337- Insulin resistance masterclass: The full body impact of metabolic dysfunction, treatment & more

1. 0:00 – 1:10

   Intro

   1. PAPeter Attia0:00

      Talk a little bit about what insulin resistance is.

   2. RDRalph DeFronzo0:03

      Basically, every time you eat a meal, you're going to release insulin. There are many processes that insulin control.

   3. PAPeter Attia0:09

      So one of the challenges with the term insulin resistance is, as you said, it's a vague term and it's nonspecific.

   4. RDRalph DeFronzo0:15

      There are two problems in diabetes. One is you don't make enough insulin. The other is you're insulin resistant.

   5. PAPeter Attia0:20

      Type 2 diabetes.

   6. RDRalph DeFronzo0:21

      Pretty bad.

   7. PAPeter Attia0:22

      You're knocking on death's door.

   8. RDRalph DeFronzo0:23

      Correct.

   9. PAPeter Attia0:24

      You're going to go blind.

   10. RDRalph DeFronzo0:25

       Yep.

   11. PAPeter Attia0:25

       You're going to have your toes amputated. You're not ever going to have an erection again, and you're going to die of cardiovascular disease or kidney disease or Alzheimer's disease quickly.

   12. RDRalph DeFronzo0:36

       Some people say that Alzheimer's disease is, you know, diabetes type 3. I'm not sure I agree.

   13. PAPeter Attia0:40

       Brain diabetes.

   14. RDRalph DeFronzo0:41

       Yeah. Yes. You are obese when you're four years of age, you're going to be obese when you're adult.

   15. PAPeter Attia0:46

       And your life expectancy will be significantly shorter.

   16. RDRalph DeFronzo0:50

       Significantly decreased.

   17. PAPeter Attia0:50

       And your quality of life will be significantly reduced. What has changed so much in the last thirty years that has created this epidemic? [upbeat music] Hey, everyone. Welcome to "The Drive" podcast. I'm your host, Peter Attia.

2. 1:10 – 5:59

   Metabolic disease as a foundational driver of chronic illness

   1. PAPeter Attia1:10

      Ralph, thank you so much for coming down to-- I guess up to Austin from San Antonio. Um, very excited to sit down with you and talk about, uh, you know, potentially one of the most important subject matters in all of health. Uh, people who listen to me all the time hear and are familiar with me talking about these four horsemen, right? Cardio-- uh, cardiovascular disease and cerebrovascular disease, cancer, uh, neurodegenerative and dementing diseases. And then there's this fourth horseman that I talk about, and it's in many ways the squishiest because it's not the one that shows up on the most death certificates. Um, but in many ways, it's the foundational one that is amplifying the risk of all of those other causes of death. And I refer to it as, you know, sort of metabolic disease spanning the spectrum from hyperinsulinemia to insulin resistance to fatty liver disease all the way out to type 2 diabetes. Um, so given how much I speak about that, it seems very important that we should have a really, uh, thorough discussion of that foundational metabolic disease and no one better than you to have that discussion. So let's start a little bit with just kind of telling folks briefly about, you know, what you're doing at UT San Antonio and why you've spent the last almost forty plus, almost fifty years now working on this problem.

   2. RDRalph DeFronzo2:31

      So for me, I actually have been sort of in this field of metabolic disease for a long time. Um, I, I think I'm the longest consecutively funded fifty-three years NIDDK, uh, investigator. Uh, and, uh, I actually started even long before that, uh, when I was a medical student, uh, in, uh-- at Harvard. I had this fantastic teacher, Professor Cahill, who gave us all of the lectures on intermediary metabolism, and I decided this is what I wanted to do. Uh, and I worked each summer with Professor Cahill and, uh, you know, sometimes in life you meet the right person, the right opportunity, it changes everything you do. And basically what I do now, I can tribute, uh, directly to George. And, you know, when I gave the Banting lecture in two thousand and eight, people usually, you know, put a picture of their mother and father and children, and I love my mother and father and children, but I only showed one picture, and that was Professor Cahill-

   3. PAPeter Attia3:30

      Mm

   4. RDRalph DeFronzo3:30

      ... because he's really the person who's ended up sort of directing me to where I am today.

   5. PAPeter Attia3:37

      You know, people who are listening who are particularly astute might recall, um, I've referenced a number of Cahill's, uh, papers, but one of the more interesting studies he did, which it's possible he did while you were even a student there, was, uh, the forty-day starvation study. Um, now you might have not been quite at Harvard yet because this was, if I recall, in the mid-'60s, maybe '66, '67, where-- and it was probably a group of medical students that actually volunteered, if not medical students, undergrads. And they, they, they did a water-only fast for forty days. And the study basically just followed all of the metabolites, uh, what happened to glucose levels, obviously insulin, beta-hydroxybutyrate, acetoacetate. Anyway, it was very fascinating stuff. One of the things that was most interesting to me in that study was even under a period of such extreme starvation, the brain never gave up its dependency on glucose. So even though ketone bodies began to, um, service the brain by about day seven to ten as the majority of the fuel, even at three and four weeks of starvation, glucose was, if my memory serves me correctly, still providing about a third of the brain's energy.

   6. RDRalph DeFronzo4:48

      Your memory is very good. The brain did switch over to ketone metabolism and believe it or not, I didn't do the forty-day fast, but I was one of the people who fasted for five to seven days.

   7. PAPeter Attia5:00

      Mm-hmm.

   8. RDRalph DeFronzo5:00

      Uh, and, uh, if you fasted for, uh, three days, uh, you could get paid fifty dollars.

   9. PAPeter Attia5:06

      Hmm.

   10. RDRalph DeFronzo5:07

       And I thought I was the richest guy in the world, uh, from this study. So I, I can assure you that the physical specimens in this study were phenomenal. Uh-

   11. PAPeter Attia5:16

       What did the forty-day fasting students get?

   12. RDRalph DeFronzo5:18

       Uh, I don't know, but they-- [chuckles] I'm sure he paid them a lot of money-

   13. PAPeter Attia5:22

       That's amazing

   14. RDRalph DeFronzo5:22

       ... in order, uh, to do that. Uh, the interesting thing about that is you realize that we have so much energy stored in the human body. Who would have thought that, you know, you're a lean type person, you can, you know, fast for forty days. But [coughs] the real problem is at some point [coughs] you start to break down muscle.

   15. PAPeter Attia5:40

       Yep.

   16. RDRalph DeFronzo5:40

       And then if you start to break down cardiac muscle, then, uh, prolonged fasting at that point becomes a problem. But you have a lot of energy stored in fat and, uh, uh, you can s- uh, starve for a long time and obese people e- easily can go for three, four months, uh, with all the reserves that are in the body.

3. 5:59 – 9:59

   Defining insulin resistance: effects on glucose, fat, & protein metabolism, & how it varies between healthy, obese, & diabetic individuals

   1. PAPeter Attia5:59

      Well, let's maybe Talk a little bit about, um, what insulin resistance is. Um, I-- we'll get into what causes it, um, but, but let's just maybe define for people this term that gets thrown around constantly.

   2. RDRalph DeFronzo6:14

      Yep.

   3. PAPeter Attia6:14

      And, and let's, you know, explain what it is from a technical standpoint.

   4. RDRalph DeFronzo6:18

      Yeah. So basically, every time you eat a meal, uh, and your blood sugar level goes up, you're gonna release insulin, and insulin is sort of a master regulator for all, uh, biochemical processes in the body. So one of the things that insulin is going to do is gonna talk to your muscles and gonna say, "Take up glucose and, uh, burn that, uh, glucose." Uh, so what we need to know is, in a normal person, when I infuse insulin, uh, how much, uh, of the glucose is taken up by the muscle? And then we could look at someone who is, say, overweight, or we could look at someone who's diabetic, and I actually developed the gold standard technique, which is the insulin clamp technique, to look at this. So we could take an obese person or a diabetic or a normal person, we raise the insulin, and then I'm using muscle as an example. How much, uh, glucose is taken up that's supposed to have by the muscle? And then I can compare if you're overweight compared to the lean person. Well, obese people are very insulin resistant in terms of muscle glucose uptake. I could look at the diabetic. They're even more insulin, uh, resistant. But there are many processes that insulin control. So insulin regulates, uh, how much, uh, fat is, uh, released from your fat cells. And obese people, unfortunately, insulin keeps the fat in your fat cell. But in obese people, insulin doesn't work so well, so instead of keeping the fat in the fat cell even though your insulin is high, you're breaking down the fat. So you have to look at each individual process that insulin is controlling. And so for that process, we know this is what a normal person should respond like, this is what a diabetic response like, and the diabetic is much, much more insulin resistant. They're not responding. Uh, so it's, i- in a certain way, it's a general term because insulin controls so many, uh, things. Protein metabolism. Insulin's very important in helping you to build protein. Uh, so I could infuse insulin, and we've done this using, uh, carbon-labeled, uh, leucine, and we can define how insulin promotes protein metabolism in a normal, healthy person, and then I could do the same kind of study in an obese person, and we know that the obese people don't respond to the insulin as well in terms of aggregating protein metabolism. Uh, so it's kind of a general term.

   5. PAPeter Attia8:46

      And does that translate not just to structural proteins such as enzymes, uh, or cellular structural proteins, but also macro structural proteins such as muscle?

   6. RDRalph DeFronzo8:56

      Uh, absolutely. So, uh, I, I can look at specific enzymes within the cell. I can look at certain genes within the cell that are turned on or off, or I can look at muscle in terms of muscle as a bulk. Uh, so, uh, there are many, as I said, many ways in which you could define insulin resistance, but basically, whatever the particular process you're looking at, you're comparing what would be the normal response, uh, in a normal, healthy person compared to what might happen in a diabetic person or an obese, uh, individual.

   7. PAPeter Attia9:30

      So one of the challenges with the term insulin resistance is, as you said, it's a vague term and it's nonspecific because the actions of insulin are so many.

   8. RDRalph DeFronzo9:39

      Yes.

   9. PAPeter Attia9:39

      It has an action in the liver. It has an action in the muscles. It has an action with response to glucose. It has an action with response to amino acids, and it has an action with response to fat, both in the liberation of fat, uh, lipolysis, and presumably in response to oxidation.

   10. RDRalph DeFronzo9:55

       Absolutely.

   11. PAPeter Attia9:56

       And we'll go through all of these, but let's maybe

4. 9:59 – 13:38

   The historical significance of the development of the euglycemic clamp technique for measuring insulin resistance

   1. PAPeter Attia9:59

      start with, um, how the euglycemic clamp test is done.

   2. RDRalph DeFronzo10:04

      Yeah.

   3. PAPeter Attia10:05

      And, uh, let's assume that I'm a healthy enough individual that we can use me as a proxy. I come into your clinic. Um, what are we going to do? How do you run this test?

   4. RDRalph DeFronzo10:15

      Yeah. So let me bring you back in time when I was a fellow because at that time, we didn't really have a good measure of insulin sensitivity. So what people would do is you do an oral glucose tolerance test.

   5. PAPeter Attia10:27

      Yes.

   6. RDRalph DeFronzo10:28

      And the insulin level would go up. And so then some people would say, "I'll look at how much insulin comes out compared to the rise in glucose, and that's a measure of beta cell function." And then someone would just turn it around and say, "Look, I'm gonna see how much the rise in glucose was per insulin, and that's a measure of insulin resistance."

   7. PAPeter Attia10:48

      Mm-hmm.

   8. RDRalph DeFronzo10:48

      And it was very clear to me, well, this is insane. You can't take two variables and then just depending upon how you want to look at them, switch, uh, denominator and numerator. And so I said, "We need to develop something, uh, that is really more specific."

