Ralph DeFronzo
Appearances
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
We don't let the glucose change. All we're going to do is raise the insulin. And that means you're giving glucose. 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.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Sure, sure.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And it should be obvious that if you're very sensitive to insulin, I have to infuse a lot of glucose. But the other beauty of it, as I said, when I was a young guy at Yale, there was a a physician in New York, Dr. Altshuler, he was the first one to use treated glucose to trace metabolic pathways. And I said, this is astounding. So I actually went to visit Dr. Altshuler and learned how he did it.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So all of the insulin clamp studies that we did, we were the first people to use treated glucose in humans. and to show that the ability of insulin to shut down the release of glucose from the liver was markedly impaired.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Yeah.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Yeah. In general, that's correct, except in the muscle. Remember, some of the glucose is going to be oxidized. So if you look at the glucose, once it gets into the cell, one third would go through the glycolytic pathway and be oxidized. Right away. Yes. And the other two thirds would be stored as glycogen.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Well, of course, in a certain way you are, but it's not like when you go out and you exercise and you run a mile or two. So I would say you are turning on a number of cycles, which are, of course, going to increase energy expenditure. You're generating ATP, so there is a certain increase in energy expenditure.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
But if I really want to increase energy expenditure, I'd get you to go jog five miles or so, because exercise is really the thing that really increases energy expenditure.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So I'm going to do it first in terms of rates, the way we express it, and then I'll translate that. Under basal conditions, you wake up in the morning and your liver is producing and your tissues are taking up about two milligram per kilogram body weight per minute. Liver is producing, that's hepatic glucose output. That's hepatic glucose output, two milligram per kilogram body weight per minute.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And we were the first to actually show this many years ago. And this is humans. Mice are very, very different, totally different. And that's why extrapolating from mice to humans can be a problem.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
You know, in the old days, they actually used to use pig liver perfusion. I know. But that was in the old days. We don't do that anymore. And baboon as well.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
But now when I do an insulin clamp, depending on how much I raise the insulin and over the years, we've done a dose response curve and I can come back to this because your fat is exquisitely sensitive to insulin. If I raise the insulin just by 10 micro units per ml, the fat stops producing free fatty acids and glycerol. You inhibit lipolysis literally, completely.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
The liver, you need to get the insulin up to about 50 micro units per ml to really get it shut down.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Yeah, they're at 5 to 10. So I'm going to raise them from 5 to 10 to maybe 15 or 20, and that's going to, in large part, shut down lipolysis. In fact, all of this sort of work was work that we originally did many, many years ago. Now, at the level of the liver, you really need to get up to about 50 micrometers per ml.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So maybe at 10, I'm going to bring you up to 50, and that's in large part going to shut off glucose production by the liver. Now that's critical because you wake up in the morning and your liver's producing glucose. Now if you eat a meal, glucose is coming in from the gastrointestinal tract. You can't have glucose coming in from the liver at the same time. Otherwise you get very hyperglycemic.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So when you eat a meal and that insulin comes out, it really needs to shut down hepatic glucose production. Now, what's replacing the liver is what's coming from the meal. But then after you absorbed all of the meal, the liver needs to turn back on. So understanding how the liver is responding to insulin is really very important.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And then if I want to look at what's going on in the muscle, the reason why we go to 100 micrograms per ml, which is above physiologic, but it's still within the physiologic range. If you really want to stimulate muscle glucose uptake completely in a normal healthy person, you'd probably have to get the plasma insulin to about 200. micro units per ml. At 200, what happens?
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Probably about 25% more uptake as you go from 100 to 200. Wow. And these are all early studies that we did. 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.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And if you want to talk about enzymes, you need to talk at what specific enzyme because 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, but you all have to be a little bit more specific about what aspect you want to address.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So you can have insulin resistance in the fat cell, you can have insulin resistance in the liver, you can have insulin resistance in the muscle and then something that's now pretty exciting, you may have insulin resistance in the brain and the suggestions now and there are many insulin receptors in the brain
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Jesse Roth, very famous diabetes person, maybe 50 or 60 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. Some people say that Alzheimer's disease is diabetes type three. I'm not sure. Brain diabetes. Yes.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So the insulin resistance is a very important concept. Let's say we're going to talk about diabetes. even though there's an ominous octet that I developed that's used everywhere in the world for the pathophysiology of type 2 diabetes, if we really wanted to solidify it and say, what are the two big concepts? Insulin resistance would be here, and the other hand would be impaired beta cell function.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
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. Hyperinsulinemia can damage you in other ways, but you won't become diabetic.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
But what happens is if you're insulin resistant, particularly if you have a genetic predisposition, if your beta cells have to continuously pour out insulin, they start to exhaust. And insulin resistance is a disaster for someone who has a genetic predisposition. It's going to bring out the diabetes. Insulin resistance, in my opinion, is intimately related to cardiovascular disease.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
That is why when you see a diabetic patient, 10% of them, you walk in, you have diabetes, first time I see you, 10%, 15% of the people already have a clinically significant cardiovascular disease. And if you look carefully, virtually 100% of them do.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
All of the above. More importantly, what we showed, and we were, again, the first people to show this, and the cardiologists, they're hemodynamically oriented. They're looking at vessels. Stenosis, yeah. 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.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
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, IRS1, 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.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
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. and it's in cardiac muscle, and it's in skeletal muscle. This is all human data that I'm talking about, not animal data.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
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 from diabetes. Now, as you pointed out, rightfully so, I believe that high levels of insulin are also atherogenic.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
I don't want people saying, Dr. DeFranco said you shouldn't be giving insulin to people who need it. Of course, if people need insulin, you need to give them insulin. But our beta cells make 35 units of insulin per day.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So we showed this many years ago when I actually was at Yale, that if you were to take a type 1 patient and they were lean, they would only need 35 or 40 units of insulin to get their glucose controlled, assuming you gave the doses at the right time. But we have a lot of people who are taking 100 units of insulin, both type 1s and type 2s. So 3x physiologic. Yes.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
That kind of hyperinsulinemia, I think there's evidence to support that's atherogenic. But now we have a problem. Can you have the glucose remain high? Yeah, it's a question of do you want to die quickly or slowly?
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
You're stuck. You have to treat. But you also know that when you're giving these big doses of insulin, there may be some side effects.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
There are things, as you already insinuated, weight loss, if you can get people to do it, exercise. And then we can add medications in combination with insulin, insulin sensitizers or some drugs to help you lose weight that will also allow you to get that dose of insulin reduced.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
The other thing we showed in this study, Dr. Del Prado, who's past president of the European Diabetes Association, we took normal, healthy, lean kids, 18, 25 years of age. And we put them on the clinical research center for three days. And we gave them a very, very low dose of insulin infusion.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And we raised their fasting insulin from eight, which is what a normal person would be, to 20, which is really quite low. And within 48 to 72 hours, they were as insulin resistant as a type 2 diabetic patient. So hyperinsulinemia induces insulin resistance. Wait a second. Why is that the case? So what insulin does is it downregulates the insulin signaling transduction system.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So that insulin, when it binds to its receptor and then it activates IRS1 and PI3 kinase and AKT, that system is downregulated by hyperinsulinemia. All of this that I'm telling you about, it's all published. These are all studies done in humans. And this has also been shown in rodent models as well. So this is another reason why we don't want people to be hyperinsulinemic.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
It's the direct effect of insulin down-regulating the insulin signaling system and probably other distal metabolic within the cell as well.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
We didn't do that.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
I would predict probably within 24 to 48 hours, they would return to normal because we did this acutely. Now, if we were able to do this for several months, then I would anticipate that the insulin resistance would remain for a long period of time. And remember, when we treat type 1 diabetics, we're always giving the insulin into the periphery.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And you or I, when you ingest the meal, where does the insulin go? It goes into the portal vein. So the liver is seeing a high level of insulin. That's good. It says stop making glucose, but now it removes half of the insulin. So how much insulin gets into the periphery? Half of what you secreted. Why?
