. So what you say is that,

00:32:33.640 well, there must be something that's gumming up the system. So like a piece of gum that's sort of

00:32:38.580 stuck in that lock, it's gumming up the things. You have a normal key, you have a normal lock, but when

00:32:44.260 you put the key in the lock, it doesn't really work. And then therefore the glucose can't get into the

00:32:49.380 cell. And the cell is now facing a internal starvation. And the internal starvation is why

00:32:56.480 we give insulin to move the glucose into the cell. And that's our current thinking, or at least what I

00:33:02.280 was taught and what most people still think about insulin resistance. But it's almost completely

00:33:07.560 incorrect. And there's no possible way it can be correct because there's a central paradox of insulin

00:33:14.600 resistance, which is that insulin has actually many, many different functions, only one of which

00:33:22.720 is letting glucose into the cell. So for example, we know in the liver that insulin is responsible for

00:33:30.240 de novo lipogenesis. That is, if you have a lot of carbohydrates, glucose, it will build it into

00:33:38.240 glycogen. And that is working fine. If there's too much glucose after the glycogen is full, it's going

00:33:45.200 to turn it into triglycerides or fat. And that is working fine. So de novo lipogenesis is working fine.

00:33:52.740 Let's take a state of type 2 diabetes, which is we acknowledge is a high insulin resistance.

00:33:58.060 How can it be that you have a liver cell, which can't let in the glucose, so it's resistant to the

00:34:05.140 insulin. Yet the other effect of insulin, which is de novo lipogenesis, is not only working fine,

00:34:12.100 it's actually going over time, right? You can measure de novo lipogenesis and type 2 diabetes.

00:34:18.000 It's super, super high. And what about the mitogenic effects of insulin? So insulin is a

00:34:24.540 growth factor. You can measure it, for example, with large for gestational age babies. And you say that

00:34:30.320 a woman is insulin resistant, yet insulin is actually doing what it's supposed to do. It's actually

00:34:34.500 stimulating a lot of growth. So there again, insulin is super sensitive. Or say, testosterone. We know

00:34:41.960 insulin has effect on testosterone and PCOS. And there, it's working again, not just normally,

00:34:48.460 like super high. So in the liver, you have this sort of central paradox where you say in the same tissue

00:34:55.320 to the same levels of insulin, you have both resistance and super sensitivity. Like that's not

00:35:04.900 really possible. It's the same cell, same thing. But people call it selective insulin resistance.

00:35:11.060 So that's sort of the central paradox of insulin resistance. And it doesn't really make any sense

00:35:17.340 that this can be the way.

00:35:19.960 And Jason, I would just add an even simpler observation to that, which I've always struggled

00:35:24.420 with, which is a very common phenotype of insulin resistance is adiposity, obesity, meaning obesity,

00:35:31.300 which of course means the accumulation of fat in a fat cell. So a fat cell is getting bigger.

00:35:35.200 Well, for a fat cell to get larger, it needs to incorporate triglyceride. To incorporate triglyceride

00:35:42.400 requires insulin. And to keep insulin in the fat cell requires insulin to prevent lipolysis.

00:35:49.560 And so on the one hand, you say, well, this patient is insulin resistant. We'll talk about

00:35:55.160 which cells, you know, maybe the muscle is insulin resistant, but at the very least looking at the

00:35:59.120 fat cell, it appears to be quite well insensitive to insulin, right?

00:36:03.480 Exactly. And it's the same thing with de novo lipogenesis. And that this is why I say,

00:36:07.780 we know that de novo lipogenesis in this state of insulin resistance is taking sort of glucose and

00:36:14.040 turning it into fat. And then the liver sort of exports this fat as VLDL and triglycerides. Well,

00:36:21.600 the thing is that if you have internal starvation of this liver cell, that is the glucose cannot get

00:36:27.260 into this liver cell. How on earth is this liver going to package glucose and turn it into fat?

00:36:34.880 Because we know that is happening. But where's this glucose? Like it's taking glucose, making it

00:36:40.660 into fat. But you're telling me with this paradigm that no glucose is getting in, you're facing internal

00:36:46.820 starvation. I mean, it's like making a brick wall with no bricks. It's just impossible. But yet this

00:36:52.780 is the paradigm that we face, this internal starvation paradigm. And you look at the person,

00:36:58.160 you look at a type 1, untreated type 1 diabetic, where there actually is no insulin. And they're

00:37:04.360 like a stick. So if you've ever seen some pictures, these type 1 diabetics could not gain fat no matter

00:37:09.700 how much they ate. Then they, you know, they peed out all their glucose, then they died. That's not

00:37:15.500 what it looks like in type 2 diabetes, in insulin resistance, because type 2 diabetes is a disease of

00:37:20.540 too much insulin resistance. So there's no way that is possibly true. So what you have to come up with

00:37:26.320 is a different sort of a new paradigm of thinking about what insulin resistance actually is. And

00:37:33.300 this is one of the things that, you know, why I say physics always appeals to me, because that's where

00:37:39.080 you can come up with a new theory, which explains all these sort of paradoxes much better. And that is

00:37:45.060 that it's not a sort of underfill problem. It's an overflow problem, because there's two possible

00:37:52.760 ways. So we say they're insulin resistant, because the glucose does not go into the cell. That's the

00:37:59.260 whole reason we say it's insulin resistance, lock and key paradigm, the gate is closed. But there's

00:38:04.860 actually two reasons why that glucose might not go into the cell, because either the door is closed,

00:38:11.740 or it's already too full. That is, if you have a cell that is already bursting to the seams with glucose,

00:38:19.120 that glucose from the blood simply can't get in. So this is a totally different paradigm than this

00:38:26.880 sort of internal starvation paradigm, because it's an overflow paradigm, but it solves the problem

00:38:32.100 of the central paradox. That is, why is this liver cell making so much new fat from glucose? Because it's

00:38:41.800 jammed full of fat. The glucose from the outside cannot go in, but the liver cell is so busy trying to,

00:38:49.100 make new fat, de novo lipogenesis, that is just shoving it out the door. But there's too much

00:38:54.240 going in. So the problem is not insulin resistance per se. The problem is hyperinsulinemia. That is,

00:39:01.720 in the first place, it was all this insulin that put all this glucose into the cell, but you're putting

00:39:06.380 so much into the cell that it's too full. I use an analogy. Like, suppose you have a suitcase,

00:39:13.460 and you're putting your shirts in your suitcase, which is fine. And your wife says, here, put these

00:39:17.460 shirts in, you put it in, that's fine. And then at some point, your wife says, here, put these two

00:39:21.560 shirts into your suitcase, but you don't put them in. Well, why don't you put those two t-shirts,

00:39:26.920 last two t-shirts into your suitcase? Either the suitcase doesn't open, or it's just full.

00:39:33.220 There's two possibilities, and they're completely different.

00:39:36.420 Or to extend on that analogy, you could say, well, you're just not listening to your wife.

00:39:40.540 What you're basically saying is, look, the conventional view here is,

00:39:44.240 when your wife said, put these two shirts in your suitcase the last two times, you just decided,

00:39:48.960 I don't want to, eh, you know, I don't want to do that. But what if there's another approach? What

00:39:53.260 if you're fully well and willing to put those last two t-shirts in the suitcase, but when you open up

00:39:58.100 the suitcase, there is simply no more room. The output looks the same, excess shirts outside of the

00:40:05.240 suitcase, right? But the reason could be entirely different. Exactly. But the implications are huge,

00:40:13.780 because the thing is that if it's just the fact that you're not listening to your wife and you're

00:40:18.740 not putting the t-shirts in, then the solution is for somebody to grab those two t-shirts and just

00:40:24.040 shove them in, right? And that's what we did with type 2 diabetes, because we said the glucose can't

00:40:30.480 get into the cell. What we need to do is give you exogenous insulin, sometimes huge doses of exogenous

00:40:37.400 insulin so that we can shove the glucose, ram it down the throats of the cell that's for some reason

00:40:44.520 not listening to us, right? But if it's an overflow paradigm, the implication is completely different

00:40:51.880 because the solution is to get rid of the sum of the stuff that's in your suitcase, right? So if you

00:40:57.520 bring it back to insulin resistance or hyperinsulinemia, then the solution to trying to get rid of this so-called

00:41:05.920 insulin resistance is not giving more insulin, because that was the problem in the first place.

00:41:11.680 Putting those shirts in the suitcase, that was the problem in the first place. So putting more in is

00:41:15.380 not the solution. The solution is to get rid of it. So the solution is to empty that cell of glucose.

00:41:23.500 That's the whole solution, which is a totally different paradigm than what we've been taught,

00:41:28.120 right? Because we use sulfonylureas, we use insulin. Based on just trying to shove more glucose into

00:41:35.100 this already filled cell. And it solves a problem. It explains the paradox of, I tell you the whole

00:41:41.600 thing. It actually goes much further. But it solves a problem of this central paradox of why

00:41:48.260 it's making testosterone, why the insulin effect that the is so high, right? Why do you get PCOS?

00:41:53.760 Why do you get the mitogenic effects of insulin, the growth effects of insulin? Because you know that

00:41:58.900 insulin is a growth factor. It has huge implications for cancer, for example. So breast cancer,

00:42:03.820 colon cancer, very insulin sensitive, much higher rates in type 2 diabetes and obesity. So you're

00:42:10.060 getting the cancer causing effects of the insulin, but yet you're saying people are insulin resistant,

00:42:14.820 the fat and the whole thing. It solves the problem of why you're having continued de novo lipogenesis,

00:42:21.100 even in the face of this so-called resistance, because you actually have too much. It's not just a

00:42:26.200 theoretical thing. It actually has huge implications for the treatment because your treatment now has to be

00:42:32.320 getting rid of the sugar, getting the insulin down.

00:42:35.660 So let's pause for a moment and talk about the treatment. So I want to just sort of synthesize

00:42:39.440 this for the listener because what you're suggesting is quite radical. Let's be honest,

00:42:44.000 right? The conventional view is, going back to your analogy, which I love by the way,

00:42:47.700 is that after your wife asking you enough times to put more t-shirts in, you stop doing it. And the

00:42:54.320 consensus view is you just stopped doing it for some reason. You're not sensitive enough to her

00:42:59.340 request. You're being an insensitive guy. Look, that's an easy thing to understand. You're just

00:43:03.760 an insensitive guy. Well, the current approach is your wife walks over and opens the suitcase and

00:43:11.600 gets a few of her friends and your friends to help jam those t-shirts in there. Because if you had

00:43:17.340 enough people and you could put enough weight on the t-shirts, you could probably sneak a few more in,

00:43:21.680 right? In other words, if you had more insulin, or another analogy would be she yells louder is

00:43:26.320 probably a better analogy, right? So if her polite request is insulin, then raising her voice is more

00:43:32.420 insulin than yelling and screaming. And then by the end, she's going to like take your favorite

00:43:36.720 football and throw it at your head. And at that point, you're mainlining insulin into the patient.

00:43:41.800 Let's talk a little bit about some of the other drugs because most of the approaches to type 2

00:43:46.820 diabetes pharmacologically are not actually aimed at reducing glucose. Metformin is one of the very few

00:43:54.200 drugs. You mentioned the SGLT2 inhibitors, which I want to come back to. So we'll carve out the ones

00:44:01.160 that actually lower glucose, but most of them are trying to amplify the noise. So walk us through

00:44:07.720 the classes of those drugs. So we have the sulfonylureas, which stimulate insulin, and there's

00:44:13.280 insulin, which stimulates insulin. And the DPP-4s, for example, which are also similar in terms of they

00:44:19.600 increase insulin. This is more than incretins, but they increase insulin basically.

00:44:24.200 So the classic response of the older class of medication, so I'm going to leave, so metformin,

00:44:31.680 I'm going to leave aside because that's actually a totally different thing. SGLT2s is the sort of

00:44:36.120 newest class, but the old ones are all about increasing insulin. So that's your wife screaming

00:44:41.820 louder at you to shove more shirts in. And this is the thing. So if you do that, so say you give

00:44:47.660 somebody a sulfonylurea and you start shoving more, you know, your wife starts yelling at you. So you

00:44:52.460 start shoving more t-shirts in. At first, you can do it. But as you keep doing that, the problem just

00:44:59.720 keeps getting worse and worse because at first it's a little full, then it's a lot too full. And then

00:45:05.940 what happens? Well, even if she's yelling at you really loud, you still can't put any more in because

00:45:12.540 you've now, you're just way over the limit. So this is what happened in the body. Because look,

00:45:19.260 if we look at the way we treated type 2 diabetes sort of 20 years ago, it was to give

00:45:24.160 sulfonylureas, then insulin, then more insulin, then more insulin. You're just shoving more shirts

00:45:29.360 into that suitcase. And the cell is getting more and more glucose and it's getting more and more full.

00:45:35.120 As it gets more and more full, the insulin resistance gets worse and worse. So what do

00:45:41.040 you do? You keep going up, you keep going up. And guess what? That's exactly what happened.

00:45:45.080 But if you think about it, if you have a patient who 10 years ago was on one drug and now they're

00:45:50.320 on huge doses of insulin, that diabetes never got better. The sugars might have gotten better,

00:45:55.900 right? But the actual disease itself of type 2 diabetes never got better. It only got worse.

00:46:03.760 And that's the reason we say it's chronic and progressive because the treatment

00:46:07.600 was completely incorrect. We did the wrong thing. We kept putting more shirts in when we should have

00:46:14.120 been taking shirts out. We kept putting more glucose into the liver, which is what insulin does,

00:46:19.440 right? Instead of taking all that glucose out of the liver. It was the wrong thing. That's why people

00:46:25.780 got worse. That's why we could never show any benefit to tight glucose control in type 2 diabetes.

00:46:32.440 That's why the ACCORD, the ADVANCE, the VADT, and all those trials failed because they're

00:46:38.900 working on this incorrect paradigm of insulin resistance. This is the lock and key paradigm.

00:46:46.200 So now we have a drug class, which does something completely different. So this is the SGLT2s.

00:46:52.180 Before you go to that, Jason, I'll just add another point to this because I know I discussed this with

00:46:56.500 Jake Kushner several months ago, but it's important to revisit this in case folks have either forgotten

00:47:01.360 that or didn't listen to it. I want to emphasize what you just said a second ago because you said

00:47:06.340 it's sort of like, yeah, we all know this, but it's such an important point, right? When diabetes

00:47:11.260 trials are using glycemia as their endpoint, meaning how low can you get the hemoglobin A1c,

00:47:20.100 how quote unquote tightly can you control the glucose, they do seem to have some benefits.

00:47:25.260 Anything that is macrovascular does seem to get a little bit better. So where glucose at high levels

00:47:33.520 causes problems, those things seem to get a little bit better. But where glucose at modest levels in

00:47:41.340 the presence of high insulin, sorry, at the micro, I said macro, I meant microvascular, but the opposite

00:47:48.040 is not true. So by taking someone's average glucose from 200 down to 150, that would be considered

00:47:53.220 a huge win in a diabetes trial if you took their glucose from 200 down to 150. And that benefit

00:47:59.000 might show up in their kidneys. But if you had to double the amount of insulin you gave them to do

00:48:04.420 that, it turns out at the macrovascular level, for example, heart and brain, they don't get any

00:48:11.020 better. In fact, they might get worse. I remember the first time I sort of saw that about three years

00:48:16.800 ago, it was a big aha moment, which is why aren't they getting better? And that's sort of when I

00:48:22.860 began to think about hyperinsulinemia itself. I mean, maybe it was longer than that, but not that

00:48:28.060 long ago, right? It was like hyperinsulinemia itself is problematic if you normalize for glycemic

00:48:34.720 levels. Yeah, because this is the thing that it's not the blood glucose per se. It's the whole body

00:48:42.080 glucose. Because if you think about this overflow paradigm now, if you take the glucose that's in

00:48:48.580 the blood and simply shove it into the liver, have you done anything good for this patient?

00:48:55.860 The answer is no, because you're just covering up the problem. So you take insulin and your sugars

00:49:00.460 are amazing, right? They're normal. But you shoved all this sugar into your liver. What happens when you

00:49:05.760 stop taking the insulin? All the sugar comes rushing back out of your liver and your sugar goes high. So

00:49:10.820 you actually have to keep taking it to keep it bottled up. All you've done is you've covered up the

00:49:15.580 problem. You never made it better because it's like taking garbage and throwing it under your sink.