   9. PAPeter Attia11:04

      And, and just to be clear, Ralph, I mean, unfortunately, we as clinicians are not able to do euglycemic clamps.

   10. RDRalph DeFronzo11:10

       Correct. [laughs]

   11. PAPeter Attia11:11

       So we are still looking at oral glycemic, uh, tolerance tests. We are still giving people, you know, oral glucose and sampling glucose and insulin every thirty minutes and trying to impute what we can, which I'd love to come back and talk about interpretation. But carry on with the, with the limitation.

   12. RDRalph DeFronzo11:30

       We can do that 'cause we actually have done a lot of work on how you interpret that. So what we said is, "Why don't we develop a serious way?" And so we developed a technique where I could take a hundred people and I would infuse insulin, uh, initially as a priming dose and then just clamp the insulin level. So I give a prime continuous insulin infusion. I can take a hundred people, and all hundred people, I can raise your insulin level, uh, by a hundred microunits per ML. Uh, and I can do that for two hours. And now I know that the stimulus, the insulin stimulus, whether you're lean, whether you're obese, or whether you're diabetic, whatever particular process that I want to look at. So maybe I wanted to look at how insulin shut down hepatic glucose production. And actually, we were the first people to ever use radioisotopes to trace this and show that i- in normal people, insulin shut down glucose production by the liver very quickly. But obese people and diabetics were very, very resistant to the insulin. And then we said we wanted to know, look- Everybody now has got the same insulin level. Uh, how effectively does that insulin, uh, stimulate muscle glucose uptake? And again, what we showed, and these actually were the very first unequivocal demonstration that, uh, diabetic people, type 2, were insulin, uh, resistant. Before this, there was a lot of controversy. You know, Dr. Reaven, who is, uh, sort of the father of insulin resistance, I like to think I'm the, the son of Dr. Reaven. He's a, a great idol of mine. Uh, uh, he really, uh, was, uh, one of the very first people, uh, to insinuate that diabetics were insulin resistant. Now, with the insulin clamp, we showed this very definitively. And we also know, uh, we used, uh, labeled, uh, glycerol and free fatty acids, and we could show the ability of insulin to shut down release of, uh, lipid from, uh, the fat cell was markedly, uh, impaired. Uh, so three of the major organs, all of th- this work originally was done by us when I was back at Yale.

   13. PAPeter Attia13:37

       So let's summarize

5. 13:38 – 24:40

   How insulin affects liver, muscle, & fat cells

   1. PAPeter Attia13:38

      those again.

   2. RDRalph DeFronzo13:38

      Yep.

   3. PAPeter Attia13:39

      If, uh, we're talking about this in an insulin-sensitive person, right out of the gate, insulin is going to shut down hepatic glucose output.

   4. RDRalph DeFronzo13:45

      Absolutely.

   5. PAPeter Attia13:45

      So it's go- which again, all of this kind of makes sense if you think through the pathway. Our liver is constantly putting glucose into circulation because the muscles can't put glucose into circulation.

   6. RDRalph DeFronzo13:56

      Right.

   7. PAPeter Attia13:56

      So something has to feed the brain.

   8. RDRalph DeFronzo13:58

      Yes, absolutely.

   9. PAPeter Attia13:59

      But if insulin is high, it suggests glucose is already sufficiently high, so let's not create more glucose toxicity. Let's shut that.

   10. RDRalph DeFronzo14:08

       Yep.

   11. PAPeter Attia14:08

       The second thing it's going to do is it's going to take that excess glucose and put it in the place where we have the largest capacity to store it, which is muscle.

   12. RDRalph DeFronzo14:17

       Absolutely. Perfect.

   13. PAPeter Attia14:17

       So point two is we increase muscle uptake of glucose. And then point three, you said, was it's going to shut down lipolysis.

   14. RDRalph DeFronzo14:25

       Yes.

   15. PAPeter Attia14:26

       It's going to shut down the release of triglycerides and/or free fatty acids from the adipose tissue.

   16. RDRalph DeFronzo14:34

       Yep, and that's very critical. And w- we also, when we did these studies, uh, we would put a catheter in the hepatic vein and in the femoral artery and the femoral vein, so we could look at the individual tissues. And what we showed is that when you infuse insulin, say 80 or 90% of the glucose is going to be taken up in muscle. Only 10% is going to be taken up in the adipocyte and stored. And so-

   17. PAPeter Attia14:56

       How much in the liver?

   18. RDRalph DeFronzo14:57

       Uh, uh, basically none. Under euglycemic conditions, and we were the first to show this conclusively as well, there's no glucose uptake in the liver by insulin.

   19. PAPeter Attia15:07

       Just explain to people what a euglycemic condition means.

   20. RDRalph DeFronzo15:10

       Yeah. Euglycemic means your fasting glucose when you wake up in the morning is 80. Uh, now you're euglycemic. Uh, that means when we do the studies, we keep your fasting glucose of 80. We don't let the glucose change. All we're going to do is raise the insulin to-

   21. PAPeter Attia15:25

       And that means you're giving glucose.

   22. RDRalph DeFronzo15:27

       O- of course, because if we didn't give glucose, then your blood sugar level would drop, and then you'd release cortisol, you'd release epinephrine.

   23. PAPeter Attia15:36

       Yeah. So I just want to make sure people understand that. I was going to come back to that, but I wanted to not-- I wanted you to finish that point.

   24. RDRalph DeFronzo15:41

       Yeah.

   25. PAPeter Attia15:41

       So let's, let's make sure we go back to the test-

   26. RDRalph DeFronzo15:43

       Yeah

   27. PAPeter Attia15:43

       ... 'cause it's very counterintuitive. So I've got a catheter in each arm.

   28. RDRalph DeFronzo15:47

       Yeah.

   29. PAPeter Attia15:47

       I walk in off the street. I've been fasting. Uh, my, my blood sugar is 80 or 90, whatever milligrams per deciliter it is. You are going to have to influ- infuse both insulin and glucose-

   30. RDRalph DeFronzo15:58

       Yep
6. 24:40 – 28:56

   Different ways insulin resistance manifests in various tissues: Alzheimer’s disease, cardiovascular disease

   1. RDRalph DeFronzo24:40

      so when we talk about insulin resistance, that's why I said you need to know which tissue you're talking about and which metabolic pathway, and if you want to talk about enzymes, you need to talk at what specific enzyme because, uh, insulin resistance needs to be related to the tissue you're talking about and the process within the tissue that you're talking about. So insulin resistance is a very important concept, uh, but- You all have to be a little bit more specific about what aspect you, you want to address. So you can have insulin resistance in the fat cell, you can have insulin resistance in the liver, you can have insulin, uh, resistance in the muscle, and then something that's now pretty exciting is you may have insulin resistance in the brain. And the suggestions now, and there are many insulin receptors in the brain. Jesse Roth, you know, very famous diabetes person, you know, maybe fifty or sixty years ago was the first to describe insulin receptors in the brain, and this is an area that's now starting to unfold. It may have some relationship to neurodegenerative disease, Alzheimer’s disease. You know, some people say that Alzheimer’s disease is, you know, diabetes type three. Uh, I'm not sure I agree with-

   2. PAPeter Attia25:52

      Brain diabetes.

   3. RDRalph DeFronzo25:52

      Yeah. Yes.

   4. PAPeter Attia25:53

      Yeah.

   5. RDRalph DeFronzo25:53

      So the, the insulin resistance is a, a very important concept. And unfortunately-- And I would say in, in, in the-- Let, let's say we're going to talk about diabetes. The-- Even though there's an ominous octet that I developed that's used everywhere in the world for the pathophysiology of type two diabetes, if we really wanted to take and solid-solidify it and say, "What are the two big concepts?" Insulin resistance would be here.

   6. PAPeter Attia26:21

      Yep.

   7. RDRalph DeFronzo26:21

      On the other hand would be impaired beta cell function. Okay? So if you are insulin resistant and your beta cells work well, they know how to read the insulin resistance. They'll make enough insulin. You won't become diabetic. The hyperinsulinemia can damage you in other ways, but you won't become diabetic. But what happens is if you're insulin resistant, and particularly if you have a genetic predisposition, if your beta cells have to continuously pour out insulin, uh, they start to exhaust. Uh, and so insulin resistance is a disaster for someone who has a genetic predisposition that's going to bring out, uh, the diabetes. Insulin resistance, in my opinion, is intimately related to cardiovascular disease. That is why when you, you see a diabetic patient, ten percent of them, you walk in, you have diabetes, first time I see you, ten percent, fifteen percent of the people already have clinically significant cardiovascular disease. And if you look carefully, virtually a hundred percent of them do.

   8. PAPeter Attia27:20

      And sorry, Ralph, do you think that that is a result of the hyperinsulinemia or the untreated or poorly treated hyperglycemia?

   9. RDRalph DeFronzo27:28

      All of the above. But more importantly, what we showed, and we were again the first people to show this, uh, and the cardiologists, they're kind of hemodynamically oriented. They're looking at, you know, vessels, uh-

   10. PAPeter Attia27:42

       The stenoses, yeah

   11. RDRalph DeFronzo27:43

       ... structurally collapsing.

   12. PAPeter Attia27:43

       Sure.

   13. RDRalph DeFronzo27:44

       But if you look at the insulin signaling pathway, insulin has got to bind to its receptor, and then there's a signaling pathway. I can tell you all the molecules in there, which I'm not. And then glucose gets transported in the cell. We were the first people to show in humans that that pathway doesn't work normally. Insulin will bind to the receptor. It will activate the receptor. But the next molecule, IRS-1, PI3 kinase, all those molecules don't get activated, so glucose doesn't get into the cell. That's diabetes. That same pathway activates nitric oxide synthase, and that generates nitric oxide. Nitric oxide is the most potent vasodilator in the human body. It's the most potent anti-atherogenic molecule in the human body. So this defect that's in muscle, uh, and it's in cardiac muscle and it's in skeletal muscle, this is all human data that I'm, I'm talking about, not animal data. When you get a defect in that insulin signaling pathway, that's going to cause diabetes and it's going to promote cardiovascular disease. And that is why you can never separate cardiovascular disease, uh, from diabetes.

7. 28:56 – 38:07

   Dangers of hyperinsulinemia, & the importance of keeping insulin levels within a range

   1. RDRalph DeFronzo28:56

      Now, as you pointed out, rightfully so, you know, I believe that high levels of insulin are also atherogenic. Now, I don't want people saying Dr. DeFronzo said you shouldn't be giving insulin to people who need it. Of course, uh, uh, if people need insulin, you need to give them insulin. But our beta cells make thirty-five units of insulin per day. If you're a type one diabetic, and again-

   2. PAPeter Attia29:21

      Sorry, what, what do you mean?

   3. RDRalph DeFronzo29:22

      Uh, so, uh, you-- during the-- you're going to have your breakfast.

   4. PAPeter Attia29:25

      Yeah.

   5. RDRalph DeFronzo29:25

      You're going to have your lunch. You're going to have your dinner. And if I were to add up-

   6. PAPeter Attia29:29

      Oh, so sorry, thirty-five units.

   7. RDRalph DeFronzo29:30

      Yeah.

   8. PAPeter Attia29:30

      I thought you meant micro units.

   9. RDRalph DeFronzo29:31

      No.

   10. PAPeter Attia29:31

       Got it. Yeah, thirty-five total units.

   11. RDRalph DeFronzo29:32

       So over the course of the day, thirty-five units of insulin. So we showed this many years ago when I actually was at Yale, that if you were to take a type one patient and they were lean, they would only need thirty-five or forty units of insulin to get their, uh, glucose controlled, assuming you gave the doses at the right time. But we have a lot of people who are taking a hundred units of insulin, both type ones and type twos.