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Because we don't want the insulin in the periphery over insulinizing the periphery because it would make the muscle tissue very insulin resistant. So the pancreas secreting insulin into the portal circulation, liver sees the insulin, good, stop making glucose, but it also takes up half of the insulin.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So less insulin get enough to nourish the muscle, enough to shut down the fat producing free fatty acids, but not enough to hyperinsulinize the system.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And in a certain way, if you're a diabetic and you are insulin resistant or an obese person and you are insulin resistant and you're hyper secreting insulin, it's kind of working against you because it's a reverberating system that's making the insulin resistance aggravated. So one of the big things that we've forgotten is that insulin, I told you there are two problems in diabetes.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
One is you don't make enough insulin. The other is you're insulin resistant. You need to attack both problems. And the paper that I recently published, which is a perspective in Lancet Diabetes Endocrinology, was to bring people back to, look, we're focusing on obesity and weight loss, and we should. But we need to remember that we still have a genetic cause for the insulin resistance.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
You go back to 1950, the incidence of diabetes was 2%.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
But these people were all lean and they're insulin resistant. So there's a genetic cause of the insulin resistance.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Truly nothing. I joke. Let's say 20 years ago, we got involved in one of the biggest genetic studies called the VEGAS study, Veterans Administration Genetic Epidemiologic Study. And we were convinced that we were one of the people to do the first GWAS studies, that we would define all the genes that are responsible. Well, we were not very successful.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
We identified several and remember their associations. Of course. and they're in non-coding regions. The TCF7LT2 gene, we found that, but that had already been described by Dr. Michael Stern in San Antonio many years before. So we repeated what Michael showed, and other people have shown that. So there are a number of associations. Again, if you ask me, how many genes have we truly established?
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
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 when they talk about a genetic score, it's not that they've causably associated a gene with diabetes. It's an association. It's an association. We have a whole different approach.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
If you want, I can tell you what we're doing that may give some insight. And then people have started to think about rare diseases. that 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 got this mixture of individual genes.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
What about the phenotype?
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
The answer to that is it's very clear that lipodystrophy can cause diabetes. This is, I would say, a very, very rare and unusual cause, but well-established. But you're saying that's not what would explain 1% of diabetics. No, no. Jerry Shulman has done some beautiful work in this area.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So it's unequivocal that lipodystrophic people, because their fat cells can't take up the fat, it ends up in your myocardium, cause heart disease. Ends up in the beta cells. It ends up in your beta cell in the muscle. But that's a very, very small percentage. So the basic genetic etiology of the insulin resistance, the PPAR gamma gene has been associated. There are about seven or eight genes.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
There's a recent study, I think it's in Nature Genetics by Brown, where they've identified eight, and again, they're associations, except I would say the PPAR gamma gene, that is pretty clear, that's causal. Did Mitch Lazar do some of this work? He's worked in this area, but again- It's a long list of folks at this point. Yes.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
The number of genes that have been described, the other thing people said, well, maybe there are 20 genes involved, each giving a small component, and that's why it's so difficult. Well, all of these hypotheses have been difficult to prove. And the simple fact is we don't understand the genetic basis, in part because diabetes, in my opinion, is a very poor phenotype.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Diabetes is a very heterogeneous disease. So when we talk about diabetes, if that's your phenotype, it's not surprising to me that it's going to be difficult to define genes that are related to diabetes. So what I'm going to tell you about, I don't want to take the credit for this.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So one of the people in my division, Dr. Luke Norton, working with Steve Parker at Michigan, I'm involved because I'm doing the insulin clamp studies. We're taking as a phenotype muscle insulin resistance. This is a very, very specific phenotype. This is not diabetes. The ominous octet, my pathophysiology, that's eight problems, okay? This is muscle insulin resistance.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
I'm going to do an insulin clamp now. And then I'm going to do a muscle biopsy before I do the insulin clamp. And I'm going to do a muscle biopsy at the end of the insulin clamp. And what happens? During the insulin clamp, I know exactly how sensitive or resistant you are to insulin. I've got the most definitive phenotype in the world. No one gets this kind of phenotype. And now, what do I see?
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
An enormous amount of chromatin opens up. This is the epigenetic component. genes in chromatinuria that you're never ever going to see in the basal state. And that's why we think, this is a hypothesis now, that why it's been so difficult with all of these GWAS studies to identify genes that are associated with diabetes.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And now we're starting to see diabetic people and non-diabetic people, we're starting to see some associations which we think now are causal and we can relate to the insulin resistance with the clamp.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Yes. I've been fighting for 20 years to convince people you need to start with combination therapy from the beginning. Finally, 2022, the American Diabetes Association has made a comment. And for the first time, suggest that you should consider starting with combination therapy. We can talk about therapy later.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Before we continue, I just want to make sure that everybody understands it's Luke Norton and Steve Parker and they're the brain child. I'm involved. I understand the disease. We're doing the insulin clamps. We're giving them the phenotype and they're doing single cell. It turns out there are 10, 12 different types of cells within the muscle.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So we tend to think the muscle, oh, there's a myocyte, that's the problem. But it's probably cells also talking to each other, making it even more complex. So we're at an early stage in the development, but we're enthusiastic. We really have not discovered these genes. So we think that epigenetics are important, and this is part of the epigenetic phenomenon.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
We'll see where it takes us, but we're pretty excited about these findings.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
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.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
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 triamvirate. So from the triamvirate to the ominous octet, we needed to add five more players. So who were the new five players?
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
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 that 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.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
We've shown this is a big interest to Jim.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Counterintuitive.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
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 antilipolytic 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.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And those FFA levels, and this is lipotoxicity, and we've got a long history of studying this, high FFA levels impair insulin secretion. High FFA levels cause insulin resistance in the muscle. High FFA levels cause insulin resistance in the liver. High FFA levels impair the insulin signaling transduction system.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And in fact, one of my previous fellows who's now back with me here at UT, Dr. Belfort, was the first author on this paper showing that just physiologic rises in the plasma FFA literally obliterate the insulin signal transduction system, which is the first step in glucose metabolism.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
The arrow is more on the other side. The fat is pouring out fat. And you can show that the lipolytic enzymes are all resistant to insulin. We've shown this. Other people have shown it. So these elevated FFA levels are a disaster. So the fat cell initially is your friend. Then it becomes a bad guy. So that's number four. Number five is the gastrointestinal tract.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
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, GLP-1 and GIP, glucon-like peptide 1 and glucose-dependent insulin trophic 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?
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Is the problem that you don't release enough GLP-1 in GIP, or is it that your beta cell is refractory to the GLP-1 in GIP? Well, it's the later.
The Peter Attia Drive
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70% of the insulin that's going to come out is dependent on that GLP-1 and GIP. So you can imagine that that's a huge problem at the level of the beta cell in terms of the defect in insulin secretion.
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Yes. So this is an area, of course, intense investigation, but the clinical counterpart of this is you've already mentioned the drugs that are out there, the GLP-1 receptor agonist. What I'm doing is I'm giving you a pharmacologic dose of GLP-1 and I'm overcoming the resistance at the level of the beta cell. Now, there's another component to this that we'll get to, and that's glucotoxicity.
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And these were studies that were done by Jens Holtz and the group in Denmark. They took people and they infused GIP. We're talking about GIP. And you don't respond to the GIP. These are type 2 diabetics. And then they intensively treated them with insulin and lowered their glucose. And then when they come back with the GIP, you reach a normal amount of insulin. So this is a glucotoxic effect.
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Yeah, more than 50 years. I actually have been in this field of metabolic disease for a long time. I think I'm the longest consecutively funded 53 years NIDDK investigator. I actually started even long before that when I was a medical student at Harvard. I had this fantastic teacher, Professor Cahill, who gave us all of the lectures on intermediary metabolism.
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So you asked me mechanism. So we know that at least for the GIP, the glucotoxicity is impairing the ability of the beta cell to respond to the GIP. But not necessarily GLP-1. No, no. And that doesn't correct the GLP-1 problem. So there's true resistance still, even though I normalized the glucose in terms of GLP-1. So this incretin axis, the gut, is a very important endocrine organ.
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And that's number five in the ominous octet. Number six in the ominous octet is the alpha cell. I would say the father of hypergluconemia, this is Dr. Roger Unger in Dallas. He was one of the very first people to show that diabetics had very high glucagon levels. Tell people what glucagon does. Yeah, glucagon, it drives hepatic glucose production.
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So if your glucose gets too low, your alpha cells will release glucagon. So the alpha cell can sense the glucose. And so if you're hypoglycemic, this is an important defense mechanism. You release glucagon, that stimulates your liver and the glucose production goes up. It returns your glucose to normal. But a diabetic already has a high glucose. We don't want high glucagon levels.
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So paradoxically, there's very high glucagon levels in the diabetic and those high glucagon levels are very important contributor to the hepatic insulin resistance because they're driving the liver to make glucose.
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Gluconeogenic pathway in glycogenolysis. Acutely, so if I acutely give you glucagon, the first thing that happens, you break down glycogen. But very quickly, you get rid of all the glycogen that's in the liver. And so chronically now, you're running on gluconeogenesis. But glucagon stimulates both pathways.