00:49:20.340 You can pretend that your kitchen is nice and clean, but it's going to start to smell. And that's the

00:49:26.080 problem. It's the whole body glucose moving the glucose from one compartment of the body, which is

00:49:32.920 the blood, to another compartment, which is the liver. So you move the glucose from where you could

00:49:37.800 see it into somewhere where you couldn't see it. That doesn't do your body any good. And that was the

00:49:44.000 real lesson of the Accord Advanced VADT. That was 2008. Those were actually the trials that started

00:49:48.980 me down this whole thinking that what we're doing is actually completely incorrect. Because if you

00:49:54.060 remember, for 2008, I've been doing this for like 18 years or 17 years. And that was what we always

00:50:01.660 thought, right? You get the blood glucose low enough or normalize it, you're going to see huge

00:50:07.340 benefits. But we didn't. We didn't see any benefits at all. And that was a huge paradigm shift because

00:50:14.140 these all came in 2008. And yet, nobody wanted to propose a new theory of what is insulin resistance

00:50:22.580 and how are we treating it and why are we so wrong? We just kept doing what we kept doing. We just said,

00:50:27.600 well, maybe it's the hypoglycemia. It's like, come on, that's stupid. They weren't getting a lot of

00:50:31.720 hypoglycemia. But what they had to understand at that point, which nobody ever did, was that this

00:50:37.640 paradigm of lock and key, internal starvation is completely the wrong way to think about it.

00:50:44.720 Therefore, you're using the wrong treatments. You're using treatments that are actually going to make it

00:50:48.440 worse, not better. And when you actually get rid of the glucose, so this gets me back to SGLT2s.

00:50:55.500 So the SGLT2s are a new class of drug. And what they do is they actually make you pee out the

00:51:02.140 sugar. So it blocks the receptor on the kidneys where you're actually reabsorbing the glucose and

00:51:08.360 you actually pee out the sugar. So you get side effects. You get tons of side effects. You get

00:51:12.080 like urine infections and yeast infections. And for some reason, you get ketoacidosis too. But the point

00:51:18.740 is that if you look at the trials, they're actually quite consistent. You actually get a huge,

00:51:24.140 huge protective effect from the SGLT2s. That is, for the first time in like decades, we have a drug

00:51:32.780 that actually protects against kidney disease. So reduce the risk of kidney disease by about 25%

00:51:38.240 and reduce the risk of heart disease, which we've never seen before in any class of anti-diabetic drug.

00:51:46.420 Because what we're doing now is we're actually getting rid of the garbage. We're getting rid of the

00:51:51.980 glucose. We're emptying out that suitcase. So the amount of lowering of blood sugar was super

00:51:58.460 unimpressive in all of these trials. So there's like five or six trials now. Every single one of

00:52:04.040 these trials shows end organ protection with almost no benefit to your blood sugar. Like A1c would drop

00:52:11.100 like 0.3 or 0.4. Like nothing. It was terrible for the blood sugar. But the end points were

00:52:17.600 incredible. Why? Because you're actually getting rid of the actual problem. You're emptying out the

00:52:23.940 body of this glucose, which is what was making them sick in the first place, as opposed to simply

00:52:29.180 moving it around. And that, I think, is the explanation as to why SGLT2s are so, so effective

00:52:36.860 for organ protection, which we never saw before. Because now you're actually treating the underlying

00:52:43.480 problem of too much whole body glucose as opposed to too much glucose in the blood. You know, it's a

00:52:51.660 totally different dynamic. Like if your whole body has too much sodium versus just the blood has too

00:52:57.540 much sodium. It's a totally different problem, right? If your whole body has too much sodium,

00:53:01.580 you get edema. If just your blood has too much sodium, you have hypernatremia. Two totally separate

00:53:06.780 problems. Same thing here. If your blood glucose is high and your whole body glucose is high,

00:53:13.680 totally separate problems. Now we're actually addressing the underlying reason.

00:53:17.920 Let's consider, we're going to go to this in detail so we don't have to go deep now on it, but

00:53:22.920 just listening to the way you're describing it, it seems that another way to provide benefit,

00:53:30.900 which clinically seems to work quite well, is exercise. Because the more one would exercise,

00:53:37.480 the more one would increase a different reservoir outside of the liver, which is actually a larger

00:53:44.540 reservoir, and one that can't put its glucose back into circulation, which is the muscle.

00:53:49.940 So as I listened to you describe this, it's not inconsistent with this clinical observation,

00:53:56.480 which is you take a person with type 2 diabetes who is not exercising at all, who is sedentary,

00:54:02.640 and even if you make no change to their nutrition, exercising them quite vigorously for an hour a

00:54:08.880 day is actually going to have a benefit independent of anything else. Now, the idea here would be how

00:54:13.760 many of these things can you combine them now? So what is the magnitude of that benefit?

00:54:17.800 There is a benefit for sure. I mean, all the studies we've done on exercise are beneficial,

00:54:21.700 but it's much less efficient than attacking the diet, just because the liver is really the key

00:54:27.420 to type 2 diabetes, the fatty liver and all that sort of thing, and you really can't exercise your

00:54:32.000 liver. You can burn off a lot of this glucose with exercise, but compared to the amount that you put in

00:54:37.940 on a daily basis, it's a lot more work than to simply not eat, for example. So in terms of efficiency,

00:54:43.600 it's just less efficient, but clearly there is a benefit to exercise, and it's the same thing.

00:54:48.040 You're really just trying to empty out all this glucose from the system. The other thing is that

00:54:53.440 what always strikes me as sort of funny is that it's not really just about the diabetes. It actually

00:55:00.760 affects more than that because it actually goes into the entire metabolic syndrome, because if you

00:55:06.680 think about it, metabolic syndrome is a constellation of five things. If you take the ATP definition,

00:55:14.020 it's the increased blood glucose, which we've talked about, but also abdominal obesity,

00:55:18.920 high triglycerides, low HDL, and high blood pressure. And if you think about it, hyperinsulinemia

00:55:25.260 plays a role in the same thing, because what happens, of course, is that if you have this overflow paradigm,

00:55:31.580 this liver is now busy exporting out tons and tons of the fat, right? It's got too much glucose because

00:55:38.940 of too much insulin. So it's too much glucose, too much insulin. So therefore, the liver is jam-packed,

00:55:45.320 and it wants to get rid of all this extra fat. So it's actually putting out tons of triglycerides.

00:55:51.540 So that's why you get hypertriglyceridemia. And then, of course, as triglycerides go up,

00:55:56.660 we know that HDL goes down. So HDL goes down. As you're exporting out all of this fat,

00:56:03.540 this fat goes into all kinds of places where it's not supposed to go, into the pancreas,

00:56:09.240 into the omental fat, and you get this abdominal obesity. Not because of dietary fat, because

00:56:16.440 remember, dietary fat doesn't go into the liver. It goes into the chylomicrons, which goes into the

00:56:21.780 blood vessels, which gets taken out by the adipocytes, right? It never goes into the liver.

00:56:26.540 It's the fact that the liver is pouring out all this new fat that gets taken up

00:56:30.320 in all the organs around it. So you get fatty pancreas, for example, which I wanted to talk

00:56:35.160 about in a second. But that's abdominal obesity. And we know that insulin has an effect on blood

00:56:41.560 pressure because insulin causes reabsorption of sodium at the site of the proximal tubule.

00:56:48.640 So now, hyperinsulinemia, too much insulin, is really what is behind abdominal obesity,

00:56:56.580 high blood glucose, high blood pressure, low HDL, and hypertriglyceridemia. That's the metabolic

00:57:03.260 syndrome. The whole syndrome is not a syndrome of insulin resistance. It's a syndrome of hyperinsulinemia.

00:57:11.540 And that's a way better way to think about it, because if the problem is hyperinsulinemia,

00:57:17.420 then the solution is completely obvious. Insulin's high, how are we going to lower it,

00:57:22.260 right? It's no different than, hey, if your thyroid is too high, you want to lower it. If your thyroid

00:57:27.940 is too low, you want to give some. Well, that's not so hard to understand. But think about type 2

00:57:33.860 diabetes for a second. Type 2 diabetes, we know that insulin levels are high. So why did we think

00:57:40.140 it would get better? By giving more insulin. We totally misunderstand the problem.

00:57:45.440 Yeah. I had a mentor who trained as an endocrinologist, but now focuses exclusively on

00:57:51.120 type 2 diabetes and obesity. He said the exact same thing, which is we have to,

00:57:57.180 he doesn't like the term insulin resistance for the same reason you don't, which is he says it's not

00:58:02.580 consistent with the way we think about endocrinology. In endocrinology, we think about

00:58:07.280 hyper and hypo fill in the blank. And yeah, he uses the example of thyroid, right? And he's like,

00:58:13.120 look, if you have too little thyroid hormone, we give you more. If you hypothyroid, we give you

00:58:18.800 more. And type 1 diabetes is that analogy. If you have too much thyroid hormone, we don't give you

00:58:26.140 more of it. We treat you in a way that reduces the effect of it. And sometimes that means taking

00:58:31.300 out part of the thyroid and all these other things. It's funny. I think part of the reason I

00:58:36.120 think people struggle with this is the endocrine system is easier to replace than to shut down.

00:58:41.520 You know, hypercortisolemia is another great example, right? When you have patients whose

00:58:46.020 cortisol levels are unmeasurable, an extreme example of that would be someone in an Addisonian

00:58:51.660 crisis. You know, we're pretty good at giving more cortisol. But when you have people with

00:58:57.080 hypercortisolemia, which unfortunately comes hand in hand with hyperinsulinemia, there's no pill to

00:59:03.540 lower hypercortisolemia. Exactly. And this is the same problem we had. That is type 1 diabetes,

00:59:10.000 which is too little insulin. Hey, it was great. Just give more insulin. But when you had type 2

00:59:14.920 diabetes, which is too much insulin, there's no drug like SGLD2 for a little bit. But before that,

00:59:21.640 there's no drug. So then we just gave the same thing, right? It's so ridiculous. Just like giving

00:59:26.960 a hyperthyroid patient, hey, give them some L-thyroxin, right? It's like, that's going to make

00:59:31.360 it worse. But we did the same thing. And we watched these people get worse. We gave them insulin. And what

00:59:36.700 happened? They all gained like 30 pounds. Like every single study showed that. The CCT showed that,

00:59:43.880 right? They just gained weight and they became hyperinsulinemic. We have type 1s who actually

00:59:49.940 became hyperinsulinemic. You start out taking 20 units, 15 units a day when you're a kid. And then

00:59:56.600 by the time you're 45, you're taking like 60 units a day. Why? You developed insulin resistance. And yet

01:00:03.780 you had no insulin in your body in the first place 20 years ago, right? Because we thought that giving

01:00:09.200 more insulin was good. But we didn't realize that, hey, too much insulin is just as bad as too little

01:00:15.900 insulin or worse in this case. And the funny part about it is that we actually know a lot about

01:00:22.080 biochemically how this sort of overflow paradigm works. So if you look at the glycolytic cycle and the

01:00:29.080 TCA cycle, for example, you have glucose, which undergoes glycolysis to pyruvate. And the pyruvate

01:00:35.760 goes through pyruvate oxidation into acetyl-CoA, which undergoes the citric acid cycle, which gives you

01:00:42.920 citrate and gives you ATP, which again, we know feeds back and blocks glycolysis. Like, okay, well,

01:00:52.100 that's, you have glucose. It goes into the cell, goes, undergoes citric acid cycle. You get lots of

01:00:58.580 ATP, you get lots of citric acid, feeds back, blocks glycolysis, which means that glucose can't

01:01:05.920 go in. It's like, okay, we've worked out the whole biochemistry of how this overflow paradigm is

01:01:12.200 supposed to work. We actually teach it to like high school students that, hey, if you're feeding in way

01:01:18.400 too much of this stuff into the TCA cycle, there's a feedback, there's a negative feedback loop. And

01:01:24.880 almost every biochemical reaction does this, right? In biology, if you start stimulating stuff, you

01:01:31.960 actually have something that's going to block it. TCA cycle is no different. ATP is going to block

01:01:38.460 glycolysis, which is going to block that glucose so you don't overload the system. That's what's

01:01:43.700 happening. Glucose can't go in anymore. This is such an important point because then you can say,

01:01:48.900 okay, hyperinsulinemia, which is actually too much glucose, too much insulin, is going to feed back

01:01:55.980 and not let the glucose into the cell, which is why the glucose stays outside and you have this

01:02:01.320 so-called insulin resistance. But the key is to empty out the cell of glucose. How are you going to do

01:02:06.360 that? Well, low carbohydrate diets, intermittent fasting. There's no more potent way to lower insulin

01:02:13.020 than to fast. I mean, we're going to come to this in a moment, but I get such a kick out of watching

01:02:18.260 people argue back and forth about whether carbohydrate restriction versus fat restriction

01:02:23.480 is better at lowering insulin. My experience is that carbohydrate restriction does a better job

01:02:29.160 than fat restriction. But I feel like sitting on the sidelines saying, hey guys, there's another tool

01:02:34.240 over here you've both sort of forgotten that's like infinitely more potent. Eat nothing and watch

01:02:40.440 what happens to insulin levels. And this is what we did. We just said, okay, don't eat anything.

01:02:45.900 You got to clear out this glucose. You got too much glucose in your cell. Clear it out.

01:02:50.560 The easiest way to do that is eat nothing. Then you're going to force your body to start

01:02:54.260 using some of this fuel, right? And the first place it's going to pull it out of is this fatty liver.

01:02:58.800 Oh, by the way, the fatty liver, so of course, is driven by this de novo lipogenesis, which is why,

01:03:04.540 again, we see this huge correlation between fatty liver, which is a huge problem, by the way.

01:03:10.400 It's actually causing a ton of cirrhosis these days. And type 2 diabetes, because it's actually

01:03:16.580 part of the same problem. But exactly, you're completely ignoring your most effective tool,

01:03:23.200 which is intermittent fasting. As soon as we did that, we saw tons of people just reverse their

01:03:27.480 type 2 diabetes, which gets me to my next point, which is the type 2 diabetes. And everybody forgets

01:03:32.760 that this is actually a two-step process, right? You don't develop type 2 diabetes just with insulin

01:03:38.620 resistance. It actually is two things. You need one is insulin resistance or hyperinsulinemia,

01:03:44.240 which is a much better name. And then two, you need beta cell failure. Because what happens is,

01:03:50.980 and this is where the old paradigm was completely wrong again. So we said, okay, well, you have

01:03:55.760 insulin resistance, your body responds by increasing the amount of insulin. So we know that that happens.

01:04:01.440 So you get hyperinsulinemia. And then eventually, the pancreas is just so tired of making all this

01:04:08.860 insulin that it atrophies and it fails. And that's beta cell failure. That's when you actually see the

01:04:15.820 blood glucose go way up. And this whole process takes like 10 years or so. So the rising insulin

01:04:22.780 resistance is met with hyperinsulinemia, which keeps the blood glucose normal. And it keeps it normal for a

01:04:29.200 long time at the expense of hyperinsulinemia. And this is precisely what Kraft said. You can figure

01:04:36.380 it out much earlier if you look at insulin levels as opposed to blood glucose levels. But the point is

01:04:44.140 that now you have to hypothesize that there's two completely separate things going on. One is insulin

01:04:50.620 resistance and two is beta cell failure. And they're totally separate. And again, it doesn't make any

01:04:57.420 sense. There's too many experimental points that don't line up. One, we know that if you're going

01:05:03.240 to say type 2 diabetics, their beta cells have failed. Well, we know that's not true because

01:05:09.420 virtually all type 2 diabetics are reversible. If you do bariatric surgery, if you look at the studies,

01:05:15.020 like 80%, 90% of those type 2 diabetics, they actually get off all their meds. They actually reverse

01:05:20.900 their type 2 diabetes. So if you said that the beta cell just failed, then you're wrong. Because

01:05:26.740 even the most severe type 2 diabetics reverse. We have a three-year-old, so the youngest person in

01:05:32.400 the world to get type 2 diabetes was three years old. You're going to hypothesize that this three-year-old

01:05:37.200 pancreas has failed, has atrophied? Like that's clearly wrong. And the other thing is that you have

01:05:44.160 to say if these two things go hand in hand, why is it that you only see beta cell failure in this case

01:05:52.540 of insulin resistance and never anywhere else? Like how does that even work? Like they go together.

