#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.

Hey everyone. Welcome to the Drive Podcast. I'm your host, Peter Attia. This podcast, my website and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness and we've established a great team of analysts to make this happen. It is extremely important important to me to provide all of this content without relying on paid ads to do this. Our work is made entirely possible by our members and in return we offer exclusive member only content and benefits above and beyond what is available for free. If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of a subscription. If you want to learn more about the benefits of our premium membership, head over to peterattiamd.com subscribe My guest this week is Dr. Ralph DeFronzo. Ralph is a distinguished diabetes researcher and clinician known for his pivotal work in advancing the understanding and treatment of type 2 diabetes. He's widely recognized for his groundbreaking contribution to the concept of insulin resistance, which has reshaped the understanding of type 2 diabetes and its progression. He played a very important role in bringing Metformin to the United States as a standard treatment for the disease nearly 40 years ago, along with the discovery and development of SGLT2 inhibitor, a class of drugs you have no doubt heard me discuss many times before. With over five decades of research in the field, Dr. DeFronzo has received numerous prestigious accolades, including the Banting and Claude Bernard Awards, the highest honors that can be given to a diabetologist. This episode with Ralph is really a masterclass in the organ specific aspects, the pharmacology, the diagnosis of type 2 diabetes, and it draws from his vast experience. Now, if you listen to my conversation with Jerry Shulman a few years ago on insulin resistance, what amazed me was how little overlap there was, not because the information is not congruent, but because of how much we were able to go into different topics. So the discussion with Jerry Shulman, which I would encourage everyone to listen to if they have not really focused on one of the areas that insulin resistance manifests itself, which is in the muscle. What we talk about here is about all of the other organs. Spoiler alert. There are seven that are impacted by this condition and therefore we go into much greater detail there in addition to the pharmacologic interventions. And I just have to say I learned more in this podcast than I do in most podcasts. It's one of the few that I had to immediately go back and listen to. And my notes from this podcast are so voluminous that they even provided substrate for internal meetings with our team in the practice. In short, there are many things that I've taken away from this that will directly impact my patients. Just as far as some of the other things we discuss, we get into details about how insulin resistance impacts liver. We do talk about muscle, but we talk more about fat cells. We talk about his development of the euglycemic clamp, something that some of you have probably heard of as the gold standard for measuring insulin resistance. Again, we talk about the pharmacology, not just the SCL2 inhibitors, but the GLP1 agonists, metformin, and another class of drug that we don't talk about that often. That, frankly, for me, was a real eye opener. There's a lot more I can say, but I think at the end of the day, you just kind of got to listen to this one maybe twice. So without further delay, please enjoy my conversation with Dr. Ralph DeFronzo. Ralph, thank you so much for coming down to, I guess, up to Austin from San Antonio. Very excited to sit down with you and talk about potentially one of the most important subject matters in all of health. People who listen to me all the time hear and are familiar with me talking about these four horsemen, cardiovascular disease and cerebrovascular disease, cancer, neurodegenerative and dementing diseases. And then there's this fourth horseman that I talk about, and it's in many ways the squishiest, because it's not the one that shows up on the most death certificates, but in many ways it's the foundational one that is amplifying the risk of all of those other causes of death. And I refer to it as metabolic disease, spanning the spectrum from hyperinsulinemia to insulin resistance to fatty liver disease, all the way out to type 2 diabetes. So given how much I speak about that, it seems very important that we should have a really thorough discussion of that foundational metabolic disease. And no one better than you to have that discussion. So let's start a little bit with just telling folks briefly about what you're doing at UT San Antonio and why you've spent the last 40 plus almost 50 years now working on this problem.

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. 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. 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.