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Yes.
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And that's a important reason why you have fasting hyperglycemia. So when you wake up in the morning- Yeah, and your blood sugar is 110 milligrams per deciliter. That's the liver. And part of that is because your liver is intrinsically resistant to insulin.
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Part of it is because the liver is now responding to the glucagon and producing an excess amount of glucose, both through gluconeogenesis and through glycogenolysis. Although I would say the major contributor is the gluconeogenic pathway. Now, that gluconeogenic pathway is also turned on because fat is coming from the fat cell. Remember I told you the FFA is high. Yes.
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Glycerol is coming from the fat cell. Yes. We talked about some of the work that Jerry did. This is Jerry's work showing that glycerol coming from the fat cell is an important driver of gluconeogenesis. and then hepatic fatty acyl-CoA levels are up because you have all this fat pouring in, and that's activating the enzymes, pyruvate carboxylase, that are driving the gluconeogenic pathway.
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So the metabolic, the actual pathways, I think, are very well worked out. So glucagon, alpha cell, bad guy. And so is the alpha cell overproducing glucagon in this state?
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#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And a certain way, this is also insulin resistance because hyperinsulinemia shuts down glucagon. And we have very high fasting insulin levels in the diabetic, okay? Now, what is it? What's the sensing mechanism within?
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And I decided this is what I wanted to do. And I worked each summer with Professor Cahill. And sometimes in life, you meet the right person, the right opportunity, it changes everything you do. And Basically, what I do now, I contribute directly to George. And when I gave the Banting lecture in 2008, people usually put a picture of their mother and father and children.
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You're gonna see it gets even worse when we talk about the kidney, which is number seven on the list. All right, let's go to number seven. Okay, so people don't know I'm also board certified in nephrology. In the old days, I trained as a micropuncturist. I used to sit with a microscope.
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I would draw my little pipettes out the night before and put the little micropipette in the tubules and I collect tubular fluid. What I was interested in, and this is when I was a renal fellow at the University of Pennsylvania, I was interested in glucose and phosphate transport. And I published the series.
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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 fluorescein that blocked glucose transport in the kidney. And so I took this molecule called fluorescein and it blocks glucose transporters. There are two transporters in the kidney, SGLT2 and SGLT1.
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SGLT2 takes back 90% of the glucose. If it does its job, SGLT1 takes back the other 10%. And then in your eye, even though we filter 180 grams of glucose per day, no glucose appears in the urine. But what I showed is that Florizin, it blocked both SGLT2 and SGLT1. It blocked glucose transport and it also blocked phosphate transport. And I showed that glucose and phosphate transport were coupled.
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When I was doing these studies, even though I was a nephrology fellow, I had previous done my endocrine fellowship at the NIH in Baltimore City Hospitals. I had an interest in diabetes and I said, this would be a great way to treat diabetes.
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So in the old days, we did things for science and I published a series of four papers in the JCI and I never even thought of, to be honest with you, of patenting this. 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're probably the stupidest guy I ever met. And I said, why?
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She said, you could have patented this drug. So I actually worked with Bristol-Myers Squibb and then AstraZeneca and that eventually led to that guy closing and coming to the market. But what we showed, and this is human biopsy.
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Forsiga.
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Yeah. Canagliflozin was next? Ampigliflozin, yeah, and then Canagliflozin, Ertugliflozin, we have a bunch of them. They're all very good, basically do the same thing. But what we showed was the SGLT2 transporter was markedly upregulated in the kidney. Let's just wrap our heads around that.
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And I love my mother and father and children, but I only showed one picture, and that was Professor Cahill, because he's really the person who's ended up directing me to where I am today.
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#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And now, so here's a diabetic with a very high glucose. Right.
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So as a doctor, I want the kidney to dump the glucose out in the urine. But what is the kidney doing? It's doing the opposite. It's holding on to the glucose. Even as a renal fellow, it became clear to me, this is such a simple way to treat diabetes. And the fact is, it's so simple, no one thought about it. The only dumb thing that I did was I didn't patent it, which I should have done.
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I'd probably never have to write another NIH grant for the rest of my life. And then we went on to show, and in fact, this is the first definitive proof of the glucotoxicity hypothesis. So we did all of these studies initially in animals, and this was all published in the JCI. And Luciano Rossetti is one of the fellows at this time. Actually, Jerry Shulman was a fellow on the papers as well.
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#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And what we showed was that you could take different types of diabetic animal models, and you could show that they're reabsorbing excess amounts of glucose. And then if I treated them with fluorazine, because that's what was available, they simply peed the glucose out in the urine. And now all of a sudden their beta cells started functioning normally. Muscle insulin sensitivity improved.
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So of course, that's wonderful if you're a mouse or a rat. So we said, well, what about humans? And so the original studies actually were done, there's kind of an interesting story behind this, but the initial studies were done with dapagliflozin. And we showed with just 14 days of treatment with dapagliflozin, we markedly lowered the fasting and postprandial glucose.
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We improved insulin sensitivity by 35% and we made a major improvement in beta cell function. Now, the beauty of this, SGLT2 inhibitors are only in the kidney. They're not in your muscle. They're not in your beta cell. And the only thing that the SGLT2 inhibitors do makes you put glucose out in the urine. The only change in the plasma was the glucose came down.
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#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And now insulin sensitivity improved in muscle and beta cell function improved. And this was the first, now in humans, even though the original studies were done in animals, first studies to show an improvement and the reality of glucotoxicity.
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What was interesting is that when we started to work on developing this with BMS and AstraZeneca, the company decided, well, we should get some nephrologists in to see about this story. They said, look, if you listen to what Dr. DeFranco says, this will be a disaster. And they said, why? Because you put glucose in the urine, it will glycosylate the proteins, then you'll cause kidney damage.
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And they actually held up the development of the SGLT2 inhibitors. And the way we finally convinced them to go ahead was that there's a disease called familial renal glucosuria. From day one of their life, they're bringing out tremendous amounts of glucose. They have perfectly normal kidney function.
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It kind of depends on what the level of your GFR is, but it could be anywhere from 40 to 60 grams up to 120 grams of glucose. And the higher would be in somebody with a higher gradient? Yeah, the higher the glucose. The higher the, yeah. Yes, because you filter more glucose, then there's more glucose to be blocked at the level of the kidney. And these drugs are very, very good.
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#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Now, I actually, in developing these drugs, as I said, I'm also a nephrologist. Based on the Barry Brenner hypothesis, I predicted these drugs would save your kidneys, according to the Brenner hypothesis. And that's all turned out to be correct. These drugs are great for the kidney. What I never, ever envisioned, that these drugs were going to save your heart.
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The brain. So the brain plays a role in a somewhat indirect way. So every day 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 did you ever think? Why does that happen?
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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, that same thing that's increasing 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.
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Your brain is resistant to leptin. So there are a lot of these anorectic molecules that your brain has become resistant to. And these molecules, it's another area of interest of mine, they work in the hedonic areas in the brain. So in the putamen, the prefrontal cortex, and they tell you to stop eating.
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And unfortunately, 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 UT,
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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, the brain is insensitive to insulin in your eye. In obese people, these areas in the brain where there's abnormal marked increase in glucose uptake. Incredible finding.
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Who would have thought?
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So what is their fuel source? Lactate? Well, in response to insulin, they don't take up more glucose. Oh, oh, oh. Okay. I'm sorry. Got it. Because remember, this is from the Cahill studies. As long as your glucose is about 50, your brain is happy. So this is actually in the evolution of the human being. This is phenomenal because in the old days, you may not eat.
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You may slaughter one of these beasts. Yeah. You're not eating for days. You're not eating for days. So your glucose would drop. So if your normal fasting was 80, if it dropped to 40, you're okay because your brain saturated at 40. You got below 40, you're in trouble. So you have a big buffer here. But now if I infuse insulin and your glucose is 80, your brain doesn't take it up more glucose.
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It's, quote, insulin insensitive in a certain way.
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This also suggests that there's brain insulin resistance, which is, I'd say, an interesting concept and may play some role in this neurocognitive dysfunction, Alzheimer's, whole different story that's in evolution. But to come back 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.
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That's lipotoxicity. And we've done studies in both directions. I can put an IV and I can infuse an emulsion of free fatty acids. And I can show within two to four hours, I induced severe insulin resistance in the muscle, in the liver, and I markedly impaired beta cell function.