01:05:59.100 One goes with the other all the time and exclusively with each other. So this is the point that you'd

01:06:05.120 have to say that there's two separate things going on. But if you think about the sort of overflow

01:06:09.600 paradigm, again, it explains this paradox very easily. Because what happens is that, and this is

01:06:16.440 where, you know, if you look at a lot of the work on the twin cycles hypothesis fits in, is that you're

01:06:21.980 filling up your liver with all this glucose, hyperinsulinemia, you've got too much glucose in your

01:06:27.260 liver, your liver starts making fat and pumping it out. Then one of the organs that it accumulates in

01:06:34.640 is the pancreas. So now you've got fatty pancreas. And that is the problem, is that your pancreas is not

01:06:42.480 failed. Your pancreas is just clogged with fat. And you can measure these in an MRI and whatever.

01:06:49.340 And you can see that all these people who have type 2 diabetes actually have big fatty pancreases as

01:06:55.480 well. And as you simply get them to fast, so the counterpoint study, which was done by Royce Taylor

01:07:01.540 and so on, they showed that the type 2 diabetes was reversible because you simply unclog the fat. But now

01:07:07.640 the fatty liver is responsible for the insulin resistance or hyperinsulinemia. And the fatty

01:07:13.180 pancreas is responsible for the beta failure. So they're both manifestations of the same thing.

01:07:18.100 They're both manifestations of hyperinsulinemia. And that explains why it's not two defects of type 2

01:07:25.120 diabetes. It's actually a single defect and why it's a reversible problem. So again, this hypothesis

01:07:31.080 fits the anomalies so much better than everything else. And, you know, if you look at fructose, for

01:07:40.140 example, it's like, why is fructose so bad? And it's like, well, it doesn't have any glycemic effect.

01:07:47.320 It really doesn't have that much of an insulin effect, but causes a lot of this fatty liver, right? All that

01:07:52.040 fructose goes into the liver, gets turned into fat through nemolypogenesis. And now that's all part of

01:07:58.140 the same pathogenesis, the fatty liver, the hyperinsulinemia. So it explains everything about

01:08:04.000 how this disease of type 2 diabetes, more than just hyperinsulinemia or insulin resistance,

01:08:10.780 explains how that all kind of comes about. It sort of fits a lot better. And this is what I mean.

01:08:16.360 That's why I like the physics model, which is like, okay, we have a theory now, which now fits the facts

01:08:21.840 so much better than the old lock and key model. And therefore, you have to adopt it and say,

01:08:29.560 what are the treatments that come out of this that are going to be more effective?

01:08:32.980 There are actually two separate things I want to ask about. The first one is, do you see a way that

01:08:40.580 NAFLD is causal towards hyperinsulinemia and separately where hyperinsulinemia is causal to NAFLD?

01:08:49.180 The literature is really not clear on this. And you could just say, well, let's just dismiss the

01:08:54.100 literature out of hand. But clinically, these things are so tightly wound. And I've never really

01:09:00.600 done the clinical experiment to tackle one without the other. So it's a very common presentation is

01:09:07.340 hyperinsulinemia that you describe. And I also am a big fan of Joseph Kraft. And actually, I would

01:09:13.180 credit it to Najee Torbay, who was one of my mentors, the endocrinologist I referred to, who

01:09:17.440 really got me to think of it as hyperinsulinemia as the endocrine condition. And his view was, look,

01:09:23.640 the oral glucose tolerance test with frequent sampling is our best tool because long before

01:09:29.380 glucose levels get out of whack, you're going to see inappropriate amounts of hyperinsulinemia early

01:09:36.320 on. But nevertheless, the common presentation is patient has hyperinsulinemia with or without normal

01:09:42.480 glucose levels. Their hemoglobin A1c is often completely normal. Their ALT is high, much higher

01:09:49.620 than we would like it to see, though not so high that people would get alarmed by it. And if you

01:09:54.760 really felt like doing it and you were resource unconstrained, you could get an ultrasound of the

01:09:59.280 liver and you would almost assuredly see the accumulation of fat. Well, with that patient,

01:10:05.300 we take a treatment plan that addresses both. The NAFLD resolved, the LFTs within a very short period

01:10:13.220 of time normalize, and so too does the hyperinsulinemia. And so I've never tried to

01:10:18.420 disentangle if the high level of insulin is really pushing the fat accumulation in the liver or the

01:10:25.020 other way around. Although, of course, you could argue that there's different scenarios, right? If you

01:10:29.220 put somebody on a very high fructose diet that wasn't necessarily overly abundant in glucose,

01:10:34.220 it might actually be that the NAFLD drives the hyperinsulinemia versus a diet that is too high

01:10:41.220 in carbohydrates for the individual such that it's the hyperinsulinemia that ultimately leads to

01:10:47.960 what? Help me think through the arrow of causation in the other direction.

01:10:52.980 Well, I think it does both, right? So you have those studies by Havel from 2009 where he took

01:10:59.280 people and gave them a lot of fructose, right? So the experiment was great.

01:11:03.120 They took people, two groups of people. One, they gave sort of Kool-Aid that was sweetened with

01:11:08.120 glucose and one that they gave Kool-Aid sweetened with fructose. And then they actually looked for

01:11:13.140 insulin resistance and so on. And what they found was that when you gave a lot of fructose, people

01:11:18.900 got type 2 diabetes. You could measure the oral glucose tolerance test and they actually became

01:11:23.940 diabetic. So what you see is that the fructose, which is metabolized in the liver, is causing this

01:11:30.580 fat accumulation specifically in the liver. And that is going to cause hyperinsulinemia, right?

01:11:37.560 Because the liver is full of, you know, all this excess fat. Now you're trying to shove all this

01:11:43.540 glucose into this fatty liver cell and the liver is like, no, I can't take anymore. So I'm going to be

01:11:49.320 resistant to this. So as it gets resistant, the blood glucose goes up and the body starts to

01:11:55.520 have to make more insulin to sort of get rid of this other situation, which is a, hey, there's too

01:12:00.380 much glucose in the body. So I think the arrow of causation goes both ways, which means it's sort of

01:12:06.180 a vicious cycle. Each is making the other worse. So you have to take care of the problem. So when

01:12:11.800 you take care of one, you sort of take care of both. And I always say that what's interesting is

01:12:16.580 to look at this way of thinking. And then if you think about it, if you take it sort of one step

01:12:21.300 further, what you see is that the obesity, the insulin resistance, and the type 2 diabetes,

01:12:27.480 which is the fatty pancreas as well, is they're actually not detrimental. They're actually protective.

01:12:32.580 They're actually mechanisms of protection against the problem. So for example, let's take obesity. So I

01:12:39.840 say, okay, so let's think about this one step at a time. Suppose you have houses on a street and

01:12:46.840 insulin. Every day you take a little bit of sugar, so a bit of glucose, and insulin comes by and

01:12:53.060 knocks on the door and gives you a little, you know, a bit of glucose. And you say thank you,

01:12:57.720 and you use it for energy and everything's great. Now, all of a sudden, you start taking a lot of

01:13:02.020 glucose. So insulin comes by and instead of giving you a little cup of glucose, it gives you a big

01:13:07.300 barrel of glucose. And it's sort of like too much, right? But you take it because you're supposed to.

01:13:12.840 But eventually, you know, your house fills up with all this glucose. So after a while,

01:13:20.100 the glucose keeps coming in. And insulin keeps giving you a big barrel full that you can't use

01:13:26.300 every single day. And now your house is full. So what are you going to do? Well, you're going to

01:13:30.660 stop taking that glucose. So that's insulin resistance. So that's not actually, that's

01:13:35.140 protective. It's protecting itself from the effect of too much glucose. That's what the fatty liver is

01:13:41.020 doing. It's protecting itself from too much glucose. It says, hey, hey, I can't take any more

01:13:45.820 of this. So what happens, of course, is the insulin is like, oh, I got to get rid of this glucose,

01:13:50.360 right? I can't have it hanging around. I'm going to lose my job. So it gets more insulin and starts

01:13:55.040 battering down the door and just shoving in all this glucose. Not that glucose is bad, but there's

01:14:00.600 just too much of it. So it just keeps shoveling it in. So then you're overcoming that protective

01:14:06.720 response. The obesity, which is the filling up of your house, was actually trying to protect yourself

01:14:11.700 against this excessive insulin resistance. And we see actually evidence of that in the

01:14:17.000 lipodystrophies. So I don't know if you saw that paper a few years ago about lipodystrophy. So you

01:14:23.320 had these people that actually had no fat. And you think, okay, if they're so thin, if they're so skinny,

01:14:29.140 they must have no insulin resistance. They had the worst insulin resistance you've ever seen,

01:14:32.960 like off the charts. They wrote about it in the New York Times. Yeah. This is the thing that sort

01:14:37.280 of explains that paradigm, which is if you are truly insulin resistant and you at least buy the

01:14:43.820 argument that that's a global term, meaning one cell is insulin resistant, they all are. Well then,

01:14:49.280 yes, you should be the leanest individual on the face of the earth because your adipose tissue does not

01:14:56.920 have the ability to integrate or assimilate the signal that says, one, bring triglyceride

01:15:02.940 in and two, halt the process of lipolysis. The problem is not insulin resistance per se. It's

01:15:09.940 actually hyperinsulinemia. So what your body is doing is taking all this fat and sort of storing

01:15:16.280 it away so it doesn't cause a problem, right? So these people with the lipodystrophy, they couldn't

01:15:21.660 store the fat. So what happened is that the fat stored up in their liver and they had the highest

01:15:26.180 insulin resistance you've ever measured because it's really a protective mechanism. The fat is trying to

01:15:32.240 suck away all this glucose so that it doesn't cause a problem. This is why obesity itself is

01:15:38.300 actually a protective mechanism against hyperinsulinemia, against too much sugar. So the

01:15:42.640 ultimate problem is too much glucose and too much insulin. So then the next step is, okay, so now

01:15:50.160 insulin sort of is way too much. The insulin's got all his cousins out, you know, battering down your

01:15:55.520 door, throwing in all this stuff and you can't take it anymore. So then what do you do? Well, you start

01:15:59.680 to take some of these barrels and you try and give it to like your friends and your family and so on,

01:16:04.960 right? So this is what the liver does, right? It's got way too much fat sitting around. So it takes

01:16:09.280 this fat and shovels it out the door as VLDL and it goes into the other organs. So it goes into the

01:16:16.400 pancreas, it goes into the liver, it goes into your omentum. That's how you get the obesity, the abdominal

01:16:22.580 obesity that you see. So now you've got obesity as a protective mechanism and insulin resistance itself as a

01:16:28.780 protective mechanism because the cell is trying to protect itself from too much insulin, too much

01:16:33.900 sugar. The last part is that you're throwing out all this glucose into your pancreas, all this fat

01:16:40.160 into your pancreas. Your pancreas stops. It makes a lot of insulin, makes a lot of insulin, makes a lot

01:16:44.920 of insulin up onto a certain point. Now it's all clogged up and it can't make the insulin. So what

01:16:49.660 happens? Well, you start to pee out all this sugar, right? You get the polyuria, polydipsia,

01:16:57.060 glycosuria. Your body is actually trying to protect itself by peeing out all this sugar.

01:17:04.760 So it's like you have to look at it the other way. We think of all these responses, obesity,

01:17:09.000 insulin resistance, and the beta cell failure as pathologic. They're actually protective.

01:17:17.000 It's a totally different thing. Your body's actually trying to protect yourself against

01:17:21.280 the root cause of the problem, which is too much insulin, too much glucose. So when you enhance

01:17:27.100 that glycosuria with SGLT2s, guess what? You actually have a protective, like a hugely protective

01:17:34.480 effect because that's the protective mechanism against the root cause. When you actually give people

01:17:40.400 more insulin, you actually keep all that inside. Then what happens? They gain weight. And clinically,

01:17:45.160 you see this. Clinically, the patients know it because you give them insulin, their blood sugars

01:17:50.360 are better, but then they gain weight. And as they gain weight, their diabetes gets worse. So you give

01:17:55.260 them more insulin. And as you give them more insulin, they gain more weight.

01:17:58.260 Do you think that adiposity per se, all things equal, is also driving the hyperinsulinemia? And if so,

01:18:08.160 what is the mechanism? Or do you believe that the adiposity is a bystander of it? Because

01:18:13.080 this is also an enormously difficult problem to tease out in clinical trials, because virtually

01:18:19.720 any clinical trial that demonstrates an improvement in, quote, insulin resistance, or more accurately,

01:18:27.180 a reduction in hyperinsulinemia is, without exception to my knowledge, accompanied by weight loss and a

01:18:34.520 reduction in adiposity. And this too then drives a causal question, which is, is the adiposity driving

01:18:43.880 the hyperinsulinemia? So let's for a moment posit that hyperinsulinemia is the way we will refer to

01:18:49.000 this. And we won't talk about insulin resistance because that term has really lost meaning in this

01:18:53.620 context. That the adiposity is driving the insulin resistance, or the insulin resistance is driving the

01:18:59.420 adiposity. I think it's more likely that the hyperinsulinemia is driving the obesity rather

01:19:05.960 than the other way around. I mean, it's always hard to tease out, but you can look at, to me, it's always

01:19:12.940 like, let's take sort of an experiment and see. So there was a great experiment a few years ago, where they

01:19:19.060 took people who were type 2 diabetic, and this is in the 90s, and they gave them law of insulin. So from

01:19:24.740 time 0 to 6 months, they went from 0 units of insulin to like 100 units of insulin, the blood sugars were

01:19:31.680 great. And what happened? Well, they gained like 20 pounds. And if you look at the number of calories

01:19:37.900 that they were eating per day, it actually dropped by about 200-300 calories per day. So what you see is

01:19:44.600 that the only difference, because this was a randomized sort of trial, the only difference was the

01:19:49.440 hyperinsulinemia. That's what we changed. When we changed experimentally, the amount of insulin people

01:19:55.600 were getting, because we're giving it to them, they gained weight. So to me, that is clearly a causal

01:20:02.620 relationship. We see this all the time, right? You prescribe insulin, people gain weight. You give

01:20:07.440 sulfonylureas, which increase insulin, people gain weight, right? You give them SGLT2s, which make insulin

01:20:12.940 drop, then you lose weight. And type 1 diabetics know it too, like they lose weight. So the arrow of causality

01:20:19.200 is very easy to establish going from hyperinsulinemia to obesity and forgetting all the

01:20:26.300 mechanism. All I'm saying is that when you give insulin, people gain weight. Every single time you

01:20:30.740 give insulin or raise it by sulfonylureas, or when you lower insulin with type 1 diabetes, they lose

01:20:37.140 weight. And it doesn't forget about what you eat or whatever. Like people always say, oh, let's put

01:20:41.480 equal calories in. Like forget it. Like all I'm changing is the insulin. Then obesity goes up or down

01:20:48.340 depending on what happens to the insulin. It's much harder to establish that causality the other

01:20:53.780 way around, right? You can, and they've done this with liposuction. So if you take a situation where

01:21:00.900 you remove 20 pounds of fat, what happens? And the answer is nothing. Right. Now that study,

01:21:08.160 if you're referring to the one that Sam Klein published in the New England Journal of Medicine,

01:21:11.600 I love that because it's a great example. Of course, the pushback is yes, but that was only

01:21:17.540 subcutaneous fat that was removed. We don't do liposuction on visceral fat. You know, on some

01:21:23.780 level, I think this is a great theoretical question. It might not matter. In other words,

01:21:27.560 it doesn't change the clinical decision. It's an important question as we think mechanistically

01:21:32.340 about what's happening, but it doesn't change what you do with a patient, which in the final analysis

01:21:38.060 matters more than anything. But yes, until we can really do liposuction on visceral fat,

01:21:45.200 which I personally think would just pose too much risk to justify, it's going to be very difficult

01:21:50.240 to tease out the other direction. But what about the role of inflammation? Because the other thing

01:21:55.560 that seems to go hand in hand with hyperinsulinemia in patients is they also tend to be quite inflamed.