   12. PAPeter Attia29:55

       So three x physiologic.

   13. RDRalph DeFronzo29:57

       Yes. That kind of hyperinsulinemia, I think there's evidence to support that's atherogenic. But now we have a problem, okay? Can you have the glucose remain high?

   14. PAPeter Attia30:08

       Yeah, it's a question of do you want to die quickly or, or, or slowly? Because-

   15. RDRalph DeFronzo30:11

       But we have really good drugs today.

   16. PAPeter Attia30:12

       Yes, yes, yes. But if, if, if you were only doing this with insulin-

   17. RDRalph DeFronzo30:16

       Be a problem

   18. PAPeter Attia30:16

       ... it's an awful trade-off.

   19. RDRalph DeFronzo30:17

       It's-

   20. PAPeter Attia30:18

       You're going to die very quickly from hyperglycemia if you're left untreated. But if we overdo it with insulin to maintain normal glycemia, we're going to kill you slowly.

   21. RDRalph DeFronzo30:27

       It's a quagmire. You're stuck.

   22. PAPeter Attia30:28

       Yep.

   23. RDRalph DeFronzo30:29

       You have to treat, but you also know that when you're giving these big doses of insulin, there may be some side effects.

   24. PAPeter Attia30:35

       This is something, Ralph, I don't think that has been necessarily appreciated by the medical community. Has it?

   25. RDRalph DeFronzo30:41

       Oh, absolutely not.

   26. PAPeter Attia30:42

       Yeah. There, there has generally been an ethos of when I've talked to patients with type two diabetes, um, that what they've been told is, "I'm told to cover with as much insulin as is necessary-

   27. RDRalph DeFronzo30:55

       Yeah

   28. PAPeter Attia30:55

       ... to maintain my glucose levels, uh, in this range, and it means I can eat whatever I want. It's okay if I have all the pasta and bread and sugar in the world, because as long as I'm covering it with insulin, I'm okay." And then you find out, wow, you're taking a hundred and fifty units of insulin a day in all of its forms, the short acting, the long acting, et cetera. But, but y- I didn't actually realize that, that what we would consider physiologic is thirty-five.

   29. RDRalph DeFronzo31:23

       Yes.

   30. PAPeter Attia31:23

       I, I may have known that at one point and I've since forgotten.
8. 38:07 – 47:50

   Challenges of identifying the genetic basis of insulin resistance & T2D

   1. PAPeter Attia38:07

      let's talk about what we know about the genetics of insulin resistance.

   2. RDRalph DeFronzo38:12

      That's easy. Nothing. [laughs]

   3. PAPeter Attia38:14

      Truly nothing.

   4. RDRalph DeFronzo38:15

      No, I, I, I joke. Uh, but if you, uh, uh, uh, let's say 20 years ago, we got involved in one of the biggest genetic studies called the VEGAS study, uh, Veterans Admin- Administration Genetic Epidemiologic Study. Uh, and we were convinced that we would do a G- we were one of the s- people to do the first GWAS studies, that we would define all the genes that are responsible. Well, [chuckles] we were not very successful. We-

   5. PAPeter Attia38:43

      Even if you took the subset of people with type 2 diabetes who were lean-

   6. RDRalph DeFronzo38:47

      Yeah

   7. PAPeter Attia38:48

      ... and you compared them to people who were lean and non-diabetic-

   8. RDRalph DeFronzo38:52

      Yeah

   9. PAPeter Attia38:53

      ... versus obese and diabetic, a, a GWAS was not able to identify a signal in those three cohorts?

   10. RDRalph DeFronzo38:59

       W- we identified several, and remember, they're associations. They're-

   11. PAPeter Attia39:04

       No, of course

   12. RDRalph DeFronzo39:04

       ... uh, and they're in non-coding regions. Uh, so like the TCF7L2 gene, that, uh, we found that, but that had already been described by Dr. Michael Stone in San Antonio, uh, many years before.

   13. PAPeter Attia39:18

       Hmm.

   14. RDRalph DeFronzo39:18

       So we repeated what Michael showed, and other people have shown that.

   15. PAPeter Attia39:22

       Wow.

   16. RDRalph DeFronzo39:22

       So there are a number of associations, and again, if you ask me how many, how many genes have we truly established that are really important in terms of causing type 2 diabetes, I would say very, very few. I know the genetics people out there probably hate this, and they'll say that we can put together a genetic score. But, you know, when they talk about a genetic score, it's not that they've causally associated-

   17. PAPeter Attia39:48

       Yep

   18. RDRalph DeFronzo39:48

       ... a gene with diabetes.

   19. PAPeter Attia39:49

       It's an association.

   20. RDRalph DeFronzo39:50

       It's an association. W- we have a whole different approach that will... If you want, I can tell you what we're doing, uh, that may give some, uh, insight. And then people have started to think about rare diseases, uh, um, uh, that m- maybe the problem is in one family you have this particular genetic mutation, another family you have a different genetic mutation, a third family a different genetic mutation. And then when you do the GWAS study, you, you got this mixture of individual genes.

   21. PAPeter Attia40:21

       What about, what about the phenotype, Ralph? So I've, I've taken care of-

   22. RDRalph DeFronzo40:24

       That's the answer

   23. PAPeter Attia40:24

       ... I've taken care of a couple of patients-

   24. RDRalph DeFronzo40:27

       Yeah

   25. PAPeter Attia40:27

       ... with type 2 diabetes who are very lean-

   26. RDRalph DeFronzo40:30

       Yeah

   27. PAPeter Attia40:30

       ... including one patient whose body fat by DEXA was about 8%.

   28. RDRalph DeFronzo40:38

       Yeah.

   29. PAPeter Attia40:38

       So for people listening, that is insanely lean.

   30. RDRalph DeFronzo40:42

       Very lean.
9. 47:50 – 58:45

   The “ominous octet”—a comprehensive model of type 2 diabetes

   1. PAPeter Attia47:50

      go back to the ominous octet, make sure I have that defined and all our listeners do.

   2. RDRalph DeFronzo47:54

      Yeah. So in 2008 at the Banting Lecture at the American Diabetes Association, the title of the Banting Lecture was From the Triumvirate to the Ominous Octet. So what was the triumvirate? I got the Young Investigator Award, the Lilly Award from the ADA in 1987. So the triumvirate was very simple. The beta cell, it fails. Insulin resistance in the muscle. When you ingested a meal, the muscle didn't take up the glucose because you're insulin resistant. And insulin resistance in the liver. When you ate a meal, insulin didn't shut down the liver. So that was the triumvirate. So from the triumvirate to the ominous octet, we needed to add five more players. So who were the new five players? So number four on the list was the fat cell and a very deserving guy. So the fat cell is your friend initially. You overeat, you take in excess calories, you store them in the fat cell, they can't hurt you there. But if you keep expanding those fat cells, the fat cells become very, very resistant to the anti-lipolytic effects of insulin. And now you start to pour fat out into the bloodstream. We've shown this is a big interest of James Schramm and-

   3. PAPeter Attia49:13

      Very counterintuitive.

   4. RDRalph DeFronzo49:14

      Yeah, counterintuitive, but very, very well documented.

   5. PAPeter Attia49:17

      But do you have a-- not that we should mire ourselves in teleologic things.

   6. RDRalph DeFronzo49:23

      Yeah.

   7. PAPeter Attia49:24

      Do you have a sense of why?

   8. RDRalph DeFronzo49:25

      Yeah. So the insulin signaling system in multiple early steps become severely impaired. And when you get insulin resistance in the glucose metabolic pathway, there are changes that alter the cell metabolism. So you become very resistant to insulin's anti-lipolytic effect. And so now if you look at people who are obese or people who have type 2 diabetes, their plasma FFA levels are very, very high. And those FFA levels, and this is lipotoxicity, and we've got a long history of studying this, high FFA levels impair insulin secretion. Uh, high FFA levels cause insulin resistance in the muscle. High FFA, uh, levels cause insulin resistance, uh, in the liver. High FFA levels impair the insulin signaling transduction system. Uh, and in fact, uh, one of my previous fellows who's now back with me here at, in UT, Dr. Belfort, was the first author on this paper showing that, uh, just physiologic rises in the plasma FFA literally obliterate the insulin signal transduction system, which is the first step in glucose metabolism. I-

   9. PAPeter Attia50:38

      I always thought that the reason we saw high free fatty acids in people with type 2 diabetes was not because the fat cells were undergoing more lipolysis, but because the fat cells were themselves becoming resistant to insulin and not able to take up fat. So same net effect, but I was kind of drawing the arrow of causality in the other direction.

   10. RDRalph DeFronzo51:07

       Yeah. No, the, the, the arrow is more on the other side. The fat is pouring out fat.

   11. PAPeter Attia51:11

       Being... Right.

   12. RDRalph DeFronzo51:11

       Yeah. And you can show that the-

   13. PAPeter Attia51:13

       Yeah

   14. RDRalph DeFronzo51:13

       ... uh, lipolytic enzymes are all resistant to insulin. They don't, uh, we've shown this, other people have shown it.

   15. PAPeter Attia51:18

       So interesting.

   16. RDRalph DeFronzo51:18

       Yeah.

   17. PAPeter Attia51:19

       Yeah.

   18. RDRalph DeFronzo51:19

       Uh, so these elevated FFA levels are a disaster. So the fat cell initially is your friend.

   19. PAPeter Attia51:25

       Is he's your friend, he goes to foe.

   20. RDRalph DeFronzo51:26

       [laughs] Then he becomes a bad-

   21. PAPeter Attia51:27

       Goes from friend to foe

   22. RDRalph DeFronzo51:28

       ... bad guy. Okay?

   23. PAPeter Attia51:29

       Yeah.

   24. RDRalph DeFronzo51:29

       So that's number four. Uh, number five is the gastrointestinal tract. Uh, and of course, we'll, I'm sure talk more about this when we talk about treatment, but when you eat a meal, you release two incretin hormones, uh, GLP-1 and GIP, uh, glucagon-like peptide one and glucose-dependent insulinotropic polypeptide. Those two incretin hormones when you eat a meal account for about 70% of the insulin that's released in response to the meal. So now, what is the problem? Is the problem that you don't release enough GLP-1 and GIP or is it that your beta cell is refractory to the GLP-1 and GIP? Well, it's the latter.

   25. PAPeter Attia52:12

       Just te- so let's say that again, Ralph. I want to make sure people understand this, and the reason it's important is obviously everybody listening to us right now is very familiar with drugs like semaglutide and tirzepatide.

   26. RDRalph DeFronzo52:22

       Yep.

   27. PAPeter Attia52:23

       But I want people to understand why those drugs were developed, and of course, semaglutide's already probably, what, the third generation of it anyway, so when we go back in time, we'll understand why people try to develop these drugs. But just say that again. So you eat your meal.

   28. RDRalph DeFronzo52:37

       Yep.

   29. PAPeter Attia52:37

       GIP, GLP-1 are increased.

   30. RDRalph DeFronzo52:40

       And they come out normally.
10. 58:45 – 1:08:35

    The kidneys’ unexpected role in worsening diabetes

    1. PAPeter Attia58:45

       right, let's go to number seven.