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And then we don't have this drug in the United States, but there's a drug that's available in Europe and I have an IND to use it. It's called a Cipamox. It inhibits lipolysis. It's like SGLT2 inhibitor. The only thing to do is block glucose reabsorption in the kidney. Cipamox, all it does is do block lipolysis. It lowers your FFA level.
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Over 12 days, no change in adiposity, huge improvement in insulin sensitivity and muscle. Why is it not approved in the U.S.? I don't know the company that developed it in Europe. ever tried to get it approved in the U.S., it's, I would say, modestly effective in lowering triglycerides. And we have phenofibrates, which are much more effective. So that may be the reason.
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But the triglyceride and the FFA are not the same thing. No. But that's the reason why it's approved in Europe. But if you lower the FFA, that's the precursor for triglyceride synthesis. So it has an effect to lower the triglycerides. But the key thing is if you lower the FFA, and we did this for 12 days, we did it in both obese people and in diabetic.
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You markedly improve insulin sensitivity in the muscle. If using MRI, you can measure muscle fat. It goes down dramatically and correlates with the improvement in insulin sensitivity. We also measured ATP generation because there's this issue is, there's clearly mitochondrial dysfunction if you're a diabetic. That's unequivocal. The controversy is
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Is the mitochondrial dysfunction causing the insulin resistance or is the insulin resistance causing the mitochondrial dysfunction? So in this study that we did, when we lowered the FFA and lowered the muscle lipid content, we saw about a 50% improvement in ATP generation, mitochondrial ATP generation.
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So at least this says that part of the mitochondrial dysfunction is secondary to the lipotoxicity and insulin resistance. But this still remains, I would say, a controversial topic. Clearly, it is mitochondrial dysfunction. If you can improve it, that's going to improve insulin sensitivity.
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the drug that I can't get people to use, which is a phenomenon. By activating PPAR gamma, it does a lot of good things. And one of the important things that it does, it has a huge effect to improve mitochondrial dysfunction. And it has direct effects. It works directly through PPAR gamma to do this. And it also binds directly to the mitochondrial pyruvate carrier.
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And that influences flux through the mitochondrial chain.
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Huge misconceptions. I guess we'll talk about therapy. We'll come back to it. As part of my triple therapy regimen, I use a GLP-1 receptor agonist, I use pioglitazone, and I use an SGLT2 inhibitor. There's a fourth good drug, and that's metformin. 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?
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No other endocrinologist involved in this. 1995, metformin was a revolutionary drug. Why? We had insulin and sulfonylureas. So now we had a drug that really could work. 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. Now, here's the problem. It'll become very obvious.
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We talk about these paradoxes. The more weight gain, the greater the drop in A1c. The more weight gain, the greater the improvement in insulin sensitivity. And is it fat gain specifically? No. I'll come back to that in a second. It is fat weight gain, and I also believe muscle weight gain. The more weight gain, the greater the improvement in beta cell function.
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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 greater the rise in HDL cholesterol. Sounds like a terrible drug. So here's another one of those paradoxes. We know if you overeat and gain weight, that's a disaster. But with pioglitazone, the more weight you gain, everything gets better.
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The brain did switch over to ketone metabolism. And believe it or not, I didn't do the 40-day fast, but I was one of the people who fasted for five to seven days. If you fasted for three days, you could get paid $50. And I thought I was the richest guy in the world from this study. I can assure you that the physical specimens in this study were phenomenal. What did the 40-day fasting students get?
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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. The pharmaceutical companies, if you had to go up against pioglitazone, all these NASH drugs, I don't believe you can beat pioglitazone. What's the brand name for pioglitazone? Actos. As I said, there's this paradox. So why do you gain weight?
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P-O-glutazone, it redistributes fat in the body. It gets it out of the 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 receptor is in the hypothalamus.
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#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
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 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 and moving the fat around.
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The other negative thing about pioglitazone is it causes fluid retention. So people have associated fluid retention with heart failure. Now, why do you get fluid retention? Again, people do not understand. 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.
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Pioglitazone, that insulin signaling defect that I told you about, pioglitazone corrects that defect.
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There are three tyrosine molecules, and they have to be phosphorylated. These are studies done by Ron Kahn and other people in Boston. You mutate one of those tyrosines, you become a little insulin resistant. You mutate two of them, you become moderately insulin resistant. You mutate three of them, you're severely insulin resistant. Insulin binds to the receptor.
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Okay, that happens normally in diabetics. We showed there's no problem there. Then IRS1, insulin receptor substrate 1. Which is inside the cell, comes up. Yes. It interacts with the insulin receptor and it gets phosphorylated on the same three tyrosine molecules. And then you activate PI3 kinase, AKT. We could add some more molecules in here, but this is the insulin signaling pathway.
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That's the pathway that the earliest defect that you can show in diabetics is in that pathway.
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So what Jerry has shown very elegantly is that there are certain lipids, DGAT, and it's a specific DGAT. There are several types of DGAT molecules, which has confused things. So he's shown there's a specific one of the DGATs. that activates these atypical PKC molecules and that serine phosphorylates the insulin receptor.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
When you serine phosphorylate the molecules in that pathway, it inactivates them, okay? And so, he's done these very nice elegant studies both in peripheral muscle and in the liver showing that this plays a very, very important role in the insulin resistance. This is part of the lipotoxicity. I don't believe that this is the genetic basis. the genetic etiology.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
You get fat and you start putting fat everywhere. This is very important, critically important. That was when he gave his Banting lecture. And I might say I'm delighted that I got to write his letter of nomination for the Banting lecture. He was incredibly deserving. He's done phenomenal work in this area. But that was his Banting lecture.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And you're right, very, very, very important mechanism of insulin resistance.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
I don't know, but I'm sure he paid them a lot of money. That's amazing. In order to do that. 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're a lean type person, you can fast for 40 days. But the real problem is at some point you start to break down muscle.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So what does it do? It activates that signaling pathway. You generate nitric oxide. Now you vasodilate. That's why the blood pressure drops. When you vasodilate, so I'm a nephrologist. I understand this very clearly. Anytime you underperfuse the kidney, you hold on to salt and water. You become an edematous. And so people associate fluid retention in edema with heart failure.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So we did the definitive studies published in Diabetes Care in 2017. People just don't read. So we took people who had diabetes and we treated them with pioglitazone. And then using NMR, very, very sophisticated techniques, what we showed is pioglitazone markedly improved myocardial blood flow. Now, these numbers are going to blow your mind away.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Marocardial insulin sensitivity with PET and fluorodeoxyglucose improved by 75%. Your heart, we showed this before, is severely insulin resistant. I came pretty damn close to normalize insulin sensitivity in your heart. Now, since we're doing the insulin clamp with tritiate glucose. You can track it. 74% improvement in skeletal muscle insulin sensitivity. It's the same. Exactly the same.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
If you look at ejection fraction, it went up by 5% to 10%, not down. It went up. If you look at every measure of diastolic dysfunction, E over A, E over E prime, LV, peak filling pressures, et cetera, cardiology people understand this. The point is, whether you're looking at systolic function or diastolic function, it all got better.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Like, I mean... No drug that corrects insulin resistance. Metformin is not an insulin sensitizer. And people keep going back to this. I brought metformin to the US in 1995. I know this. I did all the mechanism of action studies. What we showed was the insulin clamp. The drug absolutely does not improve insulin sensitivity.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
I'd say this is still controversial. In high doses, for sure, yes. And the kind of doses you see with giving metformin, I would say somewhat equivocal.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And then if you start to break down cardiac muscle, then prolonged fasting at that point becomes a problem. But you have a lot of energy stored in fat and you can starve for a long time. And obese people easily can go for three, four months with all of the reserves that are in the body.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Inhibiting the mitochondrial chain and inhibiting gluconeogenesis. Well, for sure, it inhibits gluconeogenesis. Metformin gets into cells through the organic cation transporter. The organic cation 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.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
It's interfering with aerobic metabolism.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Absolutely not a single molecule in the world of metformin has ever gotten into any skeletal muscle anywhere. And tell me again why? What's the transporter? The organic cation transporter. That's the transporter 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.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
It can, if you have very, very high doses, that can occur when you have very low GFR because metformin is excreted via the kidney. If the metformin levels build up, you can get lactic acidosis. That's a very, very rare complication. There's not a reason why you shouldn't be using the metformin. And I'm not saying that metformin is not a good drug. It is a good drug.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
I don't think it's as good as the other three drugs we talked about, but yes, it does at high doses increase the lactate level, all in effect on the liver. And the old drug that caused all the problem was fenformin by Guanide as well, but it had a powerful effect. Yeah, fenformin was much more powerful. Yes.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
No, no, no, no.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
See, this is the reason why some people thought it's an insulin sensitizer. 15 to 20% of people have significant GI side effects and they lose weight. And if you look at the studies, on average, there's about a three kilogram weight loss with metformin. And when you lose weight, you can improve insulin sensitivity.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So I think this is what's confused some of the old literature to make people think that metformin was an insulin sensitizer. But when we developed metformin, and I did all of the work that went to the FDA, if you look at the New England Journal of Medicine, Article 1995, there are only two names on the paper, myself and a PhD oncology lady who was the person from Liefer Pharmaceuticals.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
We did insulin clamps, many of them. We never could show metformin-improved insulin sensitivity using the gold standard with radioisotopes.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Yes.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So you can label metformin and you give it. And then where do you see? It's all accumulating in the liver in the first three, four, five, 10 minutes. And then what happens? You start to see it accumulating in the kidney. Why? Because that's where it's excreted. And then wait another five or 10 minutes, you see the bladder. And that's the only place where you see
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Metformin, you never see it in the muscle. And that's even more graphic demonstration that metformin is not getting in the muscle and it is definitely not an insulin sensitizer.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
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 edict study, what we did is we used triple therapy right from the beginning.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And my point of the Banting lecture, the ominous octet, if you have eight problems, I'm sure there are going to 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 is going to correct eight problems? It ain't going to happen in our lifetime. So the point was you need to use drugs in combination.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Basically, every time you eat a meal and your blood sugar level goes up, you're going to release insulin. And insulin is sort of a master regulator for all biochemical processes in the body. One of the things that insulin is going to do is going to talk to your muscles and say, take up glucose and burn that glucose.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
We said, we're going to use what we think are the best drugs at the time. So we started with metformin, with exenatide, an old time GLP-1. This is not the kingpin. This is the pre-liraglutide. Yeah, exactly. Because that's what was available. That drug was useless, wasn't it? No, it's a good drug. Sure, it's not semaglutide or teraceptide.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Yes. It's kind of an old timer. And PO-glutazone, that was the triple therapy. And then 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. Followed for six years. So we said, this is what we believe is the appropriate therapy.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Then we said, we'll use the ADA approach. The ADA approach is you start a metformin. And when you fail, even not explicitly said, the next drug that's used is sulfonylureas. And then the third drug that's added is insulin. And we said that the goal of therapy was an A1C of six and a half, okay?