People who are listening, who are particularly astute, might recall I've referenced a number of Cahill's papers, But one of the more interesting studies he did, which it's possible he did while you were even a student there, was the 40 day starvation study. Now, you might have not been quite at Harvard yet, because this was, if I recall, in the mid-60s, maybe 66, 67. And it was probably a group of medical students that actually volunteered, if not medical students, undergrads, they did a water only fast for 40 days. And the study basically just followed all of the metabolites. What happened to glucose levels? Obviously insulin, beta hydroxybutyrate, acetoacetate. Anyway, it was very fascinating stuff. One of the things that was most interesting to me in that study was even under a period of such extreme starvation, the brain never gave up its dependency on glucose. So even though ketone bodies began to service the brain by about day seven to 10 as the majority of the fuel, even at three and four weeks of starvation, glucose was, if my memory serves me correctly, still providing about a third of the brain's energy.

Your memory is very good. 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?

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. 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.

Let's maybe talk a little bit about what insulin resistance is. We'll get into what causes it. But let's just maybe define for people this term that gets thrown around constantly, and let's explain what it is from a technical standpoint.

Basically, every time you eat a meal and your blood sugar level goes up, you're gonna 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 it'd say, take up glucose and burn that glucose. 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, 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. 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. 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. 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.

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

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 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.

So one of the challenges with the term insulin resistance is, as you said, it's a vague term and it's nonspecific because the actions of insulin are so many. It has an action in the liver, it has an action in the muscles, it has an action with response to glucose, it has an action with response to amino acids, and it has an action with response to fat, both in the liberation of fat, lipolysis, and presumably in response to oxidation.

Absolutely.

We'll go through all of these, but let's maybe start with how the euglycemic clamp test is done. Let's assume that I'm a healthy enough individual that we can use me as a proxy. I come into your clinic. What are we going to do? How do you run this test?

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. 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. So I said, we need to develop something that is really more specific.

Just to be clear, Ralph. I mean, unfortunately, we as clinicians are not able to do you glycemic clamps.

Correct.

We are still looking at oral glycemic tolerance tests. We are still giving people oral glucose and sampling glucose and insulin every 30 minutes and trying to impute what we can, which I'd love to come back and talk about interpretation, but carry on with the limitation.

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 the technique where I could take a hundred 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. I can take a hundred people and all a hundred people. I can raise your insulin level by a hundred microunits per milliliter. 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 a pat of glucose production. 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. 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. Reeven, who is a father of insulin resistance, I like to think I'm the son of Dr. Reeven. He's a great idol of mine. 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 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. So three of the major organs, all of this work originally was done by us when I was back at Yale.

Let's summarize those again, we're talking about this in an insulin sensitive person right out of the gate. Insulin is going to shut down hepatic glucose output.

Absolutely.

Which again, all of this kind of makes sense if you think through the Pathway. Our liver is constantly putting glucose into circulation because the muscles can't put glucose into circulation. So something has to feed the brain. If insulin is high, it suggests glucose is already sufficiently high. So let's not create more glucose toxicity, let's shut that. Second thing it's going to do is it's going to take that excess glucose and put it in the place where we have the largest capacity to store it, which is muscle. So point two is we increase muscle uptake of glucose. And then point three, you said was it's going to shut down lipolysis, it's going to shut down the release of triglycerides and or free fatty acids from the adipose tissue.

That's very critical. We also, when we did these studies, we would put a catheter in the hepatic vein and in a femoral artery and a 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?

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.

You glycemic means your fasting glucose, when you wake up in the morning is 80. Now you're EU glycemic. That means when we do the studies, we keep your fasting glucose of 80. We don't let the glucose change. All we're going to do is raise the insulin.

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 release epinephrine.

I just want to make sure people understand that I was going to come back to that. I wanted you to finish that point. So let's make sure we go back to the test because it's very counterintuitive. So I've got a catheter in each arm. I walk in off the street, I've been fasting. My blood sugar is 80 or 90, whatever milligrams per deciliter it is, you are going to have to infuse both insulin and glucose into each of my arms. And the reason is when you said a moment ago, you're going to steadily increase my insulin and take it to a steady state of 100 IU per milliliter. That's a staggeringly high insulin level.

Not so high in your eye after a meal, it would be maybe 60. Obese people very commonly get 400.

Sure, sure. For a healthy person would never see an insulin level that high. And if you were not simultaneously running glucose into them, you would kill them within minutes.

Hopefully not.

Yeah. But to get to the point, they would become so profoundly hypoglycemic that they would cease to exist.