    2. RDRalph DeFronzo58:47

       Okay, so, uh, people don't know I'm, uh, you know, also board certified in nephrology. Uh, so in, in, in the old days, I trained as a, a micropuncturist. I used to sit with a microscope. Uh, I would draw my little pipettes out the night before and, and then I would put, uh, the little micropipette in the tubules, and I'd collect tubular fluid. And what I was interested in, uh, and this is, uh, when I was a, a, a renal fellow at University of Pennsylvania, I was interested in glucose and phosphate transport. And I published a series of pr- I'd say they're pretty elegant papers in the JCI looking at how glucose and what regulated glucose in phosphate transport. And I knew that there was a molecule called phloretin that blocked glucose transport, uh, in the kidney. And so I took this molecule called phloretin, and it blocks the, uh, glucose transporters. There are two transporters in the kidney: SGLT2 and SGLT1. SGLT2 takes back ninety percent of the glucose. If it does its job, SGLT1 takes back the other ten percent. And then in you or I, even though we filter a hundred and eighty grams of glucose per day, no glucose appears in the urine. But what I showed is that phloretin, it blocked both SGLT2 and SGLT1. It blocked glucose transport, uh, and it also blocked phosphate transport. And I showed that glucose and phosphate transport were co- coupled. Uh, when I was doing these studies, even though I was a nephrology fellow, uh, I had previously done my endocrine fellowship at the NIH in Baltimore City Hospitals, so I, I had an interest in diabetes, and I said, "This would be a great way to treat diabetes." So in the old days, you know, we did things for science, and I published a series of four papers in the JCI, and, uh, I never even thought of, to be honest with you, of patenting this, okay? And, uh, I have a significant other who said to me one day, she said, "Ralph, you're one of the smartest guys I ever met." And I said, "Yeah, I know that." And she said, "You know, you're probably the stupidest guy I ever met." [laughs] And I said, "Why?" She said, "You could've patented this drug." And so I actually worked, uh, with Bristol Myers Squibb and then, uh, uh, uh, AstraZeneca, and that eventually led to the, uh, dapagliflozin coming to the market. But what we showed, and this is human biopsy-

    3. PAPeter Attia1:01:17

       Which is the first SGLT2 inhibitor.

    4. RDRalph DeFronzo1:01:19

       That's correct. Yes.

    5. PAPeter Attia1:01:20

       Brand name on that one?

    6. RDRalph DeFronzo1:01:22

       Uh, Farxiga.

    7. PAPeter Attia1:01:23

       Farxiga, right.

    8. RDRalph DeFronzo1:01:23

       Yeah. And so-

    9. PAPeter Attia1:01:25

       Canagliflozin was next?

    10. RDRalph DeFronzo1:01:26

        Uh, empagliflozin, uh, yeah, and then canagliflozin, ertugliflozin, then we have a bunch of them. And they all ba-- uh, they're all very good and basically do the same thing. But what we showed was the SGLT2 transporter was markedly upregulated in the kidney, okay? And, uh, the original studies that we did-

    11. PAPeter Attia1:01:45

        Wait, hang on. Let's just, let's just wrap our heads around that. This, again-

    12. RDRalph DeFronzo1:01:47

        [laughs]

    13. PAPeter Attia1:01:47

        ... this is so counterintuitive.

    14. RDRalph DeFronzo1:01:50

        I know.

    15. PAPeter Attia1:01:51

        Okay? This does not make any sense.

    16. RDRalph DeFronzo1:01:53

        Right.

    17. PAPeter Attia1:01:53

        So you take a-- Let's-- I j- I wanna just bring it back to people listening so they understand what we're talking about here.

    18. RDRalph DeFronzo1:01:58

        Okay.

    19. PAPeter Attia1:01:58

        The kidney is this massive filtration, another remarkable organ. Not, no offense to the nephrologist, not as remarkable as the liver, but Every bit is remarkable in terms of-

    20. RDRalph DeFronzo1:02:09

        I think it's more remarkable than the, than the liver guys, but that's okay. [laughs]

    21. PAPeter Attia1:02:12

        All right. All right. So, so, so everything that's floating through our plasma is-- You know, our, our, our kidneys, by the way, rep- what? They take twenty-five percent of our cardiac output.

    22. RDRalph DeFronzo1:02:21

        Huge. Yes.

    23. PAPeter Attia1:02:22

        Yeah. So it's massive.

    24. RDRalph DeFronzo1:02:23

        Yes.

    25. PAPeter Attia1:02:23

        This organ weighs two percent of our weight-

    26. RDRalph DeFronzo1:02:25

        Huge. Yeah

    27. PAPeter Attia1:02:25

        ... and takes twenty-five percent-

    28. RDRalph DeFronzo1:02:27

        Yeah

    29. PAPeter Attia1:02:27

        ... of our cardiac output. Why? Because we have to take everything that is in our circulation and dump it out.

    30. RDRalph DeFronzo1:02:34

        Yep.
11. 1:08:35 – 1:12:15

    How insulin resistance in the brain contribute to overeating & metabolic disease

    1. PAPeter Attia1:08:35

       we do that, let's go back-

    2. RDRalph DeFronzo1:08:35

       We, we need to finish the ominous octet.

    3. PAPeter Attia1:08:36

       We gotta go. Exactly. Let's go back to number eight.

    4. RDRalph DeFronzo1:08:38

       The brain.

    5. PAPeter Attia1:08:39

       Okay.

    6. RDRalph DeFronzo1:08:39

       Okay? So the brain plays a role in a somewhat indirect way. So every day, you know, you have your breakfast, your lunch. I actually eat only once a day. But at some point you eat a meal, and at some time during the meal you'll say, "Okay, I'm hungry. I stop eating." Why'd you ever think? W-why does that happen? Well, because there are certain hormones that are released or inhibited that tell you, "Okay, you're satiated. Stop eating." Well, one of the very important ones is GLP-1, uh, that same thing that's increasing-

    7. PAPeter Attia1:09:09

       Mm-hmm

    8. RDRalph DeFronzo1:09:09

       ... insulin secretion. Your brain has become very resistant to GLP-1. When you eat a meal, amylin comes out. It comes out in a one-to-one ratio with insulin. Your brain has become resistant to amylin. Your brain is resistant to leptin. So there are a lot of these anorectic molecules, uh, that, uh, your brain has become resistant to. And, uh, these, uh, molecules and it's an-another area of interest of mine. These, uh, they work in the hedonic areas in the brain, so in the putamen, the prefrontal cortex, and they tell you to stop eating. Uh, and unfortunately, there's, uh-- and this is the big unknown, is what's going on in the brain. The neurocircuitry is clearly distorted. Not only is the neurocircuitry distorted, one of the big things that we are interested in, Dr. Peter Fox and myself at, at UT, is if you look at the gray matter in these areas, in the areas that are critically important in regulating your appetite, there's shrinkage of the gray matter area. Okay? And in these areas, if you do an insulin clamp, okay, the brain is insensitive to insulin and you are right. In obese people, these areas in the brain where there's abnormal marked increase in glucose uptake. Incredible finding. Who would have thought?

    9. PAPeter Attia1:10:30

       I'm sorry. You're saying that these are the few areas in my brain and your brain that are actually default insulin insensitive-

    10. RDRalph DeFronzo1:10:38

        Yes

    11. PAPeter Attia1:10:39

        ... don't take up glucose?

    12. RDRalph DeFronzo1:10:40

        Correct, if I do an insulin clamp.

    13. PAPeter Attia1:10:42

        So what is their fuel source? Lactate?

    14. RDRalph DeFronzo1:10:45

        Uh, well, they're saturated-- I'm sorry. The, the-- In response to insulin, they don't take up more glucose.

    15. PAPeter Attia1:10:50

        Oh, oh, oh, okay. I'm sorry.

    16. RDRalph DeFronzo1:10:52

        Yeah. Yeah.

    17. PAPeter Attia1:10:52

        Go ahead.

    18. RDRalph DeFronzo1:10:52

        'Cause remember, as long as-- Remember, this, this is from the Cahill studies. As long as your glucose is above fifty, uh, your, your brain is happy. So this is actually in, in the evolution of the human being, this is phenomenal because in the old days, you may not eat for-

    19. PAPeter Attia1:11:09

        Yeah

    20. RDRalph DeFronzo1:11:09

        ... you may slaughter one of these beasts that, uh-

    21. PAPeter Attia1:11:11

        Yeah. You're not eating for days

    22. RDRalph DeFronzo1:11:12

        ... you're not eating for days. So your glucose would drop. So if your normal fasting was eighty, uh, if it dropped to forty, you're okay because your brain saturated at forty. If you got below forty, you're in trouble. Uh, so, uh, you have a, a big sort of buffer, uh, here. But now if I infuse insulin and your glucose is eighty, your brain doesn't take it up more, uh, glucose. It's, quote, "insulin insensitive" in a certain, uh, way. Uh-

    23. PAPeter Attia1:11:37

        Now, of course, if you take people with mild cognitive impairment, we, we-- there have been some experiments that actually ch- suggest in these people, in-insulin infusion can transiently improve glucose uptake, but presumably that's because they're insufficiently getting glucose in the disease state?

    24. RDRalph DeFronzo1:11:53

        Yes. Uh, this has been postulated.

    25. PAPeter Attia1:11:56

        Yeah.

    26. RDRalph DeFronzo1:11:56

        And this also suggested that there's brain insulin resistance-

    27. PAPeter Attia1:12:00

        Yeah

    28. RDRalph DeFronzo1:12:00

        ... uh, which is, uh, s- I, I'd say an interesting concept, uh, and may play some role in this neurocognitive dysfunction, Alzheimer's whole kind of different story that's sort of in, uh, evolution. But to come back

12. 1:12:15 – 1:15:28

    Lipotoxicity: how overeating fuels insulin resistance & mitochondrial dysfunction

    1. RDRalph DeFronzo1:12:15

       to the ominous octet now, if you overeat, what happens? You gain weight. And when you gain weight, you become insulin resistant, severely insulin resistant. That's lipotoxicity.

    2. PAPeter Attia1:12:24

       Mm.

    3. RDRalph DeFronzo1:12:24

       Okay? Uh, and we've done, uh, studies in both directions. I can, uh, put an IV and I can i-infuse, uh, uh, an emulsion of free fatty acids. And I can show within twenty-- within four hour-- two to four hours, I induced severe insulin resistance, uh, in, uh, the muscle, uh, uh, in, in, in the liver, and I markedly impaired beta cell, uh, function. And then, uh, we don't have this drug in the United States, uh, but there's a drug that's available in Europe, and I have an IND to use it. It's called acipimox. It inhibits lipolysis. It's like SGLT2 inhibitor. The only thing to do is block glucose reabsorption in the kidney. Acipimox, all it does is do block lipolysis. It lowers your FFA level. And we've done this. Uh, we've done-

    4. PAPeter Attia1:13:17

       Does it result in any meaningful clinical increase in adiposity, or is it so subtle that you don't notice it?

    5. RDRalph DeFronzo1:13:23

       Over twelve days, no change in adiposity, huge improvement in insulin sensitivity and muscle. Uh, you can show all of these major biochemical-

    6. PAPeter Attia1:13:31

       Why is it not approved in the US?

    7. RDRalph DeFronzo1:13:32

       Uh, it, it, it, it, it, uh, it was n-- uh, I don't know that the company that developed it in Europe ever tried to get it approved in the US. It's, I would say, modestly effective in lowering triglycerides. And we have fenofibrates, which are much more effective. So that may be the reason, although this drug been around for-

    8. PAPeter Attia1:13:55

       But the triglyceride and the FFA are not the same thing.

    9. RDRalph DeFronzo1:13:57

       No Uh, but that's the reason why it's approved in Europe. Uh, but, uh, if you lower the FFA, that's the precursor for triglyceride synthesis.

    10. PAPeter Attia1:14:07

        Yeah.