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And that if your A1C rose above six and a half, 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. Yeah, you're already at 2x physiologic. Yeah.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Now you have to split the dose of insulin. You have to be adding rapid acting insulin. I think this is quite reasonable. Six years later, 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. It's less than six and a half. Why? Insulin clamp. Huge improvement with our therapy.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
This is the EDIC study. The three-year data 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.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Plus, remember, if to do 315 people, follow them for 16 years and do all this stuff we did, it's unequivocal.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
What we need to know is in a normal person, when I infuse insulin, how much 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.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
They finally said in 2022, there's a state, the ADA approach is not based on pathophysiology. I view myself as a scientist, as well as a clinician. As a good clinician, I've taken care of hundreds of thousands of patients and 850 publications. I do clinical research. I work in people.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
When I do an insulin clamp study and I see an improvement in insulin sensitivity, I do a hyperglycemic clamp and I see in 315 people your basal function, I don't need 5,000 people. I can't do this study in 5,000 people. No one can do this study. But the tools that we're using are so powerful.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Look, if I normalize your insulin sensitivity and I give you a normal beta cell and your A1C is less than six and a half, well, it's half of the 315 people. Why do you not think that's the best therapy? And now on the other side, I have this metformin SU insulin and 71% of the people have failed. There's zero improvement in insulin sensitivity, zero improvement in beta cell function.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Why do you think that's such a good regimen? Now, above and beyond all that, I didn't do this study. This is the GRADE study, G-R-A-D-E. It's sponsored by the National Institutes of Health. And what the GRADE study said, and I have to say, this is the third study that's shown what I'm going to tell you. Dr. Robert Turner's United Kingdom Prospective Diabetes Study showed this in 1990.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Stephen Cairn showed this in the ADOPT study in year 2005. And now we have the GRADE study, 2020. I call this the 15-year revelation. We saw what didn't work, 1990. Oh, Stephen Cairn did it again. Oh, it didn't work in 2005. And now 2020, NIH did it. You know what? All show the same thing. And this was a sequential approach.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
They want to know what's the best next drug to add to metformin. I can add a sulfonylurea. A1C went down in year one, up straight. Tell folks how a sulfonylurea works. Sulfonylureas are old-time drugs. They bind to the sulfonylurea receptor on the beta cell and they kick out insulin. And they're very good drugs in the first year. And then they burn out the pancreas.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Other drug, DPP-4 inhibitor. Tell people how those work. So a DPP-4 inhibitor increases your GLP-1 and your GIP level endogenously. It makes your gastrointestinal cells, the K and the L cells that secrete the GLP-1 and GIP, makes them make more GLP-1 and GIP. But it doesn't increase the GLP-1 and GIP enough to really give you a knockout punch.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
I give you an injection, people are out there, Monjaro or semaglutide, that's the knockout punch. When I give you the DPP-4 inhibitors, they do increase GLP-1 and GIP a little bit, but not powerful enough to give you a long-lasting effect. So first year, A1C comes down, A1C goes up. Third drug, this was very surprising to me. This was liraglutide.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
This is one of the earlier GLP-1 receptor agonists. I thought that was going to work the best. It failed. It worked in the first year and then failed. And then the fourth drug was insulin. And the docs just didn't titrate the insulin enough. So A1C down and then they failed. So five years later, all four of those regimens added to metformin failed.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Triple therapy, exenatide, an old-time GLP-1, pioglitazone, which people don't appreciate, the only true insulin sensitizer, and metformin. Six years later, 70% of the people have an A1C less than seven.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
We raise the insulin. And then I'm using muscle as an example, how much glucose is taken up, disposed of by the muscle. And then I can compare if you're overweight compared to the lean person. Obese people are very insulin resistant in terms of muscle glucose uptake. I could look at the diabetic. They're even more insulin resistant. But there are many processes that insulin control.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Our old version is incredibly effective. The problem is you can't get people to use pioglitazone.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
How many kilos? Depends on the dose. 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 dose. Okay. But their A1C is controlled. Okay.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Oh, you lose all the weight you lose with the GLP-1 receptor.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Absolutely. And it also gets rid of the edema. And believe me, their A1Cs are down in the normal range. Let me tell you this first thing about pioglitazone and the proactive. I'll come back. So in the proactive study, this was done a long time ago. You have to show cardiovascular safety. 5,238 people to get in the study, you had to have an MI stroke or something bad.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Half people on pioglitazone, half the people on placebo, okay? And the MACE endpoint, major adverse cardiovascular events, which is non-fatal MI, non-fatal stroke, cardiovascular mortality, you have to show the benefit to get approval by the FDA. The MACE endpoint was positive.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And so when I talk to cardiologists, I like to say, what was the one thing in the PO glitazone that predicted that you would not die? They don't know. You know what the one thing that predicted that you wouldn't die? Weight gain. So I jokingly say, look, you can either be a little fat and alive or you can be lean and dead. Which one you're going to pick?