And it should be obvious that if you're very sens 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 physician in New York, Dr. Altschuler. 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. Altschuler and learned how he did it. So all of the insulin clamp studies that we did, we were the first people used tritiated glucose in humans and to show that the ability of insulin to shut down the release of glucose from the liver was markedly impaired.

Sorry to interrupt, but just to make sure the people are following us, the reason you wanted to use tritiated glucose there was not to quantify the total amount of glucose disposal. You could do that on mass balance. You wanted to determine the ultimate fate of glucose. How much became hepatic glycogen, if any. It sounds like the answer is none. How much became muscle glycogen? Sounds like you said about 90%. And how much ultimately got converted through de novo lipogenesis into adipocyte, or free fatty acid? Sounds like that's about 10% under the euglycemic condition, Is that correct?

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 gluc glycogen.

I mean, presumably you're doing this test and a person is sedentary.

Yes.

Is muscle that metabolically active at rest? I guess it is, yes. Yeah. So that's really interesting. Does that mean you're increasing energy expenditure under these conditions?

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. 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.

And, Ralph, just for a sense of amount, if you're doing this in, say, somebody my size who's insulin sensitive, how many actual grams of glucose would you be able to get into the person within the hour whilst keeping insulin clamped?

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 2 milligram per kilogram body weight per minute.

Liver is producing. That's hepatic glucose output.

That's hepaticlucose output, 2 milligram per kilogram body weight per minute. 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.

Let's just reflect on that for a second. People who listen to this podcast are probably sick of me saying this, but I'm sorry, I just can't stop saying it. The liver never ceases to amaze me.

It's an incredible organ.

It's an unbelievable organ. And again, I come back to this idea. It's the only major organ for which we don't have extracorporeal support. If your heart, if you went into cardiogenic shock and we felt we could reverse it in time, we could put an intra aortic balloon pump in you, we could put an IABP in you, we could put a left ventricular device in you to stem you over until we get you out of there. If your kidneys are destroyed, we can transiently dialyze you. Even if your brain is experiencing swelling, we can, you know, put enough steroids in you or decompress your skull to give you the time to recover and keep you alive. Otherwise, go through all the major organs. If your spleen is dinged, take it out. Even if you lost your small bowel, we could at least transiently keep you alive with TPN or something like that. None of this is true with the liver.

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.

It had baboons? Yeah.

So the fact that the liver can titrate this amount is remarkable. So 2 milligrams per kilogram per minute. So you take an individual who weighs 100 kilograms, you're putting 200 milligrams per minute of glucose into circulation.

Then you can multiply that by however minutes you want to look.

So that's a gram every five minutes. That's 12 grams of glucose every hour that the liver is putting out.

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 microgrids per milliliter, the fat stops producing free fatty acids and glycerol. You inhibit lipolysis literally completely. The liver, you need to get the insulin up to about 50 microunits per ML to really get it shut down.

Sorry. And the fat, you had to get how high?

10. A rise of 10.

Tell me. These people, when they come in and healthy, they're What? They're at 5 to 10 fast?

Yeah, they're at 5 to 10. So I'm gonna 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 microunits per milliliter. 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. 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. And then if I want to look at what's going on in the muscle, the reason why we go to 100 micronuts per milliliter, 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 microunits per milliliter.

At 200, what happens, you have now.

Maximized muscle glucose uptake in reality, even.

In an insulin sensitive person?

Yes.

Just to make sure I understand what you're saying, you're saying that if you took an insulin sensitive individual at 100 units of insulin versus 200, you will actually drive more glucose uptake. You haven't saturated the GLUT4 transporter at.

100, 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. And if you want to talk about enzymes, you need to talk at what specific enzymes, 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 have to be a little bit more specific about what aspect you want to address. So you can have insulin resistance in the fat cell, you can have insulin resistance in the liver, you can have insulin 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. 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 3. I'm not sure I.

Brain diabetes.