    11. RDRalph DeFronzo1:14:07

        So it, it has an effect to lower the triglycerides. But the key thing is if you lower the FFA, uh, and we did this for 12 days, and we did it in both obese people and in diabetic, you markedly improve insulin sensitivity in the muscle. If using MRI, you can measure muscle fat. It goes down dramatically and, and correlates with the improvement in insulin sensitivity. Uh, we also measured ATP generation 'cause there's this, uh, issue is there's clearly mitochondrial dysfunction if you're a diabetic. Uh, that, that's unequivocal. The controversy is, is the mitochondrial dysfunction causing the insulin resistance or is the insulin resistance causing the mitochondrial dysfunction? So in this study, uh, that we did when we lowered the FFA, uh, and lowered, uh, the muscle, uh, lipid, uh, content, we saw, uh, about a 50% improvement in A- ATP generation, mitochondrial ATP generation. So a- at least this says that part of the mitochondrial dysfunction is secondary to the lipotoxicity and insulin resistance. Uh, s- but this still remains, uh, I would say a controversial topic. Clearly there's mitochondrial dysfunction. If you can improve it, that's going to improve insulin sensitivity.

13. 1:15:28 – 1:26:07

    Pioglitazone: an underappreciated treatment for insulin resistance

    1. PAPeter Attia1:15:28

       Is there anything that improves mitochondrial function more than aerobic exercise training?

    2. RDRalph DeFronzo1:15:33

       Pioglitazone. The drug-

    3. PAPeter Attia1:15:36

       How, how so?

    4. RDRalph DeFronzo1:15:37

       I can't get people to use, which is a phenomena- It, uh, by activating PPAR gamma, uh, it, it does a lot of good things and one of the i- important things that it does, it has a huge effect to improve mitochondrial, uh, dysfunction. Uh, and it has direct effects. It also works on the, uh, it works directly through PPAR gamma to do this and it also binds directly to the mitochondrial pyruvate carrier. Uh, and that, uh, influences, uh, flux through the, uh, through the, you know, the, the mitochondrial, uh, chain.

    5. PAPeter Attia1:16:11

       And why don't people use this drug today?

    6. RDRalph DeFronzo1:16:13

       [laughs] Uh, huge misconceptions. Uh, so we'll, I guess we'll talk about therapy, uh-

    7. PAPeter Attia1:16:22

       We'll come back to it.

    8. RDRalph DeFronzo1:16:22

       Yeah.

    9. PAPeter Attia1:16:23

       Okay. We'll park it till we come back to that.

    10. RDRalph DeFronzo1:16:24

        But, but as part of my triple therapy regimen, uh, I use a GLP-1 receptor agonist, uh, I use pioglitazone and I use an SGLT2 inhibitor. Now there's a fourth good drug and that's metformin. Uh, and you might ask, "Well, why is metformin number four on my list of good drugs since I single-handedly brought metformin to the United States in 1995?" No other endocrinologist involved in this. 1995, metformin was a revolutionary drug. Why? We had insulin sulfonylureas, okay? So now we had a drug that really could work, okay? Uh, and, uh, it's still a very good drug and of course it's very cheap. It's $5 a month in the state of Texas, but we have much better drugs. Pioglitazone causes weight gain, okay? Now here's the problem and, and it'll become very obvious. You know, we, we talk about these paradoxes. The more weight gain, the, the greater the drop in A1c. The more weight gain, the greater the improvement in insulin sensitivity.

    11. PAPeter Attia1:17:28

        And is it fat gain specifically?

    12. RDRalph DeFronzo1:17:30

        No. Oh, I, I'll, I'll come back to that in a second, okay? Uh, yeah, it is fat weight gain and I also believe muscle weight gain.

    13. PAPeter Attia1:17:37

        Hmm.

    14. RDRalph DeFronzo1:17:37

        Okay? Uh, uh, the more weight gain, the greater the improvement in beta cell function. The more weight gain, the greater the drop in blood pressure. The more weight you gain, the greater the drop in triglycerides. The more weight you gain, the rise in, the greater the rise in HDL cholesterol. Sounds like terrible drug, right?

    15. PAPeter Attia1:17:55

        [laughs]

    16. RDRalph DeFronzo1:17:55

        So here's another one of those paradoxes, okay? So why would weight g- we know if you overeat and gain weight, that's a disaster. But with pioglitazone, the more weight you gain, e- everything gets better. What pioglitazone does is it shifts weight around in the body. In my opinion, it's the best drug for treating NASH. No drug is going to beat pioglitazone, okay? Uh, and, uh, the pharmaceutical companies, they don't-- If you had to go up against pioglitazone, all these NASH drugs, I don't believe you can beat pioglitazone.

    17. PAPeter Attia1:18:27

        What's the brand name for pioglitazone?

    18. RDRalph DeFronzo1:18:29

        Actos.

    19. PAPeter Attia1:18:30

        Oh.

    20. RDRalph DeFronzo1:18:30

        Okay?

    21. PAPeter Attia1:18:31

        Yeah.

    22. RDRalph DeFronzo1:18:31

        Uh, so, uh, the, the, the, as I said, there's this now paradox. Uh, so why do you gain weight? Uh, pioglitazone, it, it redistributes fat in the body. It gets it out of the muttle, puts it, muscle, puts it in subcutaneous tissue, gets it out of the liver, puts it in subcutaneous tissue, gets it out of your beta cells, put it in subcutaneous tissue. That's not going to make you gain weight. The richest density of PPAR gamma receptors in the hypothalamus. So when I activate these PPAR gamma receptors in the hypothalamus, you eat, okay? It makes you hungry. That's got nothing to do with redistributing the fat in the body, except they parallel each other i- in association. And so you see the weight gain and people say, "Oh, that's bad." But what's really doing the thing is this recycling, okay? Uh, and moving the fat around. The other negative thing about pioglitazone is it causes fluid retention, okay? So people have associated fluid retention with heart failure. Now, uh, why do you get fluid retention? Again, this is people do not understand. Uh, pioglitazone, the only thing, the only drug that is a true insulin sensitizer is pioglitazone. Metformin is not a true insulin sensitizer. That's a total misconception. Pioglitazone, that insulin signaling defect that, uh, I told you about, pioglitazone Corrects that defect. It's incredible.

    23. PAPeter Attia1:20:03

        So, so we sh- we did-- we kind of glossed over this, Ralph, 'cause we were going to spare people the details, but it's probably worth just reminding people.

    24. RDRalph DeFronzo1:20:10

        Yeah.

    25. PAPeter Attia1:20:10

        Insulin binds to the insulin receptor.

    26. RDRalph DeFronzo1:20:13

        Yeah.

    27. PAPeter Attia1:20:13

        That's outside the cell.

    28. RDRalph DeFronzo1:20:14

        Yeah.

    29. PAPeter Attia1:20:15

        Is that a-- That's a c- that's a, that's a kinase receptor, correct?

    30. RDRalph DeFronzo1:20:19

        Yeah. There are three tyrosine molecules.
14. 1:26:07 – 1:31:46

    Metformin: the misconception that it is an insulin sensitizer & its true mechanism of action

    1. PAPeter Attia1:26:07

       Everybody wants to know if metformin is geroprotective, but let's just remind people, um, we-- So, so metformin inhibits complex one of the mitochondria. Is that-

    2. RDRalph DeFronzo1:26:16

       Yeah

    3. PAPeter Attia1:26:16

       ... of the electron transport chain? Is that- A given?

    4. RDRalph DeFronzo1:26:19

       Uh, yes. Uh, in-- I, I'd say this is still controversial.

    5. PAPeter Attia1:26:24

       Okay.

    6. RDRalph DeFronzo1:26:24

       In high doses, for sure, yes. In the kind of doses you see with giving metformin, I would say, uh, uh, somewhat equivocal, in my opinion.

    7. PAPeter Attia1:26:34

       So is it, is the belief that metformin's efficacy in diabetes is through reducing hepatic glucose output?

    8. RDRalph DeFronzo1:26:42

       That is a hundred percent true.

    9. PAPeter Attia1:26:43

       Okay, and what's the mechanism by which it reduces hepatic glucose output?

    10. RDRalph DeFronzo1:26:47

        Inhibiting the mitochondrial chain and inhibiting gluconeogenesis. I-- Well, for sure it inhibits gluconeogenesis, okay?

    11. PAPeter Attia1:26:53

        Okay.

    12. RDRalph DeFronzo1:26:54

        Uh, now, uh, uh, metformin gets into cells through the organic cation transporter. The organic cation ion transporter doesn't exist in muscle. It can't possibly be an insulin sensitizer in muscle. You're asking the drug to do something that's impossible. And if you give labeled metformin-

    13. PAPeter Attia1:27:16

        Does it get into muscle mitochondria?

    14. RDRalph DeFronzo1:27:18

        No, it doesn't get into muscle at all.

    15. PAPeter Attia1:27:19

        Why does lactate go up when people are taking metformin?

    16. RDRalph DeFronzo1:27:22

        Level of the liver. It's interfering, uh, with, uh, aerobic metabolism, and so there's a block and you-

    17. PAPeter Attia1:27:29

        This is very important. I have erroneously always believed that-- So I'm really happy to be corrected. I love being proved wrong. I have always believed that the reason we saw an increase in fasting lactate, even in healthy people, if they took metformin, was because of the inhibition of the ECT in skeletal muscle.

    18. RDRalph DeFronzo1:27:53

        No, no.

    19. PAPeter Attia1:27:53

        And you're saying, "Peter-"

    20. RDRalph DeFronzo1:27:54

        It's all in the liver

    21. PAPeter Attia1:27:54

        ... that's not possible. It can't get into skeletal muscle?

    22. RDRalph DeFronzo1:27:57

        There's absolutely not a single molecule in the world of metformin that's ever gotten into any skeletal muscle anywhere.

    23. PAPeter Attia1:28:05

        And tell me again why. What's the transporter?

    24. RDRalph DeFronzo1:28:07

        The organic cation transporter. Uh, that's the transporter that, uh, by which metformin enters cells. It does not exist in skeletal muscle. It does not exist in cardiac muscle. So metformin cannot get into these tissues. It's a huge, major misconception. It can-- Uh, if, if you have very, very high doses, that can occur when you have very low GFR, uh, 'cause metformin is excreted via the kidney. If the metformin levels build up, you can get lactic acidosis. That's a very, very rare complication. This, this is not a reason why you shouldn't be using the metformin. And, and I'm not saying that metformin's not a good drug. It is a good drug. I don't think it's as good as the other three drugs we talked about. Uh, but yes, it does, uh, at high doses, increase the lactate level, all in effect on the liver. And the old drug that caused all the problem was phenformin, uh, biguanide as well, but it had a powerful effect.

    25. PAPeter Attia1:29:10

        Yeah, phenformin was much more powerful.

    26. RDRalph DeFronzo1:29:11

        Yes, and that's why people were afraid to, uh, bring metformin to the US.

    27. PAPeter Attia1:29:18

        And when you say high dose, I mean, is two grams a day of metformin-

    28. RDRalph DeFronzo1:29:21

        No, no, no, no

    29. PAPeter Attia1:29:22

        ... that's the normal dose?

    30. RDRalph DeFronzo1:29:23

        That's the normal dose.
15. 1:31:46 – 1:40:12

    Treating diabetes with triple therapy vs. the ADA approach: a better path for diabetes management

    1. RDRalph DeFronzo1:31:46

       The classic study, which we'll talk about, which to me should change the entire approach to treating diabetes, it's called the EDIC study. And in the EDIC study, what we did is we used triple therapy right from the beginning. And my, my, my point of the Banting lecture, the ominous octet, if you have eight problems, and th-there I'm sure are gonna be more to be found, and I can give you a few more if you want, but if you have eight problems, why in the world do you think one drug's gonna correct eight problems? It ain't gonna happen in our lifetime. So the point was you need to use drugs in combination. So we said we're going to use what, uh, we, uh, what we think are the best drugs at the time. So we started with Metformin, with Exenatide, [laughs] an old-time GLP-1. This is not the kingpin-

    2. PAPeter Attia1:32:35

       This is the pre-liraglutide.