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And we've done this and we've published this. If you tied my hands behind my back and said, Ralph, you can only pick one drug, I would pick one of the newer GLP-1s. They're incredible drugs. But that's not what I'm going to do. Even for a lean diabetic? They're a little bit different story, but the answer is basically yes. Let me narrow that down a little bit.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
If I had to pick two drugs, I would pick pioglitazone with one of the newer drugs. And for sure, if you had any kind of renal or cardiac disease, I'm going to pick an SGLT2 inhibitor.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
But I would say, although this study will never be done, if you're a newly diagnosed diabetic and you don't have any cardiac symptoms, why do you think that the SGLT2 inhibitor is not doing all of the beneficial things in that newly diagnosed diabetic that it's doing and the people who get into these studies who already have cardiac disease.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So if you have a cardiac problem, I put you on the SGLT2 inhibitor, you're less likely to have MI stroke, etc. It's doing good things. It's doing, in my opinion, the exact same good thing in someone who I'm just diagnosing for the first time when I put them on the SGLT2 inhibitor, But no one is ever going to do a study. It's impossible. I'm going to take 1,000 people.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
You probably have to take 20,000 people, newly diagnosed, and then 10,000 go on SGLT2 and 10,000 on placebo. I'm going to follow them for 20 years to see who's going to have their heart attack. No one's going to do that study because they're going to get on all kinds of drugs.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So insulin regulates how much fat is 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.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Yeah. And also we have to be cognizant of the fact these newer GLP-1s. So potent. But they're $1,000 a month.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Yeah, I can, I think. It's not proven. So remember I told you that insulin knocks down glucagon. So if I give you a GLP-1 receptor agonist and I kick out insulin and I get you well insulinized, any negative effect that might be related to glucagon is going to be obviated. So That glucagon effect to drive hepatic glucose production will be totally blunted by the insulin secretory effect.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
This is the other thing that bothers me about these GLP-1s. These are the best drugs in the world for losing weight. These are the best drugs in the world for saving your beta cell. I told you that when you eat a meal, 70% of the insulin that's secreted is coming from the GLP-1 and the GIP. People have stopped talking about this effect on the beta cell.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
I told you, if you want to look at type 2 diabetes, big problems, beta cell failure, insulin resistance. These GLP-1s, they're saving your beta cell. We've forgotten about it. We've become so enamored with the weight loss. I don't want to downplay that at all because the weight loss and the lipotoxicity, a huge problem that's causing insulin resistance.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
But people have forgotten how powerful the drugs are on the beta cell. So when I give you this drug and they work on the beta cell and kick out insulin, any negative thing that glucagon is doing will be totally negated. Now, you may see some good things that glucagon are doing that we couldn't appreciate before. So what are the good things?
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Some people have suggested that increases thermogenesis energy expenditure. I don't believe that. There are animal data. I don't believe this in humans. I believe that it's exerting an anorectic effect in the central nervous system. That is, I think, yet to be established.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Pretty sure there are studies going on now at the Pennington Institute and maybe also in Orlando where they have these chambers where you can- A TRI. Yeah, yeah. So I think we'll get an answer about energy expenditure.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
I'm with you. I think it's all appetite. Here's another issue. It is very interesting. If you look at all these big GLP-1 studies, cardiovascular, what's the reduction in cardiovascular events? Almost uniformly, 20%. Old dudes, exenatide, et cetera, liraglutide. New dudes, 20%. even though the weight loss with the newer ones is much greater.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And so for that process, we know this is what a normal person should respond like. This is what a diabetic responds like. And the diabetic is much, much more insulin resistant. They're not responding. In a certain way, it's a general term because insulin controls so many things. Protein metabolism. Insulin is very important in helping you to build protein.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
I suspect in terms of cardiovascular benefit, there is a cap that once you've lost a certain amount of weight and you've gotten a certain amount of lipotoxicity and all the good things that these drugs are doing, You don't go beyond that, even though you're losing more weight.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And also, if you look at the A1C, yes, Monjaro does drop the A1C a little bit more than semaglutide, but they're both pretty powerful. Rituitide does a little bit more and does cargisema do a little bit more, but they don't do a lot more. So I also think there's also going to be somewhat of a cap on how much you drop the A1C. You get two and a half percent drop. Do you need to drop it three?
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Old time guys, right? So this is called the Qatar study. So there's this concept that's out there. And again, what drives me is science. If you understand pathophysiology and there's an abnormality and you correct the abnormality, things get better.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So in the Qatar study, and there are 220 people or so in the study, to get into the Qatar study, you had to be poorly controlled on metformin sulfonylurea. So you had to have failed on this. And the average A1C was about 10. And about a third of these people were symptomatic, meaning they had polyuria, polydipsia, they were losing weight.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And so the current concept is in those people, you would put them on a mixed split insulin regimen, you would get rid of the glucotoxicity, you would get rid of the lipotoxicity and you get their A1C down to six and a half. And then now you could put them back on the oral medications or whatever. And now they respond because you got rid of the glucotoxicity and lipotoxicity.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
We said, well, that may or may not be true. So we said, well, half of these people are starting with an A1C above 10 will go on a mixed split insulin regimen with a large gene and a rapid acting insulin. And the other half are going to go on that old dude exenatide and pioglitazone, one that people don't like to use. Three years later,
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
The A1C in the group with the mixed split insulin regimen is 7.1%. And we're very good at insulin. Why couldn't we go lower? Because we got into trouble with hypoglycemia. The A1C in the group treated with exenatide and pioglitazone is 6.1%. Then we said, okay, look, we'll do a subgroup analysis. So about one third of the people, we'll just look at the people who are symptomatic.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
The starting A1C is 12.2. Three years later, their A1C is 6.1. From 12? 12.2 symptomatic. On which combination? Xenatide and pioglitazone. Without even metformin? They had failed on metformin and SU to get into the study. So what we're saying, look, if you have drugs that correct the insulin resistance, that's PO-glitazone. This is almost impossible for me to imagine.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So I could infuse insulin, and we've done this using carbon-labeled 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. So it's kind of a general term.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
What makes these studies so solid is we have very sophisticated pathophysiologic measurements. No one can do what we do.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
These drugs are so powerful when you put them with pioglitazone. I mean, you lose almost the same amount of weight. They're huge in terms of getting you to lose weight.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
This is called the Qatar. It was done in Qatar. Qatar, the country. The country. And I need to give credit to Dr. Mohamed Abdel Ghani, who's been sort of my co-worker in all of these studies. And Mohamed's on the faculty at UT in our diabetes division.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
They are. And I can tell you we have a big program that's going on there as well as in Kuwait. And we actually have a formal cooperative agreement with the Kuwaiti people. So at the Dasman Diabetes Institute, We have trained them. My people have been there, trained them how to do these insulin clamps and sophisticated metabolic studies, and they take care of the patients.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So here's another thing that's pretty exciting that we're doing. 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. There's amino acids in the meal. That secretes insulin. And GLP-1 goes up and that secretes insulin. So now when you eat a meal, there are already three stimuli.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
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 going to be pretty confusing. So what we said, maybe what we should do is that we should do a three-step hyperglycemic clamp. So we give you three steps of glucose and we can get beta cell sensitivity to glucose.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
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. And then the M value is where it hits the axis? Then I can get glucose. But this is just now I'm going to focus on the beta cell because the hyperglycemic clamp is just for beta cell function.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
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. So you can sequentially measure the different... Three different stimuli. And now what we see is different loci. Some are associated with the defect in glucose.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
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 of the beta cell. Let's go back to the guitar study for a second. How many people were in that study? About 220. Big study. When you're doing all these insulin clamp studies and these kind of measurements are not easy to do.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
That was published when? Let's see. I would say the one and a half year data were probably about 2018. And the three year data, I would say 2021, 22, something like that. I can send you all the references. Yeah.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Because you have competing factors going on here. And I'm not trying to be elusive because what I'm telling you is actually real. It's what happens. The drug is going to kick out insulin and C-peptide is going to go up. And now the glucose is going to come down. And then you need less insulin. And then you need less.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So depending upon the relationship, when you look in absolute terms, the C-peptide and insulin levels actually may be lower. But now, when you express how much C-peptide comes up for the rise in glucose, huge increase. So you always have to have something that you compare it to, and that's the increment in glucose.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
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 glucose area. When you do that, huge increase in beta cell function. The other thing you have to be very careful about is you need to be measuring C-peptide, not insulin. What we've shown, and this is a compensatory mechanism.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Absolutely. So 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. So there are many ways in which you could
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So when you ingest a meal, there's a precursor that contains both C-peptide and pro-insulin. 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.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
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.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
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 degradation of insulin becomes markedly impaired.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So you can have a high insulin level either because you secrete too much insulin or because 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 rise in glucose.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
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 a 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?