Yes. 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, on the other hand, would be impaired beta cell function. So if you are insulin resistant and your beta cells work well, they know how to read the insulin resistance, they'll make enough insulin, you won't become diabetic. The hyperinsulinemia can damage you in other ways, but you won't become diabetic. But what happens is, if you're insulin resistant, 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. 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 clinically significant cardiovascular disease. And if you look carefully, virtually 100% of them do.

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

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, 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, pi3k, all those molecules don't get activated. So glucose doesn't get into the cell. That's diabetes. That same pathway activates nitric oxide synthase, and that generates nitric oxide. Nitric oxide is the most potent vasodilator in the human body. It's the most potent antiatherogenic 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. 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. I don't want people saying, Dr. DeFronzo 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. 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 a hundred units of insulin, both type 1s and type 2s.

So 3x physiologic?

Yes. 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?

But we have really good drugs.

Yes, yes, yes. But if you were only doing this with insulin, be a problem. It's an awful trade off. You're going to die very quickly from hyperglycemia if you're left untreated. But if we overdo it with insulin to maintain normal glycemia, we're going to kill you slowly.

It's a quagmire. 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.

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

Absolutely not.

There has generally been an ethos of. When I've talked to patients with type 2 diabetes, what they've been told is, I'm told to cover with as much insulin as is necessary to maintain my glucose levels in this range. And it means I can eat whatever I want. It's okay if I have all the pasta and bread and sugar in the world, because as long as I'm covering it with insulin, I'm okay. And then you find out, wow, you're taking 150 units of insulin a day in all of its forms, the short acting, the long acting, et cetera. But I didn't actually realize that what we would consider physiologic is 35. I may have known that at one point and I've since forgotten, but that's a great reference. So basically, if there's a person with type 2 diabetes listening to us today and they're taking 75 units of insulin, one of the takeaways should be, what do I need to do with my nutrition and other pharmacologic activities, plus exercise, plus everything that's under my control to maybe get that down to 35, where I would be at a physiologic level?

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 all also allow you to get that dose of insulin reduced. 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. And we raised their fasting insulin from 8, 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 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 also been shown in rodent models as well. So this is another reason why we don't want people to be hyperinsulinemic.

You have to explain that to me again, Ralph. That is mind boggling. I would never have predicted that. So let me say it back to you because I'm. I feel like I missed it when I was writing something down. You took normal volunteers.

Yep.

Who had a fasting insulin of 8.

Yep. And they're lean, healthy.

Okay. And simply infused insulin in them, presumably with glucose.

Oh, yes, of course. On the clinical research center where we can monitor, keep the glucose perfectly constant, we're not letting the glucose change.

Person shows up, insulin 8, glucose is 90. You do a euglycemic clamp where you bring insulin up only 1 1/2 per 1 1/2 x.

Much less than would be when you eat a meal.

Exactly. Not even a postprandial bump. But now it's constitutively sitting there at 20. And you've obviously had to bring glucose. You had to infuse glucose to maintain euglycemia.

Correct.

Did you say that in four days.

48 to 72 hours, these people are as insulin resistant as type 2 diabetics?

Okay, again, very, very counterintuitive. Because if our model is that insulin resistance, which is the hallmark factor contributing to type 2 diabetes in the combination of beta cell fatigue, is driven by lipotoxicity, which we're going to come to.

That's an important one.

Yes. These people didn't have any of that. These people didn't have any of the intramyocellular lipid that we talked about with your colleague Jerry Reaven. As a predisposing factor.

It's the direct effect of insulin down regulating the insulin signaling system and probably other distal metabolic within the cell as well.

So then when you turn the clamps off. Let's just say we ran this for 72 hours. We've made them functionally diabetic. Turn the clamps off. How many hours or days? We didn't do that. What would you predict?

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 one diabetics, we're always giving the insulin into the periphery. 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? 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. 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. 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 are 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. 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. You go back to 1950, the incidence of diabetes was 2%.

I've seen even data that says it was 1%. As recent as 1970.

It's very low. Yeah, but these people were all lean and they're insulin resistant. So there's a genetic cause of the insulin resistance.

And you think, Ralph, that the greater genetic effect is on the insulin resistance side or on the beta cell fatigue side?