    3. RDRalph DeFronzo1:32:37

       Yeah, exactly, 'cause that's what was available.

    4. PAPeter Attia1:32:39

       That drug was useless, wasn't it?

    5. RDRalph DeFronzo1:32:41

       No, it's a good drug.

    6. PAPeter Attia1:32:42

       Really?

    7. RDRalph DeFronzo1:32:42

       Sure. It's not semaglutide- [laughs]

    8. PAPeter Attia1:32:44

       Yeah, okay

    9. RDRalph DeFronzo1:32:44

       ... or tirzepatide, but you have to start somewhere, right?

    10. PAPeter Attia1:32:46

        Yeah. No, no, yeah. Let's, let's pay its dues as being the gen one OG version of that drug-

    11. RDRalph DeFronzo1:32:50

        Exactly

    12. PAPeter Attia1:32:50

        ... without which we might not have-

    13. RDRalph DeFronzo1:32:52

        We wouldn't-

    14. PAPeter Attia1:32:52

        We wouldn't have semaglutide or tirzepatide.

    15. RDRalph DeFronzo1:32:54

        Yes.

    16. PAPeter Attia1:32:55

        Yeah.

    17. RDRalph DeFronzo1:32:55

        So it's kind of an old-timer.

    18. PAPeter Attia1:32:56

        Yeah.

    19. RDRalph DeFronzo1:32:57

        And, and pioglitazone, that was the triple therapy, okay? Uh, and then, uh, we said every diabetic patient, there are 315 people in this study. They're having insulin clamps, hyperglycemic clamps, muscle biopsies. No one in the world can do this study. 315 people, follow for six years, okay? So we said, "This is what we believe is the appropriate therapy." And then we said, "We'll use the ADA approach." The ADA approach is you start on Metformin, okay? And when you fail, e- even though it explicitly said the next drug that's used is sulfonylureas, and then the third drug that's added is insulin. And we said, uh, that the goal of therapy was an A1C of six and a half, okay? Uh, and that if your A1C, uh, rose above six and a half, uh, either on our triple therapy or on the stepwise treat-to-fail approach that the ADA says. ADA says start Metformin. You fail, you add sulfonylurea. You fail, you add insulin. You titrate the insulin, basal insulin, up to 60 units. And we said 60 units is really where we'll cap it because-

    20. PAPeter Attia1:34:09

        Yeah, you're already at 2X physiologic.

    21. RDRalph DeFronzo1:34:11

        Yep, and now, now you have to now split the dose of insulin. You have to be adding rapid-acting insulin. I, I think this is quite reasonable. Six years later, okay, [laughs] 29% of the people with the ADA approach have failed. Their A1C is above six and a half. Six years later, with our approach, 70% of the people have an A1C that's less than six and a half. Why? Insulin clamp. Huge improvement with our therapy, okay? This is the EDICT study. The, the three-year data are published. The six-year data, we're writing it up. How much improvement in insulin sensitivity with the ADA approach? Zero. Beta cell function, you have almost a normal beta cell.

    22. PAPeter Attia1:34:53

        Ralph, why the disconnect?

    23. RDRalph DeFronzo1:34:56

        Between where?

    24. PAPeter Attia1:34:56

        Between, between what you're seeing in the EDICT study and what the ADA is promoting.

    25. RDRalph DeFronzo1:35:01

        Uh, [laughs] you have to ask the ADA.

    26. PAPeter Attia1:35:04

        What's their answer? If, if I'm a patient and I'm-- and, or if I'm a physician who's treating these patients and I'm saying, "Guys, I'm confused. I'm looking at the literature. I'm seeing this. I'm looking at your-"

    27. RDRalph DeFronzo1:35:13

        Yeah.

    28. PAPeter Attia1:35:13

        And by the way, I see this with the AHA and cardiovascular-

    29. RDRalph DeFronzo1:35:16

        Yeah

    30. PAPeter Attia1:35:16

        ... guidelines, so I'm not-
16. 1:40:12 – 1:56:11

    GLP-1 agonists, the Qatar study, & rethinking diabetes treatment

    1. PAPeter Attia1:40:12

       Now, it's interesting when you talk about today's triple therapy, which is way more efficacious-

    2. RDRalph DeFronzo1:40:16

       Different story

    3. PAPeter Attia1:40:17

       ... two of those three drugs are very expensive.

    4. RDRalph DeFronzo1:40:18

       Yes.

    5. PAPeter Attia1:40:19

       The SGLT2 inhibitors are very expensive and the modern day gen three, gen four, and soon we'll have a gen five-

    6. RDRalph DeFronzo1:40:25

       Yeah

    7. PAPeter Attia1:40:25

       ... GLP-1, they're very pricey.

    8. RDRalph DeFronzo1:40:27

       They're very... $1,000 a month for the-

    9. PAPeter Attia1:40:29

       Yep

    10. RDRalph DeFronzo1:40:29

        ... yeah. Now, are they great drugs?

    11. PAPeter Attia1:40:31

        So the question is-

    12. RDRalph DeFronzo1:40:32

        Of course. [chuckles]

    13. PAPeter Attia1:40:32

        Yeah, is but, but I, I guess the question is do they, do you need to be on those drugs if your old version of triple therapy-

    14. RDRalph DeFronzo1:40:41

        Uh, our old version is incredibly effective. The problem is you can't get people to use pioglitazone.

    15. PAPeter Attia1:40:47

        And the reason is the patients are frustrated with the fact that they're w- retaining water?

    16. RDRalph DeFronzo1:40:51

        Uh, no, more that they, they weight, gain weight.

    17. PAPeter Attia1:40:54

        How much weight do they gain typically? How many kilos?

    18. RDRalph DeFronzo1:40:56

        Depends on the dose. I, like I don't go to the 45 milligram dose. So at the end of the year, they may gain two or two and a half kilos at the 15 and 30 milligram, uh, dose, okay? But their A1C is controlled. [chuckles] So you have to explain to people... Here's another incredible thing. Uh, so th-there was a, a, a cardiovascular-- This is truly incredible.

    19. PAPeter Attia1:41:18

        By the way, uh, sorry to interrupt you again.

    20. RDRalph DeFronzo1:41:20

        Yeah.

    21. PAPeter Attia1:41:20

        Um, if you give PO plus a modern day GLP-1-

    22. RDRalph DeFronzo1:41:26

        Oh, goodness

    23. PAPeter Attia1:41:26

        ... would that offset the weight gain?

    24. RDRalph DeFronzo1:41:27

        You cannot belie- oh, you lose, uh, all the weight you go, lose with the GLP-1 receptor agonist.

    25. PAPeter Attia1:41:31

        So if a patient is willing to go down the path of a modern day GLP-1-

    26. RDRalph DeFronzo1:41:35

        That's my treatment

    27. PAPeter Attia1:41:36

        ... doesn't that completely eliminate?

    28. RDRalph DeFronzo1:41:38

        Absolutely. A-and it also gets rid of the edema.

    29. PAPeter Attia1:41:41

        Yeah.

    30. RDRalph DeFronzo1:41:41

        And believe me, their A1Cs are down in the normal range. You know, i-if you took my hands... So, uh, let, let me tell you this first thing about pioglitazone in the PROactive. I'll come back and we'll-
17. 1:56:11 – 1:57:59

    Using a hyperglycemic clamp to look for genes that cause diabetes

    1. RDRalph DeFronzo1:56:11

       So here's another thing that's pretty exciting that we're doing. So, uh, and again, it's looking for genes that cause diabetes. So you eat a meal, okay? You eat a meal, your glucose goes up. That secretes insulin. Uh, there's amino acids in the meal. Th- that secretes insulin. And GLP-1 goes up, and that secretes insulin. So now, when you eat a meal, there are already three stimuli, and now you're looking for a gene or a set of genes that might be associated with beta cell failure when you have three stimuli. Now, that's gonna be pretty confusing.

    2. PAPeter Attia1:56:49

       Mm-hmm.

    3. RDRalph DeFronzo1:56:50

       So what we said, "Well, maybe what we should do is that we should do a three-step hyperglycemic clamp." Uh, so we give you three steps of, uh, glucose and we can get beta cell sensitivity to glucose. From the slope, I give you a little rise in glucose, another rise in glucose, another rise in glucose. I see how much C-peptide comes up. The slope of that curve is-- that's beta cell sensitivity to glucose.

    4. PAPeter Attia1:57:16

       And then the M value is where it hits the axis?

    5. RDRalph DeFronzo1:57:18

       Uh, then I can get glucose-- But this is just now I'm going to focus on the beta cell.

    6. PAPeter Attia1:57:22

       Okay.

    7. RDRalph DeFronzo1:57:22

       Because the hyperglycemic clamp is just for beta cell function, okay? And then after that, now I'm going to give you GLP-1 infusion and I'm going to see how much insulin comes out. And then after that, I'm going to give you a balanced amino acid infusion. I'm going to see how much insulin comes out.

    8. PAPeter Attia1:57:38

       So you can sequentially measure the different-

    9. RDRalph DeFronzo1:57:40

       Three different stimuli-

    10. PAPeter Attia1:57:41

        -phases

    11. RDRalph DeFronzo1:57:41

        ... and now what we see is different loci. Some are associated with the-

    12. PAPeter Attia1:57:46

        Yeah

    13. RDRalph DeFronzo1:57:46

        ... defect in glucose.

    14. PAPeter Attia1:57:47

        Yeah.

    15. RDRalph DeFronzo1:57:47

        Some are associated with the defect in amino acid. So again, the more you can refine the phenotype, the more likely you are to identify defects that are there at the level

18. 1:57:59 – 2:03:33

    Measuring C-peptide instead of insulin to assess beta-cell function

    1. RDRalph DeFronzo1:57:59

       of the beta cell.

    2. PAPeter Attia1:58:00

       Uh, go-- let's go back to the Qatar study for a second. How many people were in that study?

    3. RDRalph DeFronzo1:58:03

       About two hundred and twenty.

    4. PAPeter Attia1:58:05

       Okay.

    5. RDRalph DeFronzo1:58:05

       It's a pretty big study for when you're doing all-- You know, these insulin clamp studies and these, you know, these kind of measurements are not easy to do.

    6. PAPeter Attia1:58:12

       That was published when?

    7. RDRalph DeFronzo1:58:13

       Uh, let's see. I would say the one-and-a-half-year data were probably about two thousand eighteen and the three-year data, I would say two thousand twenty-one, twenty-two, something like that. I can send you all the references.

    8. PAPeter Attia1:58:28

       We'll, we'll-- Yeah, we'll link to all of these in our show notes for folks.

    9. RDRalph DeFronzo1:58:32

       Yeah.

    10. PAPeter Attia1:58:32

        Um, yeah, just simply phenomenal. Uh, let me ask you a question. If you, um, take an individual with type 2 diabetes or insulin sen- or insulin resistance and you, uh, presumably collecting urinary C-peptide for twenty-four hours is the best surrogate for insulin-- total insulin secretion?

    11. RDRalph DeFronzo1:58:51

        No. Well, it's an index.

    12. PAPeter Attia1:58:54

        Okay. So i-i-if you could quantify total area under the curve of insulin for a person and then you gave them a GLP-1 agonist, is total insulin going up or down?

    13. RDRalph DeFronzo1:59:05

        [sighs] Depends. [laughs] Because you have, uh, competing factors going on here. Uh, and I'm not trying to be elusive because what I'm-

    14. PAPeter Attia1:59:17

        No, no, no. I understand. Yeah

    15. RDRalph DeFronzo1:59:17

        ... what I'm telling you is actually real. It's what, what happens. So, uh, the drug is going to kick out insulin, uh, and C-peptide's going to go up.