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Well, that's somewhat controversial. I can give you my thoughts about it. But in either case, measuring beta cell function is not just simply measuring insulin. That's probably bad. Measuring C-peptide is better. Measuring C-peptide per rise in glucose is better.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
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.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And that's why I say in the Qatar study, in the EDIC study, we're doing such sophisticated measures of insulin sensitivity and beta cell function You do 350 people, that's like doing one of these big cardiovascular studies with 5,000 people in it. The pathophysiology will always tell you the truth, in my opinion.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
define insulin resistance, but basically whatever the particular process you're looking at, you're comparing what would be the normal response in a normal healthy person compared to what might happen in a diabetic person or an obese individual.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
If you know what the problem is and you correct the problem, the A1C is going to get better. ADA does not emphasize pathophysiology. You had Jerry Schulman on. I'm sure Jerry will tell you, he and I think very similarly. You understand what causes a disease and then you come with the treatment that will make it work.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
I would say overall at the present time, I would consider these drugs to be quite safe. The major issue is you have to go slow because of the GI toxicity. Where is the controversy involved? And it's something that I'm involved with myself. When you lose 20 or 30% of your body weight, you lose muscle mass.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Now, I just gave a talk on this to one of the pharmaceutical companies that are involved in this area. I'm not going to name the name of the pharmaceutical company, but I started off by saying, look, Here is now a study with real data. This is a gastric bypass surgery study, room-wide bypass. And the people lost, I think it was 33% of their body weight.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And their lean body mass came down quite significantly. One of the problems is people measure lean body mass, and that's not a real measure of muscle mass. In fact, it 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.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And this is where the controversy is, because no one has really measured muscle mass. We're doing it. We will have a definitive answer. And you're doing that with MRI? MRI. It's gold standard. But now I said, look, in this study, they measured absolute strength. You can do grip strength or leg strength. And absolute strength went down. A little bit, maybe 25%.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Then they said, let's express strength per weight loss. Per weight, yeah. Up by 50%. Per appendicular, it goes up by 50%. And then they said, how far can they walk? They went from walking 200 yards to two miles. And then said, one of the things is how many times can you get up out of a chair in a certain period of time? It increased like three or four fold. They measured your VO2 max.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
But here, for whatever the reasons are, maybe all of the fat that's pushing on your lungs so you can't oxygenate, the epicardial fat that's not allowing your heart to contract, the fat that's in the heart that's causing myocardial lipotoxicity, which I believe is real. These things are all changing in a positive way. So again, it's a balance. Of course, they don't like this.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Why weren't they happy with these results? Well, because now the companies are all looking at developing drugs that will preserve the muscle mass or increase the muscle mass. But basically what I'm saying is that, look, it's lean body mass. We have to say it's reflecting muscle mass. Everything gets better. The patient feels better. They can walk better. They feel stronger, et cetera, et cetera.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Why are you so worried about muscle mass? I look all these gloomy faces because they're all developing myostatin inhibitors or eventin. Then the next slide comes up and says, retort. Here's a good thing. So now, if you lose all of this body weight and you improve insulin sensitivity and muscle,
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
and you improve it in the heart, and there are cardiovascular benefits, and you correct the improvement in all of the cardiovascular risk factors, now, even though you've lost muscle mass, if you've improved insulin sensitivity, there may be an enormous benefit of seeing the improvement in the muscle insulin sensitivity, even though you've lost muscle mass.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And they do have some concerns about these drugs, these myostatin inhibitors, that actually may have some negative effects on the heart. And my suggestion is actually you may find a big improvement in myocardial function.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
This is a more direct way to go. So you can either have their antibodies by Magrubab to myostatin, or you can interfere with the signaling receptor itself.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
There doesn't seem to be any adverse effect of these drugs or they wouldn't got through phase two. And there are actually some fairly large phase two studies. What's the indication? Is it sarcopenia? I don't know. The FDA, if you have a sarcopenic disease, there are criteria that the FDA has established if you want to develop a drug that you have to meet certain criteria.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
I'm not an expert in this. I can't tell you exactly what these criteria are, but they are pretty well established. Now, for these kind of people, and I'm going to come back, you asked me about lean people, I'll come back to that in a second. because this is really an issue.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Let's say I put you on a GLP-1 receptor agonist and you lost 25% of your body weight, and I put you on a myostatin inhibitor, and that prevented the muscle loss.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
This is remarkable. Right. So let's say that happened. What would be the FDA's criteria? I'm going to give you approval for this drug.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
You see, you're raising very important and critical issues. Because there are many, many companies that are going ahead with these drugs that increase muscle mass. But to me, okay, increasing muscle mass, what does that mean? There needs to be some functional translation of that.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
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 and the insulin level would go up. 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.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Insulin sensitivity, that's the one I put at the top of the list for them. Get rid of the insulin resistance. The FDA won't give them credit for that, I don't think.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And that is actually exactly the way I ended my discussion to these people. I showed them what resistance training did. And if you could show what resistance training did with your muscle mass increase, then you'd have something. But you need to design the studies appropriately. And as I said, and as you said, I don't know what the criteria are going to be that the FDA uses to judge these things.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
They do have a sarcopenia set of criteria, but that's a very different group of people that we're talking about. But this comes and hits home to one of the things you asked me earlier. What about the lean person who's 80 years of age? Is this the right drug for that person? I don't know. Maybe not.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
But now let's say you have a healthy 80-year-old person and everybody in the family lives to be 105 and they have diabetes. Well, they're at risk to the toxic effects of hyperglycemia. Would it be reasonable to treat that person? We know there's powerful effects on the beta cell.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
I would say it would be quite reasonable, but I think you need to monitor what's happening to their weight and other 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 an adult.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Now make it even better. Adolescents, these young kids with diabetes, they don't respond to any of the drugs.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
It's increasing, but I would say maybe around 4% or 5%, something like that. One in 20 teenagers has type 2 diabetes? I'm biased by San Antonio because we have more people with type 2 diabetes in our clinic.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Gosh, that is staggering. And for sure, pre-diabetes. And I'll tell you about the pre-diabetes study that we did. And we know these studies are out there. These kids and this big NIH-sponsored study, they don't respond to metformin, sulfonylureas. They don't respond to any drugs very well. Even the GLP-1 agonists? The first study has just come out. They respond better. It's a liraglutide study.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
They don't have any of the two.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
You're in trouble.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Because you can't get them controlled. Why? They're so insulin resistant, much more so than adults. These are well-published studies.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
All three, because I'm going to add one more. Genetic predisposition. So Hispanic population, huge problem. Obesity, all of these kids are huge. So you don't have the lean diabetic phenotype in this age group? No, not in these people. And then the drugs don't work very well. So all three of these things. And what now has come, it's called the RISE study.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And then someone would just turn it around and say, look, I'm going to see how much the rise in glucose was per insulin. And that's a measure of insulin resistance. 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 denominator and numerator.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And as these kids have been followed up, they're starting to develop kidney disease. I'm told a couple of people have had MIs in their 20s. They're incredibly difficult to control.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
I'll come back to this in a second, but I want to raise the issue now. Let's say you're 16 and you don't met for himself. You're A1C is nine. You can put someone on Monjaro and they're going to have to take this for the rest of their life. Because as soon as you stop the drug, so this is what I treat the person. Of course, I can't let the A1C at nine.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
I think that if they can afford the drug and they stay on the drug, The three big ifs, if the doctor knows what to do, I know what to do. If the patient will cooperate with you, if you don't, they'll lose every time. And if they can afford. If you can satisfy those three ifs, that person we know from the studies be pretty well-controlled
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Yes, if you have diabetes. The Manjaro coverage, I think, is pretty good if you have diabetes. If you have obesity without, that's a whole different issue. Should you be treating these young kids? Obesity is a disease. It's got all kinds of problems. Should you put these young kids on these newer drugs? And knowing that all I did is change you from food addiction to drug addiction.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
I didn't do anything else. It's almost like alcohol addiction. There are drugs or things I can give you that can help you, but they tend to relapse. Food addiction, I put you on the drug, you lose weight. You stop the drug, you regain the weight. This is a huge public health concern. It is almost way beyond my capacity because finances are involved here.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Can we afford to treat 42% of the people in the U.S. are obese? Or is there some way amongst the 42% we can define who are the people who are insulin resistant? Who are the people who have the metabolic syndrome that we know they're at risk, that we can treat them? My guess is that the great majority of that 42% of the people, can we treat all of those people?