Both.

Okay, so let's tackle each. Since you started with insulin resistance, let's go there. Let's talk about what we know about the genetics of insulin resistance.

That's easy. Nothing.

Truly nothing.

I joke. Let's say 20 years ago, we got involved in one of the biggest genetic studies called the Vagus 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.

Even if you took the subset of people with type 2 diabetes who were lean and you compared them to people who were lean and non diabetic versus obese and diabetic, a GWAS was not able to identify a signal in those three cohorts.

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 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 causally associated a gene with that gene.

It's an association.

It's an association. We have a whole different approach. 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.

What about the phenotype?

That's the answer.

I've taken care of a couple of patients with type 2 diabetes who are very lean, including one patient whose body fat by dexa was about 8%. For people listening, that is insanely lean.

Very lean.

So you take an individual whose body fat is 8% and yet they have type 2 diabetes. The first thing that comes to my mind is a lipodystrophy. Is this an individual whose adipose tissue is the problem? In other words, they're not able to assimilate enough excess nutrient, I. E. Glucose, into the fat cell. And so they're undergoing the toxicity associated with an insufficient reservoir. Is that what could be the causal. Not that I can tell you what's causing the lipodystrophy, but is the lipodystrophy the issue that's driving the diabetes?

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. Jerry Schulman has done some beautiful work in this area. 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.

Heart, ends up in the beta cells.

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. 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 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. 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. 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. 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? An enormous amount of chromatin opens up. This is the epigenetic component, genes in chromatin area 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. 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.

Let's just pause there for a second, Ralph. I want to make sure everybody's following what you're saying. You're saying, look, one of the challenges of having a disease that isn't perfectly, perfectly clearly defined, where every single member of the class that has the disease looks exactly the same. The word for that is heterogeneous. So let's take an example where the disease is very heterogeneous. Sickle cell anemia.

Correct.

Everybody who has sickle cell anemia, from a pathophysiology standpoint, is identical.

Correct.

And guess what? There's a single mutation that defines the disease because you have a single gene that defines the disease. One gene, mutated, produces one change in one base pair. That changes one amino acid, that changes the property of the hemoglobin molecule, and everybody looks the same. But you're saying, peter, it's totally different with type 2 diabetes. We have some people that are thin, some people that are fat, some people that have lots of insulin resistance in the muscle, some people that don't seem to have much, but it's all in the liver. I want to make sure we define the octet, the ominous octet. But if that's the case, why would you ever expect to find a simple genetic answer? By definition, it's going to be a mess.

Absolutely. And so if you don't have a very definitive phenotype, it's going to be difficult.

But the implication, by the way, is any physician who approaches a patient with type 2 diabetes as a single entity is going to be providing suboptimal care.

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 therapies, we're going.

To talk about the therapies in detail. But yes, you have to take a precision medicine approach to type 2 diabetes, which begins by trying to identify which phenotype your patient is.

Before we quit it, I just want to make sure that everybody understands. It's Luke Norton and Steve Parker and they're the brainchild. 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. So we tend to think the muscle, oh, this is 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 phenomena. We'll see where it takes us. But we're pretty excited about these findings.

Let's go back to the ominous octet. Make sure I have that defined. And all our listeners do 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 1987. So the triumvirate was very simple. The beta cell, it fails insulin resistance in the muscle. When you ingested a meal, the muscle didn't take up the glucose because you're insulin resistant. And insulin resistance in the liver, when you ate a meal, insulin didn't shut down the liver. So that was the triumvirate. So from the triumvirate to the ominous octet we needed to add five more players. So who were the new five players? So number four on the list was the fat cell, and a very deserving guy. So the fat cell is your friend. Initially you overeat, you take in excess calories, you store them in the fat cell, 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. We've shown this is a big interest.

To generate very counterintuitive.

Counterintuitive.

Not that we should mire ourselves in teleologic things. Do you have a sense of why?