01:22:02.820 And we can measure this non-specifically with things like C-reactive protein, fibrinogen,

01:22:08.220 interleukins. We can even see cardiac specific forms of inflammation. So for me, this is just a

01:22:15.160 very non-scientific clinical observation, but I'm curious as to whether you've seen it.

01:22:19.240 Yeah. In terms of inflammation, again, I look at it from an experimental standpoint. So if I think

01:22:25.220 inflammation causes obesity, for example, then what happens when you decrease inflammation? Because

01:22:32.240 we have anti-inflammatory medications. What happens to obesity? Well, you can give NSAIDs and people don't

01:22:38.780 lose weight. You can give prednisone, which is probably our most powerful anti-inflammatory. People don't

01:22:44.000 lose weight. If you give all these antibodies, this antibody, that, and, you know, there's all kinds

01:22:50.480 of inflammatory IL-2 and TNF, and you have all these things. Other than if they get super nauseated,

01:22:56.980 they lose weight. But if they don't get super nauseated, then they don't really lose weight. So

01:23:01.660 to me, that whole story, there might be a kernel of truth in that, but to me, it doesn't really make a

01:23:08.200 lot of sense. Like if you get a really bad infection, you know, some kind of inflammatory

01:23:12.800 state, so inflammation goes way up, rheumatoid arthritis, do you gain a lot of weight? It's like,

01:23:19.660 yeah, I don't really see it. As opposed to the consistency where you give insulin, people gain

01:23:25.980 weight. You take away insulin, people lose weight. To me, that's a consistent causal relationship,

01:23:31.220 whereas inflammation, it's much less. Like I don't deny that there's a lot of important inflammatory

01:23:35.460 mediators and stuff, but it's just not so simple that you can say more inflammation causes weight

01:23:42.000 gain, less inflammation causes weight loss. Therefore, treat everybody with Advil or something

01:23:47.580 like that. Yeah, where I was going to go was actually slightly more nuanced, which is, again,

01:23:51.200 getting a little bit ahead of where we're going to go because I want to start talking about some

01:23:53.960 treatment ideas. But you take a hyper-insulinemic patient with no inflammation. In my limited experience,

01:24:02.780 they tend to respond quite well to carbohydrate restriction and exercise. When I take patients

01:24:10.860 who have significant hyperinsulinemia, but it's also coupled with inflammation, I don't find that they

01:24:19.140 are as impacted by what I just said. And I find that those are the patients that initially got me to

01:24:26.940 start exploring significant periods of fasting, either significant 500 calories a day for five

01:24:33.920 days, that type of fasting, or water only for three days, five days, that sort of thing. And again,

01:24:39.320 not a very scientific observation, rather. These are small and clinical things that I see. But I

01:24:45.820 wonder if A, you've seen that, and B, if it suggests that inflammation can have a sort of negative

01:24:52.740 synergy with hyperinsulinemia. I think that there probably is something to that because there is,

01:24:59.440 I mean, for sure, other hormones are involved. Like we know for sure there are other hormones

01:25:04.800 involved. So look at cortisol, for example. Inflammation is difficult because there's so

01:25:09.800 many different mediators, right? You can have TNF, you can have IL-2, you can have all kinds of

01:25:14.380 inflammatory mediators, endotoxin and stuff. But there are for sure other hormones that make it really

01:25:21.420 are very important, like cortisol. So you give cortisol, people gain weight, right? It's not

01:25:25.860 as much as with insulin, but you give prednisone, and you know, we've all done it. You give prednisone,

01:25:31.840 you gain weight. When you take away the prednisone, like they finish their course of prednisone,

01:25:36.080 that weight kind of goes back down. So we know that cortisol, for example, is a huge impact on

01:25:42.260 body fatness. For example, we know the studies from sleep. If you get good sleep, you're more likely to

01:25:49.920 be a good weight. If you are sleep deprived, for example, it's a stressful situation where cortisol

01:25:56.760 is going to go up, then you're more likely to gain weight. So that's not an insulin thing. It's a

01:26:02.180 cortisol thing. And we know for sure that sex hormones have to play a role somewhere in there

01:26:07.120 as well, because there are women who develop gestational diabetes and their insulin, their diets,

01:26:13.660 they don't change. The difference is they got pregnant, right? And that's a difference in sex

01:26:18.400 hormones. And somehow that impacts, and I actually don't know how this works, but somehow it does

01:26:23.960 impact the response of, I'm not sure they're hyperinsulinemic either. I think there must be

01:26:29.200 something completely different about that entire thing, but it's not as common. So I don't think

01:26:34.780 about it as much. Or girls and boys at puberty, for example, the difference of girls and boys is

01:26:40.620 testosterone versus estrogen for the most part. It's not an insulin difference. Yet girls who go through

01:26:47.280 puberty have way more fat than boys, who get more muscle. So we know that there are other hormones

01:26:52.820 that clearly impact. So it's not just about insulin, but it's about cortisol, it's about sex hormones.

01:26:59.580 And I think inflammation probably comes in there somewhere, but what to do about it? And it's a lot

01:27:04.860 messier. Inflammation is a lot messier than thinking about cortisol, for example, right? Where you can

01:27:09.780 measure levels and you can think about up or down, you know, cortisol, for example, you have the too much,

01:27:15.480 which is Cushing's disease. And what's the sort of hallmark? Well, obesity. And then you can get

01:27:21.200 too little, too little cortisol is Addison's disease. And what's the hallmark? Weight loss,

01:27:25.520 right? So again, very, very clear. It's easy to measure. Inflammation, it's just so hard. It's just

01:27:30.720 too many moving parts for me. Yeah. I think this whole thing is too hard for me, but let's talk a

01:27:37.000 little bit also about the role of hyperinsulinemia specifically on the vascular system. What is it

01:27:44.540 about hyperinsulinemia and the endothelium or the capillaries that seems to wreak havoc beyond what

01:27:52.680 tends to accompany late stages of it, which is hyperglycemia, which of course has significant

01:27:59.560 damage mechanically on the microvascular system. But what about, like, for example, why would

01:28:05.920 hyperinsulinemia exacerbate coronary artery disease absent abnormal glucose levels or even once

01:28:14.380 corrected for lipid levels, which I, you know, that observation exists, right? You can take patients

01:28:19.500 that have the same lipid levels, the same glucose levels, but the hyperinsulinemic patient is going to

01:28:25.720 have worse cardiovascular disease. Why is that? For that specifically, I don't know. I think that

01:28:32.420 there's a lot more work because a lot of people still don't think about it as a disease of

01:28:36.220 hyperinsulinemia, but I think of it generally in terms of two things. So I think about two things,

01:28:41.880 like cardiovascular disease a lot and cancer, because those are actually the two top killers

01:28:45.820 of Americans is CV disease and cancer. And they're both, to me, diseases of too much growth. That is,

01:28:53.300 everybody thinks growth is good, but growth in adults is generally bad. Like, you don't want to grow.

01:28:58.900 Once you reach adult size, your liver doesn't grow, your kidney doesn't grow, you shouldn't be

01:29:05.300 growing. And if you are growing, it's generally bad. So if you gain weight, you're obese, you gain

01:29:10.600 fat, that's a disease of too much growth. If you have big fatty liver, that's too much growth.

01:29:14.480 If you have all this excess protein in your brain that's blocking your signals, and that's

01:29:19.060 Alzheimer's disease, that's bad. And it's the same thing, cancer, disease of excessive growth.

01:29:23.840 In the blood vessels, we know that there's excessive growth, right? It's not a matter.

01:29:30.560 And this whole idea of fat or cholesterol clogging your arteries like a pipe, it's super,

01:29:36.980 like even when I was in medical school, we knew that was not the case. We know it's a response to

01:29:42.120 injury. That's why you get it at bifurcation points, for example, and you get smooth muscle

01:29:48.320 proliferation, and then the foam cells which go in, and it's not clear whether the foam cells and all

01:29:53.820 that is a response to the injury, but it's because of that whole cascade, that atherogenic cascade,

01:29:59.480 it's a response to injury, but you get excess proliferation of certain things, including smooth

01:30:06.620 muscle cells and so on. But to me, it's just the disease of too much growth that's eventually

01:30:11.640 building and collapsing and closing off that artery. And this is where diseases of too much

01:30:18.280 growth is linked very tightly to insulin because insulin is a growth factor. I mean, this is one

01:30:27.220 of the things that is super exciting in cancer, I'll tell you, like the whole PI3K thing, because it

01:30:33.920 directly links insulin, which we all think about in terms of metabolism, to growth. Every single time

01:30:43.300 that you have a nutrient sensor, like insulin, like mTOR, like AMPK, it's the same insulin, the pathway

01:30:50.620 that it goes through, which goes through PI3K and then like MAPK and AKT, is it influences growth,

01:30:58.860 increases growth. And that to me is one of the big problems with insulin all the time, is that you're

01:31:07.120 telling your body to grow all the time when it really shouldn't be growing all the time. So you actually

01:31:11.540 have to decrease growth. If the problem is too much growth, you want less growth. And one of the things

01:31:16.720 that you want to influence is insulin and mTOR. mTOR, I know you talk a lot about mTOR. It's the same,

01:31:24.480 exactly the same. It's a nutrient sensor at heart. It's very sensitive to dietary protein. And what it

01:31:32.540 does is if there's a lot of protein, you turn on all these cell proliferation signals. When you have

01:31:39.660 very little protein, what happens? Autophagy. It's like, oh, okay. So you have to realize that

01:31:46.960 metabolism and growth are exactly the same thing. And it has even more implication for cancer,

01:31:53.400 which is a disease of too much growth. So being obese, for example, it doesn't give you cancer,

01:32:00.220 but it certainly increases your risk of breast and colon cancer by a whole lot. There are 13 cancers

01:32:06.560 that are listed as obesity related. And we know that there's a very strong relationship between

01:32:11.180 type 2 diabetes, even without the obesity, but because they're hyperinsulinemic. There's a

01:32:16.460 very strong relationship between type 2 diabetes and breast cancer, for example.

01:32:21.480 So to me, those are all diseases of excessive growth. And therefore, you have to start looking at

01:32:26.400 growth pathways, which actually are the exact same as metabolic pathways,

01:32:32.140 which is insulin, mTOR, AMPK, which is important, of course, for a metformin. And then all of a sudden,

01:32:40.300 you see, hey, all of these times that you can decrease nutrient sensors, that is decrease mTOR,

01:32:47.260 decrease insulin, increase AMPK, you're getting good effects for longevity. This is fascinating.

01:32:53.980 Yeah, yeah. And it's so funny you say this, Jason. So this past week, I was in Boston,

01:32:58.600 and I was meeting with a number of folks. And one of the folks I was meeting with

01:33:02.720 wrote a paper, a very interesting paper in 2006. I was not aware of it at the time.

01:33:07.880 He wrote a theoretical paper. So it was a paper that got rejected by virtually every journal out

01:33:13.760 there. But in 2006, he proposed theoretically that rapamycin would be a great longevity drug.

01:33:20.600 Now, today, we'd say, well, that's obvious. But it's important to note that the first trial

01:33:26.800 demonstrating the immense power of rapamycin to promote longevity was not published until 2009,

01:33:32.980 three years after this paper was written. And what he said was, based on all of the evidence he had

01:33:40.040 examined to date of the use of rapamycin, even in patients with transplant, its antiproliferative

01:33:47.140 properties alone speak to this. And it's so funny to hear you say what you just said,

01:33:52.400 because he said the exact same thing. He said, think about it, Peter, every chronic disease

01:33:58.320 is some amount of hyperproliferation, hypergrowth. And you have a drug here that in the most elegant way,

01:34:08.560 in the least toxic way, in the most specific way, targets one of the most important regulators of

01:34:15.020 growth. His prediction was, this is going to be the most important longevity drug there is. And

01:34:20.120 you know, I would agree with that. In 2019, I think that there is no more promising agent than

01:34:25.720 rapamycin for longevity. But again, it comes back to this growth thing. And to put another bow on what

01:34:30.860 you said, it was certainly lost on me in medical school, how anabolic insulin is. In fact, I remember

01:34:37.860 learning many years later that bodybuilders used insulin. And I remember thinking,

01:34:42.560 oh, that's odd. I wonder why. And of course, after speaking to some bodybuilders,

01:34:47.520 you know, I got to learn, well, look, testosterone is anabolic, but insulin is even more anabolic. Now,

01:34:53.620 you can't go overboard. And this is where these hormones are very sophisticated, because

01:34:59.160 testosterone is very anabolic to muscle, which insulin is as well. But testosterone is catabolic

01:35:06.680 to fat, whereas insulin is anabolic to fat and anabolic to muscle. Cortisol, just to bring it full

01:35:16.160 circle, is the worst of both worlds. Hypercortisolemia is catabolic to muscle while

01:35:22.040 anabolic to fat. I usually end up drawing this picture for patients on the whiteboard showing

01:35:27.640 estrogen, testosterone, cortisol, insulin. And then, you know, you draw a muscle cell,

01:35:32.620 a fat cell. And it very quickly starts to paint the picture that says, this whole thing is just

01:35:38.480 endocrinology. I mean, all of this comes down to how can you manipulate these hormones to the desired

01:35:44.800 outcome? Nutrition being one tool, but exercise, the use of hormones themselves, of course, in cases

01:35:50.840 where there's deficiencies being another way to do it. So it's a very interesting way to sort of frame

01:35:55.760 this as the things that we care most about avoiding, if you really look closely, involve some measure of

01:36:04.560 hyperproliferation and growth. Yeah, because that's the chronic diseases today, because there's been a

01:36:09.380 huge shift in the diseases that we treat. So if you go back 50 years, 100 years, you're talking about

01:36:15.080 treatment of infectious diseases, right? Hepatitis virus and pneumonias and diarrheas and all this sort

01:36:20.680 of stuff. And we did great. We developed all these great drugs, antibiotics, antivirals, like really,

01:36:28.080 really good stuff. And they haven't been as big a problem. Now we have a problem with resistance,

01:36:33.380 of course, which is actually the same thing. Interestingly enough, I think there's a huge

01:36:38.140 parallel between antibiotic resistance and insulin resistance, in that they're the same thing.

01:36:45.160 Right. Antibiotic resistance is not caused by some phantom things, caused by using too much

01:36:51.180 antibiotic. Insulin resistance is the same thing. It's caused by too much insulin. So you have almost

01:36:57.680 the same thing where antibiotic resistance is caused by too much antibiotics. And we try and treat it by

01:37:02.320 using even more antibiotics, right, to overcome that resistance, which is the dumbest thing you could

01:37:06.580 do. In insulin, we have insulin resistance. We treat it with more insulin, which is what caused it in the

01:37:11.880 first place. And then things get worse. And we don't understand why. So you know that treating

01:37:15.880 antibiotic resistance is about using less. Same with insulin. You ought to use less. But anyway,

01:37:21.000 we shifted from using, from treating these diseases, which are infectious diseases, to these chronic

01:37:27.060 diseases. But we never changed our paradigm of medicine, which is the paradigm was, you come in to

01:37:32.660 me as a doctor, I give you a pill, an antibiotic, and you get better. Then people came in with these

01:37:37.720 diseases like diabetes and obesity and the related diseases of hyperproliferation, or I call them

01:37:43.460 diseases of too much growth, cardiovascular disease and cancer, and all this other stuff too.

01:37:49.420 Like it's all about fibrosis, right? Which in the end is just about you revving the system too hard.

01:37:54.760 But it's basically hyperproliferation. And then we said, let me give you a pill. It's like,

01:38:00.880 that's totally the wrong thing because you don't have that pill to decrease proliferation.

01:38:05.240 Rapamycin might be one. But rapamycin to me is limited because you've got not one problem.