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And moreover, are they going to stay on the drug? We know on average what the data is saying. I put you on the drug. We don't know all the reasons why, but within a year, half of the people stopped the drug. Yeah, and it's probably a combination of cost and side effects. Yeah, and my patients very commonly tell me, I enjoy eating and I can't eat anymore.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Some people just tell me they just want to eat, so I'm going to get fat again, so I'm going to eat. Some is GI side effects and some is cost. $1,000 a month is a lot of money for people.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So I said, we need to develop something that is really more specific.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
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, that's now initiated a process in the brain, which is going to be a self-fulfilling process.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
This is something that I'm very interested in Dr. Peter Fox and I at the Health Science Center. But if you go through the literature, and we've published on this 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 basal energy intake, what you need to be, keep your BMI of 25, do what you do during the day.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
But what is it that makes your BMI go to 35? That's all related to the hedonic areas in the brain, the putamen, the amygdala, the prefrontal cortex, etc. And then when you do structural MRI, what you can show is that those areas in the brain, the gray matter is shrunk down.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And if you now map the neurocircuitry, which Peter Fox has been involved with, you can see that there's clear disruption using functional MRI of the neurocircuitry in the brain. 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 the brain.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And in concert with this, these are not I'm 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, I told you that in your eye, your brain doesn't respond by taking up glucose.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
But in people who are obese, actually almost in proportion to how obese you are, in these areas in the brain, the hedonic areas, there's a marked increase in, it's called fluorodeoxyglucose, which is the petraryoisotope tracer we use in these areas. And that correlates inversely with the muscle insulin resistance.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
The more insulin resistant they are in the muscle, the more FDG glucose uptake there is in the brain.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
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 and that somehow or other, the brain is playing a very important role in the development of the insulin resistance.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And that in large part, 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.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
What people have totally overlooked, you put fat in the kidney, you get kidney disease. Fat in the heart.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
I never saw fat kids at Yale. I was on the faculty from 75 to 88, and I kind of thought back. Now, I would say New Haven's not a large Hispanic, but it's more African-American. But I don't remember seeing 12-year-old kids with type 2 diabetes. And when I came here, and I remember this very distinctly, they're saying, oh, you're crazy. You don't see kids with type 2 diabetes.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So we don't have a large African-American population here. But like in Philadelphia, there's a lady, Silva Arslavian, she sees the same thing. And she sees, I think it's a significant African-American population. So I think that in certain ethnic minorities where the genes for diabetes are enriched, those are the populations that are predisposed.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
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 100 people and I would infuse insulin initially as a priming dose and then just clamp the insulin level. So I give a prime continuous insulin infusion.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So I told you I'd come back to the genetic study that we did. An Italian fellow was with me, Giovanni Gulli, a long, long time ago here in San Antonio. We wanted to know what is the earliest defect that you can see in people who are going to develop type 2 diabetes. So he said, okay, in the Hispanic community, it's very common to see mom and dad with diabetes.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And it's very common to see a lot of children in these families. So he said, why don't we go look at the children and let's see if we can define, because they're at high risk. 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 Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
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. And so we did an insulin clamp. They're as resistant as their parents. They have normal glucose tolerance. Why? Because their insulin levels are astronomical. And then we do a muscle bias.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
How high, just for understanding? Oh, they're like two times normal, even higher sometimes. We do a muscle biopsy. The same defect in the insulin signaling pathway. How many of the tyrosine kinase defects do they have? Starts at IRS 1. Insulin binds to the receptor is okay, just like their parents.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
The ability to activate the insulin signaling pathway at the level of the IRS-1, it's already well established. Which enzyme in particular? It starts at the level of IRS-1. Starts at the first one?
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Well, no, it's IRS-1. You can't tyrosine phosphorylate it. You cannot activate PI3 kinase. Oh, I see.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Yeah. And then the other thing, Jerry and I have both done this in somewhat different ways. I'm talking about Jerry Shulman. He uses NMR by looking at phosphate derivatives Even though I believe the primary defect is in the signaling pathway, there's clearly severe impairments in glucose transport and phosphorylation.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
His work would suggest that the primary defect is at the level of glucose transport. We developed a novel triple tracer technique using three isotopes infused into the brachial artery. We believe that the primary defect is at the level of hexokinase and phosphorylating glucose. We kind of agree to disagree because we can't do the study.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
We'd have to do the MRI study at the same time we're doing the triple tracer technique. In addition to the insulin signaling defect, there's a severe defect in glucose transport and phosphorylation.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
I can take 100 people and all 100 people, I can raise your insulin level by 100 microunits per mL. 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.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Because there's a different one in the muscle and the liver, correct? That is correct. So Jerry would say the primary defect is in GLUT4, the transporter. I would say, yes, that it's severely impaired.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
We were the first to show this defect in muscle. In fact, we're the only people, I think, that have shown this in human muscle. It's been shown in rats, et cetera. To me, metabolism in rats and mice is so different. This is all people data.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And I can show you there's a primary defect in pyruvate dehydrogenase and glycogen synthase. This comes back. I have an ominous octet for the insulin resistance. That's why people don't understand. Look, there are eight organ sort of things that are a problem. There are eight problems I can show you within the muscle. Why do you think one drug is going to correct all these problems?
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
We need drugs to work on the beta cell. We need insulin sensitizers. We probably need different types of insulin sensitizing drugs. We need drugs that reverse the lipotoxicity. And will we ever have a single magic bullet that corrects all of these? Probably not until we discover the genetic basis. And remember, I said that diabetes is a heterogeneous disease.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
In diabetes metabolism reviews, I would say 30 years ago, I wrote a review article that said, I can put a defect in the muscle and reproduce diabetes. I can put a defect in the liver and reproduce diabetes. I can put a defect in the fat cell and reproduce diabetes. I can put a defect in the beta cell and reproduce diabetes.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And I went back and read that and I said, I can put a defect that starts in the brain and reproduce diabetes. So we see someone with an A1C of eight or nine. All these defects we've been talking about, They're already there. So you put that defect in the fat cell, they can look lean. There's a syndrome called Alzheimer's syndrome. There's a specific defect. This is white adipocyte.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Phil Scherer will love me for saying this. He's the top guru in adipocyte metabolism up in Dallas. And it's Alzheimer's syndrome. There's a specific defect in the glucose transporter in white adipose tissue. You know what happens? You become diabetic. You know what happens? You gain weight. You know what happens? You get NASH. So here's a defect that I said 30 years ago.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
I just postulated and said, here's a syndrome. And not only that, now that they define this in people in this paper, they then went to the animal model and they knocked out the gene that's causing the defect and they reproduced diabetes in the normal mouse model.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
And actually, we were the first people to ever use radioisotopes to trace this and show that 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.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Is a pre-diabetic state. This is a very insulin resistant person. And two hour later, hypoglycemia is a reflection of the beta cells, early insulin secretion. This is kind of a pre-diabetic state.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
We already published this. The best predictor of who's going to get diabetes is a one-hour glucose greater than 155. And this is from prospective data from the San Antonio Heart Study, also from the Botany Study, where these people have been followed up. We were the first people to publish this, oh, I'd say seven, eight, nine, 10 years ago.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
There have been, I'd say at least 15 to 20 studies that have reproduced what we showed 10 years ago. Can send you all the references.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Yes. And if you also happen to be hypoinsulamic, that adds more to the predictive value. But just pick 155 without knowing the insulin. That's a huge predictor of whether you're going to develop diabetes or not. That's from the San Antonio Heart Study, and that's also from the Botnia Study, and also from our Vegas Study. Okay.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
How effectively does that insulin stimulate muscle glucose uptake? And again, what we showed, and these actually were the very first unequivocal demonstration that diabetic people, type 2, were insulin resistant. Before this, there was a lot of controversy. Dr. Riven, who is a father of insulin resistance, I like to think I'm the son of Dr. Riven. He's a great idol of mine.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
30-minute insulin is deficient. That's a predictor as well.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
That's a primary beta cell defect. And one of the earliest things you can detect in people who are predisposed to develop diabetes is loss of first phase insulin secretion. Now, first phase insulin secretion, strictly speaking, can only be measured with the hyperglycemic clamp that we developed.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So when I acutely raise the glucose from, say, 90 and I raise it to 200, in the first 10 minutes, there's a big spike of insulin that comes out. That is typically lost in people who are going to develop type 2 diabetes. And its counterpart during the OGTT is the insulin level at 30 minutes. So when you ingest the glucose, of course, the rise in glucose is more gentle.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
When I acutely raise your glucose from 90 to 200, that big spike of glucose gives the first phase. But a low insulin response in the first 30 minutes is another predictor of who's going to get into trouble.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Yeah, you might be being overly aggressive, but for sure, if they meet those numbers, you're probably safe.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
I sign up. All right.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
He really was one of the very first people to insinuate that diabetics were insulin resistant. With the insulin clamp, we showed this very definitively. And we also know we use the label glycerol and free fatty acids, and we could show the ability of insulin to shut down release of lipid from the fat cell was markedly impaired.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
So three of the major organs, all of this work originally was done by us when I was back at Yale.
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
That's very critical. We also, when we did these studies, 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. How much in the liver?
The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
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. Just explain to people what a euglycemic condition means. Euglycemic means your fasting glucose when you wake up in the morning is 80. Now you're euglycemic. That means when we do the studies, we keep your fasting glucose of 80.