    16. PAPeter Attia1:59:25

        Yep.

    17. RDRalph DeFronzo1:59:25

        And now the glucose is going to come down.

    18. PAPeter Attia1:59:27

        And then you need less insulin.

    19. RDRalph DeFronzo1:59:28

        A-and then you need less. So depending upon the relationship, okay, when you look in absolute terms, okay, the C-peptide and insulin levels actually may be lower. But now when you express how much C-peptide comes up per the rise in glucose, huge increase, okay? So you always have to have, uh, an, a, something that you compare it to and that's the increment in glucose. And anytime you look at how much insulin comes out or C-peptide, which is another confusing factor which I'll mention in a second, you always have to relate it to the, the glucose area. When you do that, a huge increase in, in beta cell function, okay? And the, the other thing you have to be very careful about is you need to be measuring C-peptide, not insulin. Uh, because what we've shown is that when-- uh, and this is a compensatory mechanism.

    20. PAPeter Attia2:00:21

        Maybe just tell folks, I threw out C-peptide as though everybody knew what it is. I, I-- that's a mistake. Tell people what C-peptide is and what its relationship is to insulin.

    21. RDRalph DeFronzo2:00:28

        Yeah. So when you ingest a, a meal, uh, you, uh, there's a precursor that contains both C-peptide and insulin proinsulin and so you split off C-peptide and you split off insulin and they both come out in a one-to-one molar ratio. The problem is half of the insulin that comes out is taken up by the liver so you never see it in the circulating bloodstream. The C-peptide is not taken up by the liver so everything that comes out you see in the circulation. So when we want to know how much insulin was secreted, we actually don't measure the insulin, we measure the C-peptide and that's the true measure. Now the other confounding feature here is, and we've shown this and this has now been reproduced by many other people, is that when you become insulin resistant and diabetic, your beta cells don't secrete enough insulin. That's one of the big defects. How do you compensate? You don't destroy the insulin that's secreted. So the, the, the degradation of insulin becomes markedly impaired. So you can have a high insulin level either 'cause you secrete too much insulin or 'cause you don't destroy the insulin. So measuring the insulin level is not a good measure of beta cell function. If you want to know about insulin secretion, measure the C-peptide and express it per, uh, rise in glucose. It gets a little bit more clouded because your beta cell also can recognize how insulin resistant you are and so it knows, "Look, if you're this insulin resistant, I need to secrete more insulin." If you're very insulin sensitive like you're a lean person with normal glucose tolerance, you don't want to secrete much insulin or you get hypoglycemic. How does your beta cell recognize that? Well, that's somewhat controversial.

    22. PAPeter Attia2:02:12

        Mm-hmm.

    23. RDRalph DeFronzo2:02:12

        We, we-- I can give you my thoughts about it. But in either case, so measuring beta cell function is not just simply measuring insulin. That's probably bad.

    24. PAPeter Attia2:02:21

        Yeah.

    25. RDRalph DeFronzo2:02:21

        Measuring C-peptide is better. Measuring C-peptide per rise in glucose is better and then for some way or another if you can express this all per insulin resistance, this is called the disposition index, something that Dr. Stephen Kahn developed with Daniel Port many, many years ago. So simply looking, as I said, as insulin or trying to do an OGTT and come up and say you know how the beta cell is working, that's not so good. And that's why I say like in the Qatar study, in the EDIC study, we're doing such sophisticated measures of insulin sensitivity and beta cell function. You do three hundred and fifty people, that's like doing one of these big cardiovascular studies with five thousand people in it. Uh, the pathophysiology will always tell you the truth in my opinion. Uh, if you know what the problem is and you correct the problem, the A1C's going to get better. Uh- ADA does not emphasize pathophysiology, you know?

    26. PAPeter Attia2:03:22

        Yeah.

    27. RDRalph DeFronzo2:03:22

        Uh, you had Jerry Shulman on. I, I'm sure Jerry will tell you exactly the same. He, he and I think very similarly. You understand what causes a disease, and then you can come with a treatment that will make

19. 2:03:33 – 2:15:52

    How GLP-1-induced weight loss affects muscle mass, the benefits & risks of myostatin inhibitors, & the need for better methods of evaluating functional outcomes of increased muscle mass

    1. RDRalph DeFronzo2:03:33

       it work.

    2. PAPeter Attia2:03:33

       Do you have any concerns with long-term safety or anything other than simply the economics of the GLP-1s in this current generation?

    3. RDRalph DeFronzo2:03:44

       [laughs]

    4. PAPeter Attia2:03:44

       Again, huge-

    5. RDRalph DeFronzo2:03:46

       Yeah

    6. PAPeter Attia2:03:46

       ... huge leap forward between liraglutide and semaglutide.

    7. RDRalph DeFronzo2:03:50

       Yeah.

    8. PAPeter Attia2:03:50

       And, uh, I've discussed briefly elsewhere on the podcast what the roadmap looks like for how many of these drugs are in the pipeline.

    9. RDRalph DeFronzo2:03:59

       Oh, yeah. [laughs]

    10. PAPeter Attia2:03:59

        There seems to be no end in sight.

    11. RDRalph DeFronzo2:04:01

        You're right. [laughs]

    12. PAPeter Attia2:04:01

        And we're gonna look back at semaglutide and say, "God, that thing was pedestrian."

    13. RDRalph DeFronzo2:04:04

        That's what's gonna happen.

    14. PAPeter Attia2:04:06

        So, so what... Give us the bare case.

    15. RDRalph DeFronzo2:04:08

        Yeah.

    16. PAPeter Attia2:04:08

        What should we be concerned with? What should we be at least looking out for?

    17. RDRalph DeFronzo2:04:11

        Yeah. I would say overall, at the present time, uh, I would consider these drugs to be quite safe. The, the major issue is you have to go slow 'cause of the GI toxicity. Where is the controversy involved, and it's something that, uh, I'm involved with myself. Uh, when you lose 20 or 30% of your body weight, you lose muscle mass, okay? Uh, now, uh, I just gave a talk on this to one of the pharmaceutical companies that are involved in this area. I'm not gonna name the name of the, the pharmaceutical company. Uh, but I started off, uh, by saying, "Look, here is now a study with real data. This is a, a, a gastric bypass surgery study, Roux-en-Y bypass, and the people lost, I think it was 33% of their body weight, and their lean body mass came down quite significantly." One of the problems is people me- measure lean body mass, and that's not a real measure of muscle mass. In fact, it's, can be a very bad measure. You should measure muscle mass. But let's assume that the lean body mass largely reflects, it's a reasonable assumption, muscle mass. So muscle mass came down, okay? So why is that so bad?

    18. PAPeter Attia2:05:26

        But how much did it come down? Because if your total body mass came down by 33%-

    19. RDRalph DeFronzo2:05:32

        Yeah

    20. PAPeter Attia2:05:32

        ... but three quarters of that mass was fat-

    21. RDRalph DeFronzo2:05:37

        Yeah

    22. PAPeter Attia2:05:37

        ... and only one quarter of that was lean, we would consider that acceptable.

    23. RDRalph DeFronzo2:05:42

        And this is where the controversy is.

    24. PAPeter Attia2:05:43

        Yeah.

    25. RDRalph DeFronzo2:05:44

        'Cause no one has really measured muscle mass.

    26. PAPeter Attia2:05:46

        That's right.

    27. RDRalph DeFronzo2:05:46

        We're doing it, okay?

    28. PAPeter Attia2:05:48

        Okay.

    29. RDRalph DeFronzo2:05:48

        We, we will have a definitive answer.

    30. PAPeter Attia2:05:49

        And you're doing that with MR-
20. 2:15:52 – 2:21:43

    Growing crisis of childhood obesity & challenges in treating it

    1. RDRalph DeFronzo2:15:52

       features. Here's a bigger issue, childhood obesity. You are obese when you're four years of age, you're going to be obese when you're adult

    2. PAPeter Attia2:16:03

       And, and your life expectancy will be significantly shorter.

    3. RDRalph DeFronzo2:16:06

       Significantly decreased, yes.

    4. PAPeter Attia2:16:07

       And your quality of life will be significantly reduced.

    5. RDRalph DeFronzo2:16:10

       And you're going to get diabetes. Now make it even better. Adolescents, these young kids with diabetes, they don't respond to any of the drugs.

    6. PAPeter Attia2:16:18

       What is the prevalence of type 2 diabetes in under 18?

    7. RDRalph DeFronzo2:16:22

       Uh, it's, uh, increasing, but I would say maybe around 4% or 5%, something like that.

    8. PAPeter Attia2:16:28

       Five, one in 20 teenagers has type 2 diabetes?

    9. RDRalph DeFronzo2:16:33

       I, I, I guess I'm biased by San Antonio because we have more people with type 2 diabetes-

    10. PAPeter Attia2:16:36

        Okay

    11. RDRalph DeFronzo2:16:37

        ... in our clinic.

    12. PAPeter Attia2:16:38

        But you would, you would s- and, and you could say potentially in San Antonio, one out of 20 teenagers-

    13. RDRalph DeFronzo2:16:42

        It's going to be very high, yes.

    14. PAPeter Attia2:16:43

        Gosh, that is staggering.

    15. RDRalph DeFronzo2:16:44

        And for sure prediabetes. And I'll tell you about the prediabetes study that we did. So now let's say you're-- And, and we know the, these studies are out there. These kids, uh, uh, in this big NIH-sponsored study, uh, they don't respond to metformin sulfonylureas. They don't respond to any drugs very well.

    16. PAPeter Attia2:17:05

        Even the GLP-1 agonists?

    17. RDRalph DeFronzo2:17:07

        Uh, the first study has just come out. They respond better. It's a liraglutide study. They don't have any of the two-

    18. PAPeter Attia2:17:13

        But if you just clinically, if you're in the clinic and you're treating them without, you know, you're using the best drugs you have available.

    19. RDRalph DeFronzo2:17:19

        You're, you're, you're in trouble. And we know-

    20. PAPeter Attia2:17:22

        Wait, wait, why?

    21. RDRalph DeFronzo2:17:23

        Because you can't get them controlled.

    22. PAPeter Attia2:17:25

        Why?

    23. RDRalph DeFronzo2:17:25

        Uh, there's a incr- they're so insulin resistant, much more, more so than adults. Uh, these, these are well-published studies.

    24. PAPeter Attia2:17:33

        Is this not so much-- Is the, is the causality here not... I- is this really a selection bias where for someone to develop type 2 diabetes as a 16-year-old, the underlying genetics and pathology are so severe that the current crop of drugs are the problem, as opposed to when you take the current crop of drugs and you apply them to people who are young, they don't work?

    25. RDRalph DeFronzo2:17:59

        Uh, all three. Uh, 'cause I'm gonna add one more. Genetic predisposition, so Hispanic population-

    26. PAPeter Attia2:18:06

        Yes

    27. RDRalph DeFronzo2:18:06

        ... huge problem. Obesity, all of these kids are huge, okay?

    28. PAPeter Attia2:18:11

        So you don't have the lean diabetic phenotype in this age group?

    29. RDRalph DeFronzo2:18:13

        No, not in these people. And then the drugs don't work very well in this. So all, all three of these things. And what now has come, it's called the RISE study. Uh, and what, as these kids have been followed up, they're starting to develop kidney disease. They're even, I'm told a couple of people have had MIs in their 20s. They're incredibly difficult, uh, to control.