Yeah. So the insulin signaling system in multiple early steps become severely impaired. And when you get insulin resistance in the glucose metabolic pathway, there are changes that alter the cell metabolism. So you become very resistant to insulin's anti lipolytic effect. And so now if you look at people who are obese or people who have type 2 diabetes, their plasma FFA levels are very, very high. And those FFA levels, and this is lipotoxicity, and we've got a long history of studying this. High FFA levels impair insulin secretion. 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. 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.

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

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, he's your.

Friend, he's your friend, he goes to.

Foe, then he becomes your friend to foe, bad guy. So that's number four. Number five is the gastrointestinal tract. 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, GLP1 and GIP. Glucon, like peptide 1 and glucose dependent insulotrophic polypeptide. Those two incretin hormones, when you eat a meal, account for about 70% of the insulin that's released in response to the meal. So now what is the problem? Is the problem that you don't release enough GLP1 in GIP, or is it that your beta cell is refractory to the GLP1 in GIP? Well, it's the later.

Let's say that again, Ralph. I want to make sure people understand this. And the reason it's important is obviously everybody listening to us right now is very familiar with drugs like semaglutide and Tirzep. But I want people to understand why those drugs were developed. And of course, semaglutide's already probably, what, the third generation of it anyway, so when we go back in time, we'll understand why people try to develop these drugs. But just say that again. So you eat your meal, GIP, GLP1 are increased and they come out normally.

Yep, that's not the problem.

And they're telling the beta cell, hey, make more insulin.

Beta cells, deaf, not listening, is resistant.

To the GLP1 and GIP, he should be responding to. 70% of his input should come from that signal.

70% of the insulin that's gonna come out is dependent on that GLP1 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.

And tell me, why is it mechanistically that the beta cell becomes deaf to GLP1 and GIP?

I don't know that we know the answer to that.

So it's just another horrible piece of this puzzle where everything starts to work against the patient.

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 GLP1 receptor agonist. What I'm doing is I'm giving you a pharmacologic dose of GLP1 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. And these were studies that were done by Jens Tolz 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 two diabetics. And then they intensively treated them with insulin and lowered their glucose. And then when they come back with the gip, you receive a normal amount of insulin. So this is a glucotoxic effect. So you asked me mechanism. So we know that at least for the gipsy, the glucotoxicity is impairing the ability of the beta cell to respond to the GIP.

But not necessarily GLP1.

No, no. And that doesn't correct the GLP1 problem. So there's true resistance still, even though I normalize the glucose in terms of GLP1. So this incretin axis, the gut, is a very important endocrine organ. And that's number five. And the ominous octet, number six in the ominous octet is the alpha cell, I would say the father of Hypergluginemia. This is Dr. Roger Unger in Dallas. He was one of the very first people to show that diabetics had very high glue gun levels.

And glugugon drives tell people what glucagon does?

Yeah, glue gun. It drives hepatic glucose production. 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 glucon levels. So paradoxically, there's very high glucon levels in the diabetic. And those high glucagon levels, a very important contributor to the hepatic insulin resistance because they're driving the liver to make glucose.

And sorry, just to make sure, I'm embarrassed to say I forget this from biochemistry. Is it driving the liver to make glucose out of, for example, glycerol amino.

Acids or 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, glucose get rid of all the glycogen that's in the liver. And so chronically now you're running on gluconeogenesis. But glucon stimulates both pathways.

And does it also drive hepatic glucose output or does it just drive the creation of glucose?

No, no, no.

In absolute terms, it increases hepatic glucose output as well, as gluconeogenesis.

Yes. 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. 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.

Cholesterol 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. So the metabolic. The actual pathways, I think, are very well worked out. So glue gun, alpha cell, bad guy.

And so is the alpha cell over producing glucagon in this state?

Yes, absolutely. Absolutely. And this is really Roger Unger and Dallas's.

And again, why is it overproducing? Why is it doing something that doesn't make any sense in the context of.

What'S happening in 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?

It's counterintuitive. Usually when things go wrong, they get attenuated. Right. Like, it makes sense that the beta cell eventually fatigues, because that's an attenuation of doing something that it's getting tired of doing. The. The. The alpha cell ramping up is a little less intuitive.