01:38:14.120 You don't have one nutrient sensor. You have three nutrient sensors. You have insulin,

01:38:18.900 you have mTOR, and you have AMPK. And it's a very sophisticated system. Look, insulin responds to

01:38:25.860 dietary carbohydrates and dietary proteins. mTOR responds mostly to dietary protein. AMPK is actually

01:38:32.580 like a, you know, measures the ATP, the AMP-ATP ratio. So it actually doesn't care what you eat. It

01:38:39.180 just cares about the cellular energy availability. So they're all three measuring different sort of

01:38:46.140 things. And they all work on different timescales. So insulin goes up and down within minutes. It's

01:38:51.540 gone within hours. mTOR is sort of up and down between 18 and 30 hours. And AMPK is sort of days to

01:38:59.180 weeks. So you have such a sophisticated system because you have three nutrient sensors that are

01:39:03.400 giving you different information based on your diet and also based on your time scale. So your body

01:39:08.380 actually gets such incredible information just by integrating which one is up and which one is down.

01:39:14.620 But rapamycin only affects the one. Whereas some things like intermittent fasting is going to decrease

01:39:20.400 your insulin, is going to decrease your mTOR, and increase your AMPK, which is all three things that

01:39:27.620 you need to do in order to sort of decrease proliferation. Because you know that all three

01:39:33.880 of them, insulin feeds into mTOR and AMPK also feeds in. They're all part of that same thing.

01:39:40.020 You're affecting three different parts of that pathway as opposed to one. And that is going to

01:39:46.580 give you the best bang for your buck. And it's free and you can do it anytime you want. And it's like,

01:39:51.080 oh, hey, they told people this 2,000 years ago, right? When all the religions said, oh,

01:39:57.200 you should fast and you should do this and you should do that. Which is, to me, this sort of

01:40:01.140 just incredible that, you know, it all comes sort of back to what we knew 2,000 years ago, which is

01:40:07.400 that, hey, fasting every so often has incredible benefits because you're going to be able to affect

01:40:13.640 those diseases of excessive growth.

01:40:16.660 So let's pivot to this now. Let's talk about fasting. You and I are certainly two folks that

01:40:21.880 are no strangers to this. Anyone who's been cared for by you or anyone who's been cared for by me

01:40:26.600 pretty much is used to the same drumbeat, which is, I mean, I don't actually, I'd like to hear about

01:40:31.140 how you do it. In our practice, you know, generally for the first year, we don't push too hard on the

01:40:35.520 fasting thread. But boy, by the end of that first year and into their second year with us,

01:40:40.620 we're really having a hard discussion about this in some cases for patients that are resistant.

01:40:45.220 Now, I have this sort of framework that I think about for fasting, which is you start out on this

01:40:49.540 sort of crappy standard American diet. And how do you escape that gravitational pull of that horrible

01:40:54.680 thing? And I'll be sensitive and call it the standard crappy diet, the Canadian crappy diet or

01:40:59.160 whatever as well. They're comparable. To me, the two easiest ways to help patients escape the

01:41:05.740 gravitational pull of pure garbage is time-restricted feeding and or some measure of dietary

01:41:12.480 restriction. So the way that I explain that is time-restricted feeding says ostensibly, you don't

01:41:18.180 restrict what a person eats. You just restrict when they eat, nor do you restrict how much for

01:41:24.240 that matter. But you just put a feeding window on and you say, look, for 16 or 18 hours a day,

01:41:28.980 you'll consume nothing and you will eat ad libitum in the remainder of that period of time. And you

01:41:34.740 contrast that with dietary restriction, which we've already alluded to. Carbohydrate restriction is a form of

01:41:39.820 dietary restriction. And it can come with and without caloric restriction, but the simplest

01:41:44.200 way to execute it would be to say, look, no restriction on when you eat, no restriction on

01:41:49.240 how much you eat. You just can't eat these foods. And that's sort of where the majority of the diet

01:41:53.620 wars live is, are you a vegetarian? Are you vegan? Are you on a low-fat diet, a Mediterranean diet,

01:41:58.740 a paleo diet, a low-carb diet, a ketogenic diet? They're all forms of dietary restriction.

01:42:04.340 And to my knowledge, I'm not aware of one of them that is not significantly better than just being on

01:42:09.640 the standard American diet. So that speaks probably less to their individual efficacy and more to the

01:42:16.580 abject misery metabolically that is being exerted on people. Before we get into fasting, let's get

01:42:23.740 everybody really dialed in on those two things, time-restricted feeding plus or minus dietary

01:42:28.860 restriction. How do you visit those two things before we get into fasting? I focus a lot more on the

01:42:37.360 fasting. So I've always said, yeah, it comes down to the when you eat and what you eat. And this was

01:42:43.600 the thing that I sort of pointed out years ago, like three or four years ago, which everybody focuses

01:42:49.480 so hard on the what to eat and nobody talks like ever about the when to eat. That is, there is a sort

01:42:57.140 of consensus. It was never intentional that we should eat all the time, right? You should eat six or eight

01:43:02.580 times a day. You should grace throughout the day. And, you know, there's all sorts of reasons that

01:43:06.360 were made up to suggest why we should be eating six times a day. But there was never any science,

01:43:12.660 right? So, you know, if you ever look back and say, hey, where did we get this idea that we should eat

01:43:17.420 six or eight times a day? It's like from nowhere. Somebody made it up. It stuck. And that was about

01:43:21.820 it, right? It didn't, there was no studies. There was no randomized control trials. There's nothing.

01:43:26.340 Somebody just thought it was a great idea. And a few years ago, I said the same thing,

01:43:30.440 which is that, hey, we're sort of missing half of the problem because if it's two problems,

01:43:35.620 when to eat and what to eat, and nobody's talking about when to eat, then you're not going to succeed

01:43:40.440 no matter what you do. And this is why there's this sort of diet wars. I wasn't that interested

01:43:45.660 in getting into that. I was like more, hey, let's look at this whole other problem. So what we do

01:43:51.420 generally is start with that because it's a lot easier to change the frequency as opposed to what it is

01:43:59.520 they're actually eating. And this just comes from experience. So the first thing I did when I

01:44:03.520 started really focusing in on diet was try and change people's diet. But I did it from a clinical

01:44:08.880 standpoint. That is, I'm not seeing one person sort of for an hour every week. I have a clinical

01:44:14.260 practice, which means you get like 10 minutes like every three months. So it has to be something that is

01:44:20.700 sort of easy to understand and super effective as opposed to sort of counting carbohydrates or

01:44:29.340 something, which takes a long time to explain to somebody and then explain why eating fat's not that

01:44:34.940 bad for you and so on. I needed something that was sort of much more efficient in that way. And that's

01:44:41.600 why we started using fasting quite a lot because it's something that people sort of understood. You can

01:44:46.920 explain it within the 10 minutes and then you can follow up with them and see if they're eating and

01:44:52.020 they know sort of what it means to be fasting as opposed to some of these people who really didn't

01:44:57.960 have any idea what a low carb diet really meant. And that was the issue. Tell the story again. I

01:45:02.260 remember last year you were telling me a funny story about, and I don't remember what the ethnicity was

01:45:07.420 and the point was not to poke fun at one ethnicity or other. It was just like within this culture

01:45:13.080 to say don't eat carbs meant, oh, okay, well, I won't eat bread or pasta, but I'm still going to

01:45:18.480 eat lots of noodles and lots of this and lots of that. And they came back in and you said, how is the

01:45:22.940 carbohydrate restriction going? And they said, oh, it's fantastic, Dr. Fung. I'm doing so well.

01:45:27.720 Great. What are you eating? And it was like all carbs. It was just different carbs. And that was,

01:45:32.560 I remember you describing that being sort of an aha moment of culturally, it can be very difficult to

01:45:38.380 get people to restrict carbohydrates. Yeah, because it's their traditional food. So I have a lot of

01:45:44.780 Asians, so both East Asians and South Asians. And of course the diet is based on rice and rice noodles

01:45:50.880 and for the South Asians is rice again. So there's a lot of cultural difficulty, which is why it was

01:45:57.100 very difficult to sort of push too hard on it. You can if you make enough of an effort. And I think

01:46:03.640 that message anyway is getting across that eating all these carbs are not great for you,

01:46:08.800 these refined carbs. But the point was that you have to still come up with something. This is where

01:46:13.440 the practical experience sort of comes in. Like you can't just say, okay, well, I'm just going to stick

01:46:19.380 with carb restriction, right? I'm going to put these Chinese and Filipino and South Asian Sri Lankan people

01:46:26.040 on no rice, no noodles, ketogenic diet. They might say yes, but they actually won't do anything to,

01:46:32.540 you know, to follow it because it's just so difficult, right? Their culture is like that.

01:46:36.820 They've been eating this way for 70 years and it's very hard for them to change. And their family eats

01:46:42.020 like this. So it's like, what are you going to do? As opposed to fasting, which to me was a much

01:46:48.000 simpler idea that was already embedded in every culture. So you talk to Muslims about, and they're

01:46:53.720 all like, ah, I know what you're talking about. And you talk to Catholics and you talk to, you know,

01:46:58.640 Jewish people, like they will go, aha, this is a Greek Orthodox or whatever. And they're all like,

01:47:02.500 aha. And the Buddhists were like, aha. So it was way easier just from a practical standpoint.

01:47:08.380 That was where I started using it. And then I saw like these crazy, like crazy good,

01:47:12.800 like results. It was like insane. So we wrote a case report that was published in BMJ case reports. It was

01:47:19.880 three patients who had like sort of 20 to 25 years of type two diabetes and like five years of insulin on

01:47:26.980 big, big doses of insulin. We told them about low carb diets, but you know, we don't spend a lot of

01:47:32.600 time, but we put on 24 hours of fasting three times a week, which is like a one meal a day,

01:47:37.400 right? Nothing too strenuous or anything. We got off all their insulin, like between five and 18 days.

01:47:43.840 It was ridiculous how quickly they responded. And years later, we still have people who are

01:47:48.300 like non-diabetic. They went from 20 years of diabetes to non-diabetic and have maintained it for

01:47:53.740 the last six years, right? It was ridiculous how good, like, I just couldn't believe the results

01:47:59.980 that we're getting. And that's when we were like, okay, let's tell people and let's start writing

01:48:04.320 about it and all this sort of stuff. And it took ages to get that. It took like two, three years to

01:48:09.700 get that case series published. You alluded to bariatric surgery earlier. And about five years ago,

01:48:16.060 I was involved in an effort to do a clinical trial to try to tease apart the observation you alluded

01:48:25.100 to, which was that when you take a patient with type two diabetes who undergoes bariatric surgery,

01:48:32.760 at the time, I believe this was true primarily for the Roux-en-Y gastric bypass. So for the listener,

01:48:38.080 that's a surgical procedure where the part of the bowel that comes out of the stomach, which is called

01:48:44.760 the jejunum, is the first part after the duodenum, you cut a piece and then reattach it as a piece

01:48:49.640 of a Y and then bring it up such that you are basically bypassing not just significant parts

01:48:56.440 of the volume of the stomach as a reservoir, but also the initial part of the duodenum and the

01:49:02.000 jejunum. The observation was the following. You do this operation on a patient. Within about 10 days,

01:49:08.600 they haven't lost a meaningful amount of weight, but all of a sudden they don't need insulin anymore.

01:49:13.540 And very quickly, their diabetes resolves. In fact, I believe we are still at a point,

01:49:20.860 although this may be changing, where the only treatment that is viewed by an insurance company

01:49:27.420 to actually reverse type two diabetes is bariatric surgery. So the question we were trying to ask was,

01:49:34.580 how would you design a clinical trial to parse out how much of that is due to the change in the

01:49:41.620 internal architecture? Is there something problematic about the duodenum of that patient?

01:49:48.480 How much of that is due to the change in the nutrition of the patient? Because a patient who

01:49:54.200 undergoes a gastric bypass has to make significant changes in their nutrition. And how much of that is

01:50:00.040 due to the perioperative period of caloric restriction? So what's your take on those patients,

01:50:08.100 which again, pretty profound results? Again, not that profound, I think, when you consider them in

01:50:13.240 the context of what we now talk about with what fasting can do. But what's your take on that?

01:50:18.500 My take is that the fasting does everything. So you can actually get, I think, exactly the same

01:50:23.920 results if you simply didn't feed them for 14 days or something like that. Because the thing is that

01:50:30.880 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

01:50:37.200 because generally they're older. So we want to be a little bit more sort of regimented. And there's

01:50:43.140 also these cases of late-nonset type one and so on. But you actually see exactly the same thing where

01:50:49.040 the diabetes completely resolves. And the thing about it is that you can understand it perfectly

01:50:54.060 by understanding this sort of overflow paradigm. Because what you're doing, of course, is dropping

01:50:59.580 insulin levels very low. And then you're forcing the body after the first 24 hours, glycogen runs

01:51:06.120 out. So now you're going into a period where your body is going to have to metabolize fat for energy.

01:51:13.580 So the first place it's going to start pulling it out of is going to be the internal organs because

01:51:19.380 it's right there. The liver is going to be the first place that it's going to start pulling the fat

01:51:23.600 out of. And if you look at Royce Taylor's data, what you see is that the liver fat starts to go down

01:51:29.640 right away. The insulin resistance starts to go down right away because that's the problem, right?

01:51:34.680 It's this big fatty liver which you can't shove any more glucose in. That's what insulin resistance is.

01:51:39.920 As this big fatty liver goes down, just like emptying your suitcase, the insulin resistance starts to melt

01:51:46.060 away. And slower, because he showed this incredible data which looked at pancreatic function,

01:51:53.600 with ultra low diet. It wasn't fasting, but it's an ultra low calorie diet. You can start to see

01:51:59.660 that the pancreatic fat starts to go down because the body's not pumping out. Your liver's not pumping

01:52:05.320 out fat and dumping it in your pancreas. And as you get rid of that pancreatic fat, you're unclogging

01:52:11.140 the pancreas and you're producing enough insulin that you don't get the hyperglycemia anymore.

01:52:16.720 Your glucose isn't that high because now you're at a stage where insulin production is going to go up

01:52:22.660 because they measured that in Royce Taylor's counterpoint study, the one from UK. And you can

01:52:28.060 see that the first phase insulin response starts to go up. It takes a few weeks, but that's exactly

01:52:32.920 what you see clinically. That is, before you lose the weight, which is all a lot of sort of subcutaneous

01:52:38.340 fat, you're getting rid of the visceral fat, the fat around the organs, which is the heart of the

01:52:44.220 matter. The insulin resistance is fatty liver. The beta cell failure is fatty pancreas. You're getting

01:52:49.820 rid of that first. And that's why that diabetes goes away so quickly before you see significant

01:52:56.560 weight loss. So the whole pathophysiology makes sense to me. And to me, I call it medical bariatrics.

01:53:02.780 Fasting is what I call medical bariatrics. You get all the benefits of bariatric surgery without

01:53:06.740 doing any surgery because you can get almost everything the same. Like obviously it's a lot

01:53:11.680 more, you know, you have to do it. The compliance with bariatric surgery is easier than the compliance

01:53:17.540 with fasting. I guess for me, I don't know. I still entertain the notion that there may be more

01:53:22.540 than one way to skin this cat. And that I think bariatric surgery is probably a great example of

01:53:27.660 putting three things in place. I've actually seen data that look at making no change to a patient

01:53:34.280 other than altering the morphology of the duodenum. And that improves type two diabetes, which again,

01:53:42.400 if you bypass the duodenum, you would bypass what that problem is there. So, because you know,

01:53:47.640 the thing with the bariatric surgery patients is they're not fasting for that long, right? They're

01:53:52.660 going to have fasted for 12 to 18 hours before surgery. And nowadays those patients are dripping in

01:54:01.780 liquids that are caloric, even the day of, or the day after surgery. So they might have a 24 hour fast,

01:54:09.680 but there's no question that their caloric intake is lower during that first three or four days.

01:54:15.920 But remember that you've got the malabsorption too, right? So the Roux-en-Y is both restrictive

01:54:21.640 and malabsorptive, right? That is not only do you restrict how much they can eat, the amount they eat

01:54:28.140 doesn't all get absorbed. And that's why I get dumping syndrome and so on. I agree with you.

01:54:32.520 That's a good point. It's hard to do it based on just how much they're eating. I mean,

01:54:35.800 technically we don't know how much they're absorbing. I like your term, right? Which is,

01:54:40.760 look, let's just refer to this as medical bariatrics and it's super potent.

01:54:44.340 When you have purely restrictive things like the lap band, it's like, boy, those things didn't work

01:54:50.560 at all, right? We thought they'd be great. Lap bands, purely restrictive, easy to put in and so on.