    30. PAPeter Attia2:18:33

        What do you think-- I mean, not that, I mean, yes, we're going to argue that these kids are, that this is due to what they're eating, but what is it in the environment that is so obesogenic to these kids?
21. 2:21:43 – 2:25:39

    Environmental & neurological factors driving the obesity epidemic

    1. PAPeter Attia2:21:43

       so Ralph, again, I just kind of bring it back to this, this question which I mean, everybody wants to understand this, which is what has changed so much in the last 30 years that has created this epidemic? And, you know, um, everybody has their favorite pet theory for what it is. It's the sugar. It's the carbs. It's the plastics. It's the video games. It's the internet. It's the whatever. Perhaps suggesting that it's many, many things. What is, what is your best explanation for what's going on?

    2. RDRalph DeFronzo2:22:21

       I would say all of the above. Processed foods, calorically dense foods, lack of exercise are critical. But these are, I would say, the stimuli that has done something, that's changed the neurocircuitry in the brain. So yes, there's a stimulus, and because now you've been oversubscribed to these stimuli, uh, that's now initiated a process in the brain which is going to be a self-fulfilling prophecy. This is something that I'm very interested in, Dr. Peter Fox and I at the, uh, at the Health Science Center. Uh, but if you go through the literature, and we've published on this, uh, as well, in the areas of the brain that control food intake, and I'm not talking about the hypothalamus. That kind of regulates your, your basal energy intake, what you need to be-- keep your BMI of 25, do what you do during the day. But what is it that makes your BMI go to 35? Uh, those-- that's all related to the hedonic areas in the brain, the putamen, the amygdala, the prefrontal cortex, et cetera. And then, uh, when you do structural MRI, what you can show is that those areas in the brain, the gray matter is shrunk down. Uh, and if you now map the neurocircuitry, which Peter Fox, uh, uh, has been involved with, uh, you can see that there's clear disruption using functional MRI, uh, of the neurocircuitry in the brain. Uh, we have a particular interest in defining where this dysfunction occurs and we have some ideas, which I'm not going to go into, but how we might be able to sort of reprogram, uh, the brain. And sort of in concert with this, uh, these are not, um, data, but these are data that are published in the literature and I think I mentioned this earlier. If you do an insulin clamp, okay, uh, I told you that in your eye, your brain doesn't respond by taking up glucose. But in people who are obese, actually almost in proportion to how obese you are, in these areas in, in the brain, the hedonic areas, there's a marked increase in, uh, it's called fluorodeoxyglucose, which is the PET radioisotope tracer we use in these areas. And that correlates inversely with the muscle insulin resistance. So-

    3. PAPeter Attia2:24:41

       The more muscle-- the more insulin resistant they are in the muscle, the more FDG glucose they-

    4. RDRalph DeFronzo2:24:46

       uptake there is in the brain. Now, this is very interesting because what it's saying, there's a connection. That somehow or another, we believe that the brain is talking to the muscle or the muscle is talking to the brain, uh, and that, uh, that, uh, somehow or other, the brain is playing a very important role in the development of the insulin resistance and that in large part, that this deranged neurocircuitry, which is related to food intake, is now making you overeat. And as you overeat, then all of the things that we know that we've studied, that other people have studied that go with lipotoxicity, you put fat in the muscle, you're insulin resistant. You put fat in the liver, you got NASH and NAFLD. What people have totally overlooked, you put fat in the kidney, you get kidney, uh-

    5. PAPeter Attia2:25:33

       Yeah

    6. RDRalph DeFronzo2:25:34

       ... disease. Uh, you put fat in your arteries-

    7. PAPeter Attia2:25:36

       Fat in the heart.

    8. RDRalph DeFronzo2:25:36

       Yeah.

    9. PAPeter Attia2:25:36

       Yeah. Yeah.

    10. RDRalph DeFronzo2:25:37

        Yeah.

    11. PAPeter Attia2:25:37

        So, so you've been

22. 2:25:39 – 2:34:41

    Role of genetics, insulin signaling defects, & lipotoxicity in insulin resistance & diabetes treatment challenges

    1. PAPeter Attia2:25:39

       in San Antonio since the late '80s. When did you really start to notice this was a problem, at least in your community?

    2. RDRalph DeFronzo2:25:45

       Almost instantaneously, uh, because, uh, I run the Texas-

    3. PAPeter Attia2:25:49

       E-even in kids?

    4. RDRalph DeFronzo2:25:50

       Even in kids. Uh, uh, and, uh, uh, it, it was very clear-

    5. PAPeter Attia2:25:55

       So you can't-- we can't blame video games. We can't blame social media 'cause that-

    6. RDRalph DeFronzo2:25:59

       No

    7. PAPeter Attia2:25:59

       ... wasn't going on in the late '80s. So-

    8. RDRalph DeFronzo2:26:01

       I never saw fat kids at Yale. Uh, I was on the faculty from '75 to '88 and, uh, I kinda thought back. Uh, now, uh, I would say New Haven's not a large Hispanic, but it's more African American. But I don't remember seeing, you know, twelve-year-old kids with type 2 diabetes. And when I came here, uh, and I remember this very distinctly, they're saying, "Oh, you're crazy. We-- You can-- You don't see kids with type 2 diabetes." Believe me, I see them.

    9. PAPeter Attia2:26:34

       And what did your colleagues at San Antonio tell you as far as when they started to notice that in the Hispanic kids?

    10. RDRalph DeFronzo2:26:42

        I think they just-- I, I don't know that I can give you a specific time that they told me, except they knew it.

    11. PAPeter Attia2:26:49

        But-- So okay, what about in non-Hispanic kids? Because if the Hispanic kids are, are genetically predisposed to this-

    12. RDRalph DeFronzo2:26:55

        And they are

    13. PAPeter Attia2:26:56

        ... then the question becomes when did you begin to see this in African American kids and Caucasian kids?

    14. RDRalph DeFronzo2:27:01

        Yeah. So we don't have a large, uh, African American population here. But like in Philadelphia, there's a lady, Sylvain, uh, uh, Sylva Arslanian. Uh, she sees the same thing. Uh, and she sees, uh, uh, I think it's a significant African American population. So I think that in certain ethnic minorities where the genes for diabetes are enriched, that those are the populations that are, uh, predisposed.

    15. PAPeter Attia2:27:29

        And do you think this is mostly an energy balance issue and therefore it's mostly a food environment issue?

    16. RDRalph DeFronzo2:27:35

        No, I think it's both. So I told you I'd come back to the genetic study that we did. So, uh, we, we, uh, in the-- uh, it's a-- an Italian fellow was with me, Giovanni Guldi, a long, long time ago here in San Antonio. We wanted to know what is the earliest defect that you can see in, uh... people who are going to develop type 2 diabetes. So we said, "Okay, in the Hispanic community, it's very common to see mom and dad with diabetes, and it's very common to see a lot of children in these families." So we said, "Why don't we go look at the children and let's see, uh, if we can define..." 'Cause they're at high risk.

    17. PAPeter Attia2:28:16

        Yep.

    18. RDRalph DeFronzo2:28:17

        Uh, and if you have mom and dad with diabetes, you probably have a 70, 80% chance if you're Hispanic, if you're born in that family developing diabetes. It was very easy to find the children. The problem was we couldn't find lean children. So it took us a while because if you're obese, then you got the lipotoxicity. So we finally found them. This is a JCI paper, I believe. Uh, and so we did a insulin clamp. They're as resistant as their parents. They have normal glucose tolerance. Why? 'Cause their insulin levels are astronomical. And then we do a muscle biopsy.

    19. PAPeter Attia2:28:48

        How, how high just for understanding?

    20. RDRalph DeFronzo2:28:50

        Oh, they're like two, two, two times, uh, uh, normal.

    21. PAPeter Attia2:28:53

        Hmm.

    22. RDRalph DeFronzo2:28:54

        Even higher sometimes. We do a muscle biopsy. The same defect in the insulin signaling pathway.

    23. PAPeter Attia2:29:01

        How many of the, how many of the tyrosine kinase defects do they have?

    24. RDRalph DeFronzo2:29:06

        They have-- It starts at IRS-1.

    25. PAPeter Attia2:29:08

        Uh-huh.

    26. RDRalph DeFronzo2:29:09

        Insulin binding to the receptor is okay, just like their parents. The ability to activate the s- insulin signaling pathway at the level of IRS-1, it's already well established.

    27. PAPeter Attia2:29:19

        Which enzyme in particular?

    28. RDRalph DeFronzo2:29:21

        It starts at the level of IRS-1.

    29. PAPeter Attia2:29:22

        Starts at the first one.

    30. RDRalph DeFronzo2:29:23

        Yeah.
23. 2:34:41 – 2:42:17

    The oral glucose tolerance test (OGTT)

    1. PAPeter Attia2:34:41

       So Ralph, I want to close by bringing it back to something that people can do to help, um, understand if they're at risk-

    2. RDRalph DeFronzo2:34:48

       Yeah

    3. PAPeter Attia2:34:48

       ... either lean or otherwise. We talked about it at the outset but didn't go into it in detail, which was the OGTT.

    4. RDRalph DeFronzo2:34:54

       Yeah.

    5. PAPeter Attia2:34:54

       The oral glucose tolerance test. Now again, um, n- none of us have the privilege of being able to use a euglycemic clamp, both clinically as physicians or as experienced it as patients, so we're going to have to kind of rely on other things. We're going to have to rely on body fat. We're going to have to rely on triglycerides. We're going to have to rely on hemoglobin A1C, although I find that to be a particularly useless, uh, metric.

    6. RDRalph DeFronzo2:35:20

       Not that useless, but i- i- it-

    7. PAPeter Attia2:35:22

       At the individual level, I find it very unhelpful.

    8. RDRalph DeFronzo2:35:24

       Yeah.

    9. PAPeter Attia2:35:24

       I think at the population level it's great and in deltas it's great, but boy, the correlation between a hemoglobin A1C and realized glucose levels, it's, it's pretty weak. But let's talk about the OGTT.

    10. RDRalph DeFronzo2:35:36

        Yeah.

    11. PAPeter Attia2:35:36

        Because this is not a test that is done frequently.

    12. RDRalph DeFronzo2:35:39

        Yeah.

    13. PAPeter Attia2:35:40

        I believe it should be.

    14. RDRalph DeFronzo2:35:41

        Yeah.

    15. PAPeter Attia2:35:41

        And I'd love to have you walk us through the interpretation-

    16. RDRalph DeFronzo2:35:44

        Yeah

    17. PAPeter Attia2:35:44

        ... of the following. I'm going to give you a couple scenarios.

    18. RDRalph DeFronzo2:35:46

        Yeah.

    19. PAPeter Attia2:35:46

        So case one. I'm making this up as we go.

    20. RDRalph DeFronzo2:35:49

        Yeah.

    21. PAPeter Attia2:35:49

        So you got a, you got a person who starts out... All these people are going to start out normal, okay?

    22. RDRalph DeFronzo2:35:52

        Yeah.

    23. PAPeter Attia2:35:52

        They're going to start out with a glucose of 90 and an insulin of six.

    24. RDRalph DeFronzo2:35:55

        Yeah.

    25. PAPeter Attia2:35:56

        Okay. At 30 minutes, this is after 75 grams of oral glucose.

    26. RDRalph DeFronzo2:36:02

        Yeah.

    27. PAPeter Attia2:36:02

        The, um, the insulin rises to, uh, 90. The-

    28. RDRalph DeFronzo2:36:10

        I'm nervous.

    29. PAPeter Attia2:36:11

        Yep. The n- the, the glucose rises to 130. At 60 minutes, the glucose is, uh, down to 100. The insulin is down to 60. And we'll just do one more check at two hours. Uh, the glucose at this point is, uh, 60.

    30. RDRalph DeFronzo2:36:30

        Yeah.

Episode duration: 2:42:17