You're going to 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. 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 a series, 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 fluorescent that blocked glucose transport in the kidney. And so I took this molecule called fluorescent and it blocks glucose transporters. There are two transporters in the kidney, SGLT2 and SGLT1. SGLT2 takes back 90% of the glucose. If it does its job, SGLT1 takes back the other 10%. And then in you or I, even though we filter 180 grams of glucose per day, no glucose appears in the urine. But what I showed is that fluorescent, 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. When I was doing these studies, even though I was a nephrology fellow, I had previous done my endocrine fellowship at the NIH and Baltimore City hospitals. I had an interest in diabetes, and I said this would be a great way to treat diabetes. 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. I said, why? She said, you could have patented this drug. So I actually worked with Bristol Myers Squibb and then Astrazeneca, and that eventually led to the dapagliflozin coming to the market. But what we showed, and this is.

Human biopsy, which was the first SGLT2 inhibitor.

That's correct, yes.

Brand name on that one, Forsiga. Forsiga. Tanagaflozin was next.

Empagliflozin. Yeah. And then canoglyflozin, ertogliflozin. Then 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. This again, this is so counterintuitive.

I know.

Okay. This does not make any Sense. I want to just bring it back to people listening so they understand what we're talking about here. The kidney is this massive filtration, another remarkable organ. No offense to the nephrologist, not as remarkable as the liver, but every bit is remarkable in terms of.

I think it's more remarkable than the liver guy. So that's okay.

Everything that's floating through our plasma, our kidneys, by the way, they take 25% of our cardiac output.

Huge. Yes.

So it's massive. This organ weighs 2% of our weight and takes 25% of our cardiac output. Why? Because we have to take everything that is in our circulation and dump it out, and then the kidney has to selectively bring back in what's normal. This was explained to me, I still remember, in medical school, as a brilliant trick of evolution. Evolution was never going to be able to predict every toxic thing we might encounter. And therefore, teaching the kidney how to spot toxic things and get rid of them would have been a failed mission. Rather, it was better to teach the kidney what was absolutely necessary and to discard all other things.

So, pretty simple way.

Yep. So it's the take everything out of your drawer and dump it out and only bring back the socks and underwear that you need. So glucose, potassium, sodium, you name it, chloride, phosphate, all of these things get dumped along with everything else. And then it knows I need this much glucose, I need this much sodium, I need this much potassium. So SGLT2 does the lion's share of this.

It takes back 90% of the glucose. And now, so here's a diabetic with a very high glucose, Right?

So My point was, SGLT2, if it had a brain, would say, oh, you have too much glucose.

Turn off, turn it off.

How about we just stop reabsorbing all this glucose? But you said it's the opposite.

I told you earlier, it's gonna get worse.

It ramps up SGLT2.

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. 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 in the papers as well. 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 fluorescent, 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. 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. 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. And now insulin sensitivity improved in muscle, and beta cell function improved. And this was the first nine humans, even though the original studies were done in animals, first studies to show an improvement in the reality of glucotoxicity. 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. DeFronzo 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. 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.

How many grams of glucose can be differentially or extra secreted, basically, in the presence of an SGLT2 inhibitor?

Today, 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 than. There's more glucose to be blocked at the level of the kidney. And these drugs are very, very good. 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 the heart.

Yeah, I want to come back to that because I'm making notes of other things I want to come back to. And so I want to come back to. Just so you can hear me say it now. And we remember. I want to come back to combined inhibitors, the SGLT2. SGLT1 inhibitor. I think there's a new drug, sodagliflosis. Yeah. That does both. Both. We want to just touch on that. And then I want to also come back to the broader zero protective nature of the SGLT2s as documented by the ITP in mice and then also in the human studies for cardio protection. But before we do that, we need.

To finish the omniscient.

We gotta go. Exactly. Let's go back to number eight, 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'd you ever think, why does that happen? Well, because there are certain hormones that are released or inhibited that tell you, okay, you're satiated, stop eating. Well, one of the very important ones is GLP1, that same thing that's increasing insulin secretion. Your brain has become very resistant to GLP1. 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 amlin, 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. These, they work in the hedonic areas in the brain, so in the putamin, the prefrontal cortex, and they tell you to stop eating. 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 neural circuitry distorted, one of the big things that we are interested in, Dr. Peter Fox and myself at UT, is if you look at the gray matter in these areas, in the areas that are critically important in regulating your appetite, there's shrinkage of the gray matter area. Okay. And in these areas, if you do an insulin clamp, 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. Who would have thought?