01:54:56.480 And it's like, yeah, you look at the numbers of people and they're just dropping. You know,

01:55:02.300 my friend who is a surgeon says, yeah, you know, he used to put in lots of lap bands. He says, now

01:55:07.180 the most common procedure I do is removal of lap bands because everybody wants to get rid of them

01:55:12.020 because the pure restriction didn't work because they're dripping in. They're drinking sodas and

01:55:16.600 they're drinking milkshakes and stuff and they're not getting the malabsorptive part, which is that

01:55:20.880 Roux-en-Y and therefore that was the problem. But I agree with you. I'm not against bariatric surgery.

01:55:25.740 I just think that as a sort of solution for everybody, it's a much more difficult problem

01:55:32.000 because there's a lot of expenses. There's a lot of expertise as opposed to the sort of easy thing,

01:55:37.920 which is, hey, everybody can do fasting. It's just a matter of spreading knowledge and making it easy,

01:55:44.520 right? It's not that people can't fast. It's that people tell them they shouldn't fast,

01:55:49.560 right? Like if you go and look at Ramadan or something like that, right? People can fast.

01:55:54.960 If it's the norm or Lent or Greek Orthodox, if you look at what the norm is, people can follow that.

01:56:02.820 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

01:56:06.980 have a, you know, you have kids, right? It's like after school is a snack. Like you get a, you know,

01:56:12.340 the other day I got a thing home saying, oh, your son is going on a trip, but don't worry,

01:56:16.980 we're going to give him lots of snacks. I'm like, oh, like why? Why did you need to do that,

01:56:22.500 right? Or, you know, you send your kids to play soccer, which I do, right? I did. No,

01:56:28.020 they don't anymore. And it's like somehow everybody thinks that between the halves of

01:56:33.160 soccer, the parents were taking turns, bringing snacks. It's like, you don't need to give them

01:56:38.740 juice and cookies in between halves of soccer. Just let them play the game. The game is fun,

01:56:43.920 right? But it's, it's this culture where it says you must eat all the time. This skipping

01:56:48.120 breakfast is a perfect example. Oh, as soon as you get up, you got to start putting muffins in

01:56:53.900 your mouth. Otherwise you're going to die, right? You're going to die of heart attack. Like what the

01:56:58.660 hell? Did you see the publication a couple of weeks ago that suggested that people who skipped

01:57:04.680 breakfast had a higher cardiac mortality? Yeah, that's what I was referring to. It's like,

01:57:09.600 oh my God. What's your explanation for that study? I'm sure you've been asked about it a dozen times.

01:57:14.020 Because these nutritional epidemiology studies are so dangerous, right? It's because

01:57:18.980 those people, if you tell everybody that you have to eat breakfast, then you're going to select a

01:57:24.780 group of people who don't listen to you, right? And they're going to be unhealthier. They're

01:57:28.540 unhealthier in a lot of ways you can't measure. You can measure smoking, you can measure this,

01:57:32.480 but there's so many things that you can't measure that are going to influence why those people who skip

01:57:37.660 breakfast are more likely to have heart attacks. That association may exist, but it's not

01:57:43.640 causal. And that's the thing, right? It's a correlation, not a causation. And it's a very

01:57:48.040 dangerous assumption to say that, hey, you can eat breakfast and now prevent heart attacks because

01:57:53.220 that's what gets out into the press. Put a muffin in your mouth as soon as you wake up and you'll

01:57:58.120 have less heart disease. That's not what the study shows, but that's the implication that always comes

01:58:02.760 out in the press. My issue with these studies, some of yours, I suppose, is that there's a non-healthy

01:58:08.560 user bias to a lot of these. So one of the more obvious examples are the studies that suggest that

01:58:13.520 diet sodas are worse for you than sodas. But of course, it misses a very obvious or clear thing

01:58:20.260 that might be missing, which is who are the patients who are going to disproportionately consume diet

01:58:24.540 sodas? Certainly a subset of them might be people who are more health conscious and say, well, if I want

01:58:29.600 a soda, I'd rather it be diet than not. But it's more often the people who are being told, look, you can't

01:58:35.860 have a regular soda. And so therefore, you're selecting for less healthy patients. That is my

01:58:40.720 interpretation of that study. Now, while we're on that topic, do you think there are clinical benefits

01:58:47.120 from a 16-8, just to use that example, time-restricted feeding pattern? So if you said to a patient who

01:58:54.800 came in to see you, I want you to only eat between noon and 8 p.m., nothing outside of that, but you don't

01:59:03.260 make any other change. Do you see them get better? We do. So I think that you would do better if you

01:59:11.280 fix what they eat inside that eight hours too. But if you take their diet and just squish it into eight

01:59:17.780 hours, I think that like we see people get better. Like we see people change a lot because as I said,

01:59:23.600 we did sort of one meal a day where we squished it even further. And those people basically, they

01:59:28.500 didn't even change their diet that much. We talked to them about it, but we didn't focus a lot

01:59:32.440 on it. And if you actually probably were to ask them, my guess is their diet didn't change a huge

01:59:36.820 amount. But just by squishing the time that you're eating, you're sort of forcing people away. And I

01:59:42.600 think part of the issue is that in the old days, like in the 70s, what you had was a fairly lengthy

01:59:50.340 fasting period anyway. That's why you have the term breakfast, right? So you eat dinner at 6 p.m. and

01:59:55.920 you eat breakfast at 8 a.m. It's 14 hours of fasting as your baseline, right? And that's every day

02:00:01.300 without even thinking about it. Now it's kind of spread, right? Sachin Panda has done all these

02:00:06.000 studies about how long people actually eat. And it's like, you know, constantly, the minute they

02:00:10.860 wake up to the minute you go to bed, it's almost 15 hours a day that people are eating. I think that's

02:00:14.880 gotten so bad that when you squish it back to a normal sort of 16-8 sort of thing, because 14 hours

02:00:21.900 and 16 hours, like 14 hours was sort of baseline in the 70s and 16 is just a little bit. But because

02:00:27.420 it's gotten so bad, when you squish it back into that, we do see a lot of people who benefit just

02:00:31.820 from that one intervention alone. And, you know, to me, it's always about practicalities. That is,

02:00:37.260 is it easier? So if you have people, for example, say two strategies, one is counting carbs,

02:00:42.500 which I think can work versus counting the number of hours that you don't eat. It's like, it's so much

02:00:47.980 easier to tell people between 12 and 8 is your eating window, everything else, don't eat. Versus

02:00:54.160 look at everything that you eat in the day, try and calculate how many carbs it is and add it up

02:01:01.720 so that you have some arbitrary less than, right? Less than 120, less than 50, less than 20. It's so

02:01:07.820 difficult, whether you're counting calories or whether you're counting carbohydrates or doing

02:01:11.600 macros, right? It's just so difficult to do. It's so much easier to say things like only eat between

02:01:19.020 this hour and this hour and don't eat anything that came in a box kind of thing, right? Those,

02:01:23.440 to me, that's practical, useful advice as opposed to say, let's get your carbs from 55% to 40%. It's

02:01:33.540 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

02:01:39.220 think it's so hard to implement when you're seeing patients sort of every few minutes, right? Like,

02:01:45.080 how are you going to do that from a practical standpoint, right? It's not feasible.

02:01:48.760 I completely agree. I mean, I think there is no simpler instruction than when to eat and when not

02:01:53.600 to eat. And yeah, I think combining these things can often be incredibly potent. I don't know. I've

02:01:58.580 seen mixed results on 16-8, truthfully. I've seen some patients who have really significant

02:02:05.400 improvement. I've seen other patients experience no improvement whatsoever. We typically will push that

02:02:10.360 window tighter, 18-6, 22-2. Again, the tighter you push it, the more benefits you see. But I've really

02:02:17.260 seen no substitute for what I call intermittent fasting. We use that terminology very distinctly.

02:02:24.400 We reserve the term time-restricted feeding for up to 24 hours of restriction, but we use the term

02:02:30.880 intermittent fasting to describe what I think that term means, which is you intermittently,

02:02:36.360 periodically, i.e. fast. And fasting can be a complete reduction of calories, or it can be a

02:02:44.740 hypocaloric fast. So you can consume somewhere between 20 and 40% of your normal caloric requirement

02:02:53.460 for a period of time, typically look at three to seven days, and you repeat that cycle. What type of

02:03:00.220 protocols do you use for intermittent fasting with your patients? We use all of them. So because

02:03:05.900 we're predominantly clinical, we'll individualize. So the things we take into account is one,

02:03:13.060 how severe is it? So a severe type 2 diabetic on a huge amount of insulin, we're going to give a more

02:03:20.060 stringent schedule than somebody who's just sort of pre-diabetic and wants to sort of prevent it from

02:03:25.920 getting into diabetes. So the other thing is how old they are and how willing they are to do it. So we

02:03:31.280 see a lot of people who are in their 80s. We have people in their 80s doing like, you know, we had a lady

02:03:35.580 who was like, I think she did 61 days, right? And she's not young, right? And we have people in the

02:03:40.800 80s, nothing. Yeah, that's what she said. Although sometimes when you actually go into it, sometimes

02:03:46.120 they have little things here and there. But she said she did 61. We have lots of people who do long

02:03:52.560 fast like that, and they don't have any problems. We monitor them very closely, though. But generally,

02:03:57.020 we don't do that. There's no point taking that much risk. A lot of times, she actually just felt good

02:04:02.480 on it. So that's why she did it. But we don't usually push it long like that. But we will if

02:04:07.020 we need to. But it depends on how quickly. So it's how severe is it, how old the patient is,

02:04:12.340 and how urgent it is. Because we have people who have a ton of disease, right? And we're like,

02:04:17.380 if you don't get this diabetes fixed, like right now, you're going to be in a world of trouble.

02:04:21.500 So we had this guy, he's actually in his 40s. He had a non-healing diabetic foot ulcer for like a

02:04:27.920 year, followed by a plastic surgeon. So he actually came into the hospital. And I saw him

02:04:32.360 because I was seeing him for his diabetic foot infection, gave him antibiotics. And I said,

02:04:37.320 you know, your problem is not your foot. Your problem is your diabetes, right? Because

02:04:42.920 you know, the reason you have this foot ulcer is because of diabetes. You don't get foot ulcers if

02:04:48.660 you're not diabetic, right? Unless you have severe PVD or something, right? But the point is that

02:04:53.920 if it's diabetes was just causing your foot ulcer, you got to get rid of your diabetes. I talked to

02:04:58.680 his dad because this guy was like in his 40s. And the dad was Greek Orthodox. So his dad was like,

02:05:03.360 oh, yeah, yeah, yeah, yeah, let's do this. So we put him on and we put him on fairly strict

02:05:07.960 restriction. We started him, I think, on a week of fasting and then 36 hours, three times a week.

02:05:14.340 And that ulcer healed like within three weeks. It was like ridiculous how quick that thing

02:05:19.420 just healed up. You led with a single week of fasting before cycling 36 hours weekly? Or did you

02:05:26.900 lead with the 36 hours? No, I started with the seven days and then we did like 36 hours because

02:05:32.360 it was severe. Honestly, he was going to get his foot chopped off at some point. You're definitely

02:05:37.020 more aggressive than I am because you're seeing much sicker patients. I never lead off with water

02:05:43.160 only fasting for patients. Usually what we do is we go, we push the windows of time restriction,

02:05:49.800 which as I said a moment ago, I'm not convinced there's huge benefit in time restriction. I think

02:05:53.600 there's some benefit. I think the biggest benefit of time restricted feeding is the psychological one.

02:05:58.560 It's breaking the cycle you just described earlier, which is people think intravenous access to food

02:06:06.040 is essential for life. If they go more than two hours without a meal, the sky is going to fall.

02:06:10.740 And so in many ways, time restricted feeding is just a way to prove to them that that is total

02:06:15.120 nonsense. I actually think that the long fast do exactly the same thing. Well, yes, yes, yes. But

02:06:20.180 you can't, you can't lead. I mean, at least for me, I haven't tried leading off with that. Talk me

02:06:25.140 through like that particular patient. So first of all, let's grant it that he now has agreed to try

02:06:30.580 this. This is a patient who is not entering a fast the way I would enter a fast, which is I usually

02:06:36.320 spend a week in ketosis before the fast, which means I'm showing up in a fast with a ketone level

02:06:42.160 of somewhere between 0.5 and one millimolar of beta hydroxybutyrate. I sail generally pretty easily

02:06:49.100 into these fasts, not all the time. This is a guy who's got a respiratory quotient of one. He is a

02:06:56.380 completely obligate glycogen consumer. He's probably not oxidized a fatty acid since Guns N' Roses were

02:07:05.700 popular. This is a guy who's going to be in for a world of hurt when you strip food away from him

02:07:11.700 because within a few hours, he's going to sense, his liver will sense glycogen levels are low.

02:07:19.020 It's time to eat. So how are you getting him through that? There's no easy way. We just tell

02:07:24.440 him this is like going to suck for a week because you're not going to feel that great. You're going to

02:07:29.980 be hungry and all this sort of stuff. It was the urgency. And I'll tell you that people actually can

02:07:35.320 do it. You know, quite a lot of people have. We've done it on a number of people and most of the

02:07:40.600 people, as long as you warn them ahead of time that it's going to be tough, they get through it.

02:07:46.320 But the thing is that the psychological, if you've done a week, you know that 24 hours is like nothing

02:07:51.900 and you get into ketosis so fast because that's the fastest way to get into ketosis, right? It's just

02:07:57.440 too fast. There's no faster way that you can do it than that. So it's not easy, but there's reasons

02:08:03.260 why. And that's why I say it's important that everything is individualized because I'd never

02:08:07.380 do this to somebody who's like 40 and has an A1C of like 6.0. It's like, why put yourself through

02:08:14.360 that, right? Do it gradually. You have no time restrictions. This is a guy who's actually

02:08:19.100 coming into the hospital with diabetic foot ulcers that were getting close to osteomyelitis,

02:08:24.820 right? It's like, it's a much different situation than not, right? I'm trying to make sure that somebody

02:08:30.260 doesn't wind up, he doesn't wind up getting a bad infection and somebody wind up chopping

02:08:33.980 his foot off, which is why I was super aggressive in that case. I've heard stories of other people

02:08:39.000 who have put patients on starting sort of 10 day fast and so on. So they don't all do

02:08:44.580 well. They don't all get through it, but it's an option. That's all I'll say. And I hate to

02:08:50.320 be prescriptive like, oh, you have to do this. You have to do this. And this is what seeing

02:08:53.960 patients does to you. I find that the people who are super dogmatic are the people who never

02:08:59.080 see patients. Yeah. I can't agree with you more. Yeah. Because patients always prove you wrong.

02:09:05.380 You think your stuff works. Well, like 40% of your patients, it doesn't work in, right? So then I'm

02:09:11.780 like, I'm never like, oh, you have to do this. You have to do this because it's like, yeah, I know it

02:09:16.480 doesn't work. Like carb restriction. Like some people, it really does work well. And some people,

02:09:22.360 it really doesn't work that well. And the studies show the same thing, right? Chris Gardner's study.

02:09:26.360 If you look at the splay between low fat and low carb, some people do great on a low fat diet and

02:09:31.940 some people do terribly on a low fat diet. It's the same diet. Same with the low carb. In general,

02:09:37.440 the low carb people do better. But when you look at the individual differences, that's why people get

02:09:42.720 on Twitter and they start talking about, oh, it's all about this or it's all this, all this. Then it's

02:09:49.700 like, I know you don't treat people because if you actually treated people, you'd never say stuff like

02:09:55.560 that. You'd never get on somebody about taking the opposite position because you've been proven

02:10:00.260 wrong. So many, like every day I'm proven wrong, like something doesn't work. And that's why I'm

02:10:04.560 always like, let's do this. See if it works. If it doesn't work, we're going to adjust it.

02:10:08.660 And then if it works better, then we're going to keep doing that and we'll adjust it. Right. And

02:10:12.320 that's, that's where the kind of art of medicine comes in. So you can start, but to me, I always tell

02:10:17.300 people like, there's two options when you do fasting. It's like going into a pool. You can wade in

02:10:22.060 or you can cannonball it. Right. And both are acceptable. One's a big shock to the system,

02:10:28.760 but it works. And the other is not as big a shock and it still works for this particular patient.

02:10:33.860 You know, that was one of the few, few times, because most of the time it's not that urgent

02:10:37.880 that I did recommend, oh, you just got to do this. And his father was on board and he was on board and

02:10:43.020 we monitored him super closely. We actually started him in hospital because he happened to be in hospital

02:10:48.260 anyway. So I put him on clear fluids. Right. And then, then just told him, don't take anything

02:10:53.020 with sugar, just, just water. And, and, and, and he did very, very well. And I've done it to a few

02:10:57.720 other people with diabetic foot ulcers as well, because I consider that one of the, the more

02:11:02.900 difficult, like that's, that's something that you really have to take care of. And I always think

02:11:06.920 diabetic foot ulcers to me is fascinating because it's like, if you think about this overflow paradigm,

02:11:12.140 it's like, why do diabetics get these infections that nobody else gets? Why do you get

02:11:17.340 mucormycosis? Why do you get osteomyelitis? Why do you get diabetic foot ulcers? You don't get like

02:11:23.520 foot ulcers from ischemic cardiomyopathy foot ulcer, right? You don't get that ischemic

02:11:28.960 cardiomyopathy mucormycosis. It's like, it's because what you're doing is you're putting all

02:11:34.480 this sugar into the body. Then when the blood glucose goes up, you give them insulin to really

02:11:40.220 jam that sugar into the body, right? And the body takes it and your liver gets all this sugar and starts

02:11:46.320 sending it all over the place. Pretty soon, your whole body is so full of sugar that everything

02:11:51.840 just starts rotting. And that's why you get the kidney disease. That's why I get the eye disease.

02:11:56.000 And that's why the bugs just love it because there's so much sugar and nutrients everywhere.

02:12:01.600 So they get in your foot and they never go away. Those foot ulcers never heal. You get these weird

02:12:07.700 infections that you never see anywhere else. You get the, you know, the rashes, the incanthosis and all

02:12:12.820 that. It's just, you got way too much sugar. It's all about the whole body sugar and not just the

02:12:17.740 blood sugar. That's the real shift in thinking and paradigm that to me makes a lot of sense. And as

02:12:23.600 soon as we're able to empty out all that sort of sugar, and I always use the analogy of a sugar bowl,

02:12:29.040 we're just filling up the sugar bowl. You got to empty that sugar bowl and then the sugar won't spill

02:12:33.060 out. And that's why it works. And the fasting is the same thing. So we'll individualize it. So based on

02:12:38.560 all those sort of factors, like including what they want to do, right, you got to talk to people

02:12:44.280 and say, what are you willing to do, right? And a lot of people aren't willing to do a long fast,

02:12:49.400 but a lot of people are actually, it's striking.

02:12:51.820 What percentage of your patients are willing to do a water only fast for at least a period of three

02:12:58.160 days?

02:12:58.900 Right off the bat, because we offer this as a treatment to everybody. We don't say,

02:13:03.600 okay, well, if you've never heard of it, we'll still recommend it. And like 50% right off the bat

02:13:08.340 won't do it. Any fasting at all, right? They're so like ingrained. And I had this discussion yesterday

02:13:14.780 with a fellow. I told him, oh, he needs to fast. He was, he was developing, you know,

02:13:19.720 proteinuria and he was going into renal failure. And I said, really, you need to fast. And he says,

02:13:23.940 my endocrinologist says I can't fast. No way. So it's like, okay, that's it right there. So 50%

02:13:29.360 of people won't fast for any period of time at all, like not even like five hours, right? So it's

02:13:36.100 changing. I think views on fasting are changing, but you can see like, you know, did you read that

02:13:41.780 whole thing with Jack Dorsey? He gets on CNBC or whatever, and everybody goes like crazy that,

02:13:49.340 oh, he doesn't eat for 24 hours. It's like, what's the big deal? Like, why do you think we carry body

02:13:54.840 fat? Right. And it's like, look, he's looking good. He feels good. What's the big deal? Why are you

02:13:59.880 getting on him? Right. But the idea is so ingrained that we have to eat, have to eat, have to eat,

02:14:05.020 even to lose weight, we have to eat, that they won't do it. So if you take away the 50% who won't

02:14:10.960 do it right off the bat, then you have people who will do it for short periods of time. And probably

02:14:15.480 only about 20% might agree to like a longer fast, mostly. And it's not the physical side that actually

02:14:22.660 gets them. It's always the psychological side. The physical stuff is super easy to deal with.

02:14:28.600 It's the psychological part that's really hard. That is, when you're looking at somebody who's eating,

02:14:34.340 and you're trying to fast, it's like really hard, right? And yeah, you can do it once in a while.

02:14:38.660 But if you do it sort of breakfast, lunch, dinner, breakfast, lunch, that's the hard part. And that's

02:14:43.180 where we focus a lot of our attention, working on the psychological, how to set your environment up

02:14:48.440 for success and coming up with different strategies for success and creating a supportive community

02:14:55.000 that's going to help your success. That's the hard part. Because think about religions like

02:15:00.380 Ramadan, how do they all fast? Because people say, oh, I could never fast. It's like, but you know

02:15:04.680 that literally hundreds of millions of Muslims fast? It's like, it's because the environment

02:15:10.200 is supportive. If all your friends are doing it and all your family, it's not fun, but it's not that

02:15:17.000 difficult to actually do it. And that's the difference. And now we're recommending it for

02:15:21.780 people who have no community. And that's what we're trying to create, community of people who are

02:15:26.380 accepting. And also that's part of the point of bringing it into the mainstream. I wrote a couple

02:15:31.700 of books about this, of course. And that's the point. If I wrote a couple of articles that I sent

02:15:37.140 to JAMA or something to get peer reviewed, first of all, the peer review would kill it. And then second

02:15:43.740 of all, you'd get no traction whatsoever. And then you're not doing anybody any good. Because by making

02:15:49.060 it sort of more out there, you make it more acceptable for people to talk about it and to accept it as a

02:15:55.080 viable treatment. So let's go through some of the stuff. So that, let's say that that 40 year

02:16:00.540 old patient, first of all, appreciates the severity of what you've shared with him and his dad, which

02:16:04.420 is, look, it's one thing to have diabetes, which you do, but you're actually in quite a late stage

02:16:09.180 of this. If you're, I mean, I don't remember the literature on this, but from my days in surgical

02:16:14.720 training, the five year mortality, once you have an amputation with type two diabetes is staggering.

02:16:22.220 So I don't remember what it was, but it was so high that the point was once you're getting a toe

02:16:28.220 amputated or a foot amputated or something like that, the probability you're going to be alive in

02:16:33.280 five years is incredibly low. So I could be wrong on this, but I feel like the five year mortality was

02:16:37.980 something like 70%. So if you're in your forties and you're already getting a diabetic ulcer, that's

02:16:43.300 not healing, there's a non-zero chance. There's actually a significant chance you're not going to

02:16:47.760 make it to your 50th birthday. So he says, I'm in. You mentioned something that I think can't be

02:16:53.920 overstated, which is you have to be in a supportive environment. So if a patient tries to fast and they

02:16:58.920 are surrounded by people, both their friends and family, and also their other medical practitioners

02:17:04.400 who are telling them this is a horrible idea, well, that's a recipe for failure. So now let's posit

02:17:10.060 that we've also got the support of the medical team and the friends and family. What are some of the

02:17:16.420 other tricks and trades? I mean, one of the things that I hear a lot about is, Peter, my sleep is

02:17:20.780 really hard when I'm fasting. How do you address that? Yeah, that's a tough one because they all can't

02:17:27.160 sleep. There's not that much to do. We tell them, one, to expect it. So it's one of the things is that

02:17:35.660 if they know about it ahead of time, then they're much more accepting. So we say, look, you may have a lot of

02:17:42.200 trouble going to sleep because people get so, people don't understand, but the whole sympathetic

02:17:46.520 nervous system and everything gets revved up, right? And our adrenaline and all that stuff gets

02:17:50.380 revved up. And a lot of people actually can't sleep. And we say, well, you know what, if you find

02:17:55.160 that, then, you know, stay up, do some work and so on and don't worry about it, right? This is a

02:18:00.180 temporary situation. It's not going to last forever. We just want to make sure that everything

02:18:04.420 gets better. And that patient, I don't think he had any sleep trouble, but we did warn him. So we,

02:18:10.040 one of the things we do is we warn him ahead of time of all the potential problems. So it's like

02:18:13.980 the book, What to Expect When Expecting, right? So it's not like it makes the symptoms any better,

02:18:19.220 but it makes dealing with it a lot better. So we tell them, hey, look, you can have headaches.

02:18:23.920 Those will go away. You can have cramps. This is what to do. You can have diarrhea. This is what to do.

02:18:29.100 You can have constipation. This is what to do. Sleep is, you know, you can expect this and you need to

02:18:34.780 watch this in terms of your blood sugars and so on. And this is what to do with your medications.

02:18:39.400 And that patient, we actually, I think his last A1C that we saw was like 5.9, which here is actually

02:18:45.720 classified as non-diabetic, not even pre-diabetic. So we took him from a couple of medications and

02:18:51.140 a non-healing diabetic ulcer to non-diabetic. Like within a couple of months, yeah, it took a little

02:18:58.880 bit longer than somebody else. And everybody responds differently. And even a couple of years later,

02:19:04.480 he's like non-diabetic, right? So it's like, that was the whole point we missed. You know, in medicine,

02:19:09.380 it's so difficult because we're so ingrained into these patterns of thinking. That is, you have

02:19:15.120 obesity, which causes type 2 diabetes, which causes a foot ulcer. So we get the plastic surgeon

02:19:21.240 to deprive the ulcer. It's like, that's the least important part. You need to get rid of the diabetes

02:19:29.180 and get rid of the obesity. And then he will actually get better. So warning people ahead of

02:19:35.720 time is one thing that we do. And it doesn't make the problem any better, but it makes them

02:19:40.420 deal with it. One, they trust you because they go, oh, hey, I got a headache for three days. And then

02:19:46.500 it went away. So they know you know what you're doing and that gives them confidence. And then just

02:19:51.980 having that support. So he had his father, of course, who was going, yes, yes, yes, you need to do

02:19:57.120 this. And that came from his religion. So it was a good setup for that. Many times we'll actually get

02:20:03.360 the opposite, which is what you're saying is that I'll get that patient. I'll say, this is what you

02:20:07.440 need to do. The family says, oh man, that's crazy. And the family doctor says, oh man, that's crazy.

02:20:13.540 And the endocrinologist says, you must never do this. Then nothing changes, right? They have this

02:20:18.200 and so on. My tip on this one, Jason, is that in anticipation of that sympathetic outflow,

02:20:26.280 we recommend that patients take phosphatidylserine with the fast in the evening. And that sort of

02:20:33.140 calms down the adrenal glands. And then even just an oral over-the-counter GABA, unfortunately it's

02:20:39.720 becoming harder to get centrally penetrating GABA over the counter, but even just peripheral GABA will

02:20:46.340 sort of take down some of that sympathetic tone. So that coupled with some other sort of sleep

02:20:52.400 supplements actually not only tends to help people sleep, but a number of people note that you can

02:20:58.040 have some of the best sleep imaginable with those lower levels of glucose, higher levels of ketones.

02:21:03.300 Now, what about electrolytes? How do you manage the electrolytes, in particular sodium and magnesium

02:21:07.300 during these longer fasts? There's nothing specifically we do actually. So we monitor it

02:21:13.120 very closely, of course. Magnesium is the one. So everybody worries about sodium and you can get some

02:21:18.120 people who do get a bit sodium depleted. But if you're otherwise healthy, your kidneys should never

02:21:22.600 get to that state because there are people from the Intersalt study, there are people that actually

02:21:27.580 barely eat any salt at all and still survive fine. So your body should be able to reabsorb all the

02:21:34.400 sodium it needs. Magnesium is a bit more difficult because a lot of type 2 diabetics are depleted of

02:21:40.160 magnesium to start. So we'll often recommend magnesium supplements. And that's where a lot of the

02:21:45.100 cramps and so on is kicking. Some people do get a little dizzy and so on. So that's when we use the

02:21:50.140 bone broth, which is technically not a fast, but it's like got calories and, you know, amino acids

02:21:55.660 and stuff. But that's where we'll use bone broth, for example, where you can put a decent amount of

02:22:00.180 salt in and take it and still feel well. We monitor the electrolytes more just because we want to make

02:22:07.200 sure that nobody's getting into trouble. But I'll tell you that the number of times that I've actually had

02:22:12.480 to intervene or tell somebody to stop a fast because of electrolytes is like zero, I think.

02:22:18.760 I don't think I've ever had a case where the blood work came back and said, oh my God, they have to

02:22:23.520 stop. There are some other things like if they get diarrhea, for example, and it can be fairly

02:22:29.440 significant, then that might play a role. But, you know, when they get those, we tell them to stop.

02:22:34.840 And we are always like, you know, we're always super cautious because we monitor them very closely.

02:22:39.400 These are relatively sick patients, right? So they generally have a lot of medical issues,

02:22:43.980 but we monitor them very closely and we give them very careful instructions that, hey, if you don't

02:22:48.640 feel well, you need to stop right away. Don't even tell me. Stop it and then tell me, right? Because

02:22:55.780 the point is that you can, let's figure out what's going on. Then if it's a solvable problem,

02:23:03.140 then we can do it starting tomorrow or we can do a totally different regimen, shorter fast more

02:23:09.920 frequently. We're not stuck to this one thing or we can do ketogenic diets or we can do something

02:23:15.360 else, right? There's all kinds of things that we can do without doing a long fast. And some people

02:23:20.680 actually hate the long fast and some people actually love the long fast. So we always say, don't get so

02:23:25.880 rigid in your thinking that you have to push through. Like the one thing we tell people

02:23:30.660 more than like, don't just push through because that's when you're going to get yourself into

02:23:34.860 trouble. There's always tomorrow to start another fast. If we figure out what's going on with this.

02:23:39.800 Don't you find it's helpful to explain what you're pushing through? I mean, for example,

02:23:43.700 even if I fast for seven days, there is no day during that seven when I am not at least at one

02:23:49.620 point quite hungry. Oh yeah. The hunger for sure. We always say you can be hungry, but make sure you're

02:23:54.820 not like lethargic or something. I think it's important for patients to understand even seasoned faster

02:24:00.460 still get hungry. But what I find interesting in my wife who doesn't fast, but is sort of

02:24:05.180 interested in like why I do it. She can't believe it, right? She can't believe that, you know, I'll

02:24:10.980 work long, hard days and exercise and do all that stuff while fasting. And she's like, aren't you just

02:24:15.320 starving? And I said, truthfully, yes, every single day I feel quite hungry at some point in the day,

02:24:19.740 but it's never more hungry than on a regular day. If I'm getting really hungry, like being hungry on the

02:24:26.720 seventh day of a fast is not a more profound hunger. It's the anticipation of that that becomes

02:24:32.680 problematic, which really speaks to the Shakespeare quote about nothing is either good or bad, but

02:24:37.820 thinking simply makes it so. The anticipation of that hunger seems to be a bigger problem.

02:24:43.640 Maybe for your patients, it's less of a concern because the highest priority is the amelioration

02:24:48.100 of the diabetes. But do you spend much time thinking about how they can minimize muscle mass loss

02:24:54.640 with the obvious loss of protein intake? Or do you just say, look, it's so intermittent that we do

02:25:00.900 this fasting that we're going to take whatever we have to take in the most catabolic sense and then

02:25:05.980 deal with it on the back end? Or do you do anything specifically with respect to exercise?

02:25:09.240 Nothing specifically, because again, I'm treating different population. Like I'm not treating

02:25:13.760 bodybuilders, right? I'm treating 65 year old women. For them, it's like, they don't even know how

02:25:19.840 much muscle mass they have. And honestly, I'm not even sure. Like there is some protein loss and I'm

02:25:25.660 not sure that's a bad thing. I mean, I think that most people actually don't get a lot of muscle loss.