I'm sorry, you're saying that these are the few areas in my brain and your brain that are actually default. Insulin insensitive?

Yes.

Don't take up glucose.

Correct. If I do an insulin clamp.

So what is their fuel source? Lactate.

Well, in response to insulin, they don't take up more glucose.

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 phenomen. Because in the old days, you may not eat. 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's saturated at 40. If 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 enough more glucose. It's, quote, insulin insensitive in a certain way.

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

Yes, this has been postulated. 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. 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. 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 Asipomox. It inhibits lipolysis. It's like SGLT2 inhibitor. The only thing to do is block glucose reabsorption in the kidney. Asipomox, all it does is do block lipolysis. It lowers your FFA level. And we've done this.

Does it result in any meaningful clinical increase in adiposity or is it so subtle that you don't notice it over 12 days?

No change in adiposity. Huge improvement in insulin sensitivity and muscle.

Why is it not approved in the US?

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.

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, in both obese people and in diabetics, you markedly improve insulin sensitivity in the muscle. If using mri, you can measure muscle fat, 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, 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. 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.

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

Pioglitazone, the drug that I can't get people to use which is a phenomena. By activating PPAR Gamma. It does a lot of good things. And one of the important things that it does is 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 and that influences flux through the mitochondrial chain.

Why don't people use this drug today?

Huge misconceptions, I guess. We'll talk about therapy, we'll come back to it as part of my triple therapy regiment. I use a GLP1 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, the good drugs since I single handedly brought metformin to the United States in 1995, no other endocrinologist involved in this 1995, metformin was a revolutionary drug. Why we had insulin sulfonylureas. 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. We talk about these paradoxes. The more weight gain, the greater the drop in a 1C. 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. The more weight gain, the greater the drop in blood pressure. The more weight you gain, the greater the drop in triglycerides. The more weight you gain, the rise in greater the rise in HDL cholesterol. Sounds like terrible drug. So here's another one of those paradoxes why we know if you overeat and gain weight, that's a disaster. But with pioglitazone, the more weight you gain, everything gets better. What pioglitazone does is it shifts weight around in the body. In my opinion, it's the best drug for treating Nash. No drug is going to beat pioglitazole. 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? Pioglitazone. It redistributes fat in the body. It gets it out of the muscle, puts it in subcutaneous tissue, gets it out of the liver, it puts it in subcutaneous tissue, gets it out of your beta cells, put it in subcutaneous tissue. That's not going to make you gain weight. The richest density of PPAR Gamma receptors in the hypothalamus. So when I activate these PPAR Gamma receptors in the hypothalamus, you eat. Okay. 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. 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 P. O. Glitazone. Metformin is not a true insulin sensitizer. That total misconception. Pioglitazone, that insulin signaling defect that I told you about. Pioglitazone corrects that defect. It's incredible.

We kind of glossed over this. We're going to spare people the details, but it's probably worth just reminding people. Insulin binds to the insulin receptor. That's outside the cell. That's a kinase receptor. Correct.

There are three tyrosine molecules and they have to be phosphorylated. These are studies done. 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. 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?

Yep.

It interacts with the insulin receptor and it gets phosphorylated on the same three tyrosine molecules. And then you activate pi3kinase Akt. We could add some more molecules in here, but this is the insulin signaling pathway. That's the pathway that the earliest defect that you can show in diabetics is in that pathway.

And if I recall, isn't this where Jerry argued that the intramyocellular lipid was creating the defect in that pathway, the accumulation of intramyocellular lipid.

So what Jerry has shown very elegantly is that there are certain lipids dgat, and it's a specific dgat. There are, like, several types of DCAT 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. 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. 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. And you're right, very, very, very important mechanism of insulin resistance.