02:25:32.320 Like you can get protein loss, which is connective tissue and skin. And this is one of the things that

02:25:36.280 people always rag on me about, but this is clinical medicine, right? So I've treated thousands

02:25:42.280 of people with fasting and some have lost a lot of weight, like hundreds of pounds. And I've documented a

02:25:47.120 few case studies in my blog and stuff. And one of the things that's very unusual about fasting for

02:25:53.080 weight loss, as opposed to weight loss for other things, is that we don't see the skin problems

02:25:57.040 because skin is protein. Like it's not fat, right? Skin connective tissue, it's protein. And you do go,

02:26:02.760 when you do the intermittent fasting, you do go through that period where you have gluconeogenesis

02:26:07.300 and you're breaking down protein. That's the whole point of autophagy, for example, is breaking down

02:26:11.520 protein. It's not fat. And I'm not sure that it's a bad thing. So we actually get much less. I've never

02:26:16.940 referred a patient for skin removal surgery. And some people have lost like 150 pounds for like

02:26:22.560 years, right? And they actually don't notice the problem. A couple of my colleagues who I work with,

02:26:28.220 and they've noticed the same thing, that you don't have as many of the problems that you do

02:26:33.700 with regular sort of weight loss, which is chronic calorie restriction, where you get these big

02:26:38.860 flaps of skin that you have to go in surgically and take out. The question is, why doesn't your body

02:26:44.860 get rid of them? Because it's superfluous. Your body shouldn't be keeping it around. Your body

02:26:49.620 should be getting rid of it. And it doesn't, because you never went through this period where

02:26:54.280 you're undergoing gluconeogenesis, where you actually are breaking down protein. So do you get

02:26:59.520 more muscle loss? There's been a couple of studies on alternate daily fasting, which really haven't shown

02:27:04.720 increased muscle loss or lean loss. I think that the protein loss is often confused and called

02:27:11.860 muscle loss. To me, it makes no sense. Like your body has a system. And I'm not talking the situation

02:27:18.860 where you have 4% body fat, right? I'm talking about a situation where you have 30% or more body fat.

02:27:25.080 It makes no sense that the body should store food energy as glycogen and body fat. But the minute you

02:27:33.380 need to use it, you start burning muscle. Do we think our bodies are really just that stupid,

02:27:39.460 that they're going to do that? It's like storing firewood for the winter. And then as soon as you

02:27:45.460 need to use it, you chop up your sofa and throw it in the fire. Like who would do that? But we think

02:27:50.920 that our bodies are just that stupid. Like I don't think their bodies are that stupid. I think that

02:27:56.420 there's a period which is fairly limited during the fasting where you have gluconeogenesis. Then you

02:28:02.480 can see fat oxidation goes way up, right? And Kevin Hall, I think, did some of these studies on what

02:28:07.820 happens. And Cahill, of course, did all those studies, you know, on what happens during actual

02:28:13.200 starvation. And you got to remember that he was no wimp, right? These are like 60 days of fasting,

02:28:18.780 right? Not like 16 hours. It was huge. And these people were not even overweight. It was, you know,

02:28:25.280 there are some studies that you just think, wow, how did they get away with that?

02:28:29.500 It was before the days of the IRB.

02:28:31.800 I know. There was a great study. I don't know if you've seen this. There's two studies

02:28:36.240 where they took people who were not even overweight. They fasted them for 60 days and

02:28:41.660 gave them a big slug of insulin. It's like, why? It's like, just to see what would happen.

02:28:47.400 Well, no, no. I mean, that study was to actually see if the ketones were protective in the presence

02:28:52.620 of hypoglycemia. They injected those patients with insulin, took their glucose down to below

02:28:58.200 one millimolar. These people just are walking around with it. Yeah, they did totally fine,

02:29:02.000 provided they had enough BHB. That's incredible. Yeah, it's incredible. But you'd never get that

02:29:06.840 study done today. You'd get thrown out, like you'd get laughed at, right, by the IRB. Like,

02:29:11.020 you're going to drop people's glucose to less than one? Like, are you serious?

02:29:14.980 Everybody now thinks if you don't eat for 24 hours, you can get seizures, right? But the point is that,

02:29:20.260 yes, it was for the ketones and stuff. But it's a great study, like stuff that you just couldn't do

02:29:25.040 these days. But the amount of protein, so when you look at all the Cahill studies and all the

02:29:29.180 classic studies of fasting, that's a relatively limited period that you're actually burning,

02:29:34.700 you've got the gluconeogenesis and you're burning protein, which I actually think is a beneficial

02:29:38.800 thing in the right situation where you have somebody with obesity and so on. And if you look

02:29:45.620 at studies, like Nuttall did a bunch of these studies, and he tried to estimate how much excess

02:29:51.620 protein somebody who is overweight has. It's like 20% to 50% more protein than a regular person.

02:29:57.840 There's more skin, there's more muscle, there's more connective tissue, there's blood vessels,

02:30:02.960 there's all kinds of extra protein that goes along with being overweight. And that all needs to go if

02:30:08.420 you're going to do it. So I'm not actually worried. So again, I've treated a few thousands of patients

02:30:15.860 with type 2 diabetes. Remember, I'm not talking about the guy who has 4% body fat and is a bodybuilder

02:30:23.100 and can tell how much muscle he has based on how much he can lift. I'm talking about

02:30:26.500 the 65 year old person with a lot of body fat and generally excess protein. In that case,

02:30:33.720 the question is, how many patients have I had to stop because I was worried about muscle loss? That

02:30:39.800 would be like zero, right? In six years. And because I use it in a therapeutic manner, that is,

02:30:46.000 I'm not treating one person a week sort of thing, right? It's like every person who comes in every 10

02:30:50.280 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

02:30:54.380 clinical practice. So it's like hundreds of patients a year. And over six years, it's like

02:30:59.420 thousands of patients, like zero people had to stop because I was worried about muscle loss, right?

02:31:06.240 So it's like, okay, tell me how that is going to be a big concern to me, right? And this is where,

02:31:11.100 again, it's like people who don't fast and people rag on me all the time about this, right? It's like,

02:31:17.440 oh, what about this? What about this? I'm like, okay, how many thousands of patients have you done

02:31:21.520 this for? Try it on several thousand patients and then come back to me and tell me if muscle loss is

02:31:27.200 the most important thing for this 65-year-old 300-pound man on 150 units of insulin.

02:31:33.660 It's a totally different situation. Last question, because I know you've got to get back to clinic.

02:31:37.760 We've taken you away from it. Do you think there's a role for this type of fasting in people

02:31:42.600 who are actually healthy, but looking to get benefit that goes beyond getting rid of a disease

02:31:50.340 they don't have? In other words, if you take a person who's not hyperinsulinemic, i.e. insulin

02:31:55.860 sensitive by these definitions though, we made a pretty good case that everybody's insulin sensitive

02:32:00.460 without a lipodystrophy, but you take a non-obese, non-diabetic, non-NAFLD, insulin sensitive,

02:32:07.140 non-hyperinsulinemic individual who's asking the question, will periodic fasts reduce my odds of

02:32:14.500 chronic disease down the line? How do you feel about that? Absolutely, yes, because look, the point

02:32:20.620 of fasting is to lower insulin levels, right? So if you fast and you're healthy and you're not

02:32:25.580 hyperinsulinemic, well, if you do periodic fasting, it doesn't have to be a long time or, you know,

02:32:32.180 even that frequent, right? So if you look at the 70s, right, a typical person who is eating three

02:32:38.000 meals a day, 14 hours of fasting every day, and then once a year, maybe on Yom Kippur or during

02:32:45.140 Lent or during Ramadan, he'll have a little bit longer fast. But there are times he's eating a lot

02:32:49.980 too, right? Christmas and all this sort of time. So that's just the balance, right? It's all about

02:32:55.340 balance. Like this is the whole point is that you have to balance periods where you have going to take

02:33:00.880 a lot of food like Christmas. You're eating, you're eating, you're eating, you're eating. Now you want

02:33:04.840 to balance that with like Lent where you're just not going to eat a lot because that's what they

02:33:09.580 told you to do. So this is what's going to happen is that you're going to drop your insulin levels

02:33:15.620 periodically, which will prevent you, right? It's going to clear out all that sugar every once in a

02:33:20.300 while and then prevent you from getting diseases of hyperinsulinemia. So if you drop your insulin every so

02:33:26.140 often, you're going to prevent yourself or lower your chance of getting diseases of hyperinsulinemia.

02:33:30.880 which are heart disease, stroke, cancer, Alzheimer's disease, type 2 diabetes, obesity. Well,

02:33:39.260 that's the major risk of our current population. So you want to lower your risk of getting those?

02:33:45.040 Great. Like you're not going to lower your risk of getting pneumonia. Like you're going to lower your

02:33:48.940 risk of these diseases of hyperinsulinemia. So for a healthy person, yes, I think fasting is very

02:33:55.200 beneficial, but you don't have to do five days of fasting every month or something like that,

02:34:01.180 right? You could do a little bit longer fasting once in a while and maybe not do some bedtime snacks

02:34:07.420 and stuff. But you don't buy the argument then that, for example, Walter Longo's FMD, which is a

02:34:13.120 type of intermittent fast. I know you know what it is, but you know, listener might not. So, you know,

02:34:17.760 this is one of literally a hundred different ways you could fast, but he would suggest that based on a

02:34:23.560 certain set of macronutrients, you're consuming about 1,000 calories followed by 750 calories for

02:34:29.920 four days. And that gives you a five-day cycle. And he talks about doing that quarterly and would

02:34:35.480 argue that there are actual longevity benefits, even in the non-diabetic or non-metabolically ill

02:34:41.840 person. Again, I think for some people that sounds really extreme. Personally, I don't think it's that

02:34:46.560 extreme. In your patients, that doesn't seem extreme.

02:34:49.680 It's actually fairly routine for a lot of the people that we talk to. But again, it's a different

02:34:55.560 patient population. For healthy people, I think that the data is just not there. So, prevention of

02:35:03.220 Alzheimer's, prevention of cancer, treatment of autoimmune diseases, for example, Walter's talking

02:35:10.300 about sometimes, I don't think that there's enough data to say yes or no. Like, could it work? Absolutely,

02:35:15.860 it could work. I actually think that there's a good reason to think that these things will work

02:35:20.660 to prevent a lot of those diseases. Like, not necessarily. So, of course, to me, all the diseases

02:35:25.580 of excessive growth and hyperinsulinemia, to me, are clearly are going to reduce your risk. But now

02:35:31.620 you're talking about other diseases, like autoimmune diseases. And I think that there's good reason to

02:35:36.760 think why they might work. But is there data to show it? Not really.

02:35:40.700 Yeah, this gets back to the first point of, will we ever have evidence-based guidelines to support

02:35:46.220 this? I think it's impossible, not improbable. And therefore, we are stuck thinking about this

02:35:52.880 through mechanistic lenses.

02:35:54.420 Yeah, but see, the thing is that, again, people have it all wrong. Because people say, okay,

02:35:59.440 so say they're talking about a five-day fast once a quarter or something like that. Whether you do

02:36:03.940 fasting mimicking or regular fasting, let's say somebody says, you should do five days of fasting

02:36:09.360 once a quarter or once a year. Okay, so the evidence-based medicine people are always way

02:36:15.080 off because they say there is no evidence to suggest that five days of fasting once a year

02:36:20.560 is beneficial. They're right, but they're completely wrong from a clinical perspective.

02:36:25.320 Because there's also no evidence that five days of fasting a year in a person who's normal weight

02:36:29.860 and otherwise healthy is harmful to you. So now you have to say, what is the risk of doing that

02:36:37.160 five days of fasting? So five days, so in a year, you will eat three meals a day. One year,

02:36:42.880 you'll eat 1,000 meals. For five days, you're going to make 15 meals out of 1,000. That's it.

02:36:48.280 That's the extent of what you're doing. What is the risk of that? I'll tell you, it's just about

02:36:53.120 zero. Like, yeah, you're going to be hungry and stuff. But if you're otherwise healthy,

02:36:57.220 the risk is very, very, very low. And then you say, what is the benefit? Well, there's not

02:37:01.820 really any great evidence of benefit either. But because your risk is so low, your risk to reward

02:37:07.300 ratio is pretty reasonable. Why wouldn't you do it? That's the question, because the risk is so low.

02:37:15.260 Maybe there's no benefit. Maybe there is a benefit. I can't tell you, right? And it's the same for all

02:37:19.700 drugs. You know that there's a certain number needed to treat. So a number needed to treat of 50

02:37:24.340 means that 49 out of 50 people simply do not benefit from that drug that you gave them. And it's going

02:37:30.620 to be the same for fasting. There's going to be one person who benefits and 50 people who don't

02:37:34.920 benefit. But the risk to reward, because when you give a drug, the risk starts getting so high

02:37:40.060 that the risk to reward ratios, they don't make sense. But for something like fasting,

02:37:45.840 missing 15 meals out of 1,000, yeah, it can make sense. And that's why, you know, all these sort of

02:37:53.640 EBM zealots are all like, oh, there's no evidence. There's no evidence. It's like, you don't need

02:37:57.380 evidence. It's assessing the risk and the reward and what clinically makes sense. To me, if I had,

02:38:04.340 for example, some kind of autoimmune disease, so let's take this disease, rheumatoid arthritis,

02:38:09.280 that there's no evidence that fasting is going to do anything for. And Dr. Longo says, well, you know,

02:38:15.100 you can reset your immune system if you do seven days of fasting. What would I do? I would absolutely

02:38:20.820 do it as opposed to taking a bunch of toxic drugs like prednisone. Like, you've seen what prednisone

02:38:26.680 does to people. Why wouldn't I do seven days of fasting? The risk of that is zero. Say I don't

02:38:31.420 get any benefit from that. Then I don't have to do it ever again. But what happens if things get a lot

02:38:36.720 better? I've just treated my own disease. The reward can be so high, but you don't have to guess

02:38:44.160 at it. You can just do it. Speaking of risk, there's some, in my opinion, kind of weak epidemiology

02:38:51.060 suggesting that skipping breakfast will increase your risk of gallstones. How often are you seeing

02:38:56.280 that in your practice? A lot of people have gallstones. So I don't see an increased risk.

02:39:01.340 But on the other hand, it's going to be tough because the problem is that people who follow a

02:39:06.380 low-fat diet, of course, their gallbladder, you don't need bile, right? You need bile to emulsify the

02:39:11.840 fat. So therefore, your gallbladder just sits around with all this stuff and you get sludge and

02:39:16.140 so on. So I think the low-fat diet can certainly predispose you to stones. Then you start eating a

02:39:20.660 higher-fat diet and then it's squeezing out and you're getting stones. I don't see it clinically

02:39:25.080 as a problem. I think what caused a lot of the problems was probably the lower-fat diet because

02:39:30.380 you're simply not getting the flow, the enterohepatic flow. Like, the bile is supposed to come out.

02:39:34.840 It's not supposed to sit there. But when you get rid of all the fat, it just sits there. That's just the

02:39:39.820 balance. Our body makes it, sticks it in the gallbladder so that when you eat fat, you can

02:39:45.260 squirt a little bit of it out. Now we think we're so much smarter than our body, which has survived for

02:39:51.280 millions of years, that we're going to eat zero fat and just have all this stuff, this sludge just sit

02:39:58.480 in the gallbladder because you never took it out. Like, how does that make sense? To me, it makes no

02:40:03.440 sense. Well, on that note, we are at exactly the time when I know you need to get back to clinic.

02:40:10.020 So I want to thank you greatly for your insights, both at the, what I would say are hugely paradigm

02:40:18.200 challenging level, especially as it pertains to insulin resistance and hyperinsulinemia. And then

02:40:22.800 also at the boots on the ground clinical level, I know that very few people have the experience

02:40:28.500 treating patients with fasting protocols for type two diabetes. And I think you're doing fantastic

02:40:33.720 work. So I want to thank you very much for that. Thank you. You can find all of this information

02:40:40.340 and more at peteratiamd.com forward slash podcast. There you'll find the show notes, readings, and links

02:40:46.460 related to this episode. You can also find my blog at peteratiamd.com. Maybe the simplest thing to do

02:40:52.800 is to sign up for my subjectively non-lame once a week email, where I'll update you on what I've been up

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The Peter Attia Drive - June 24, 2019

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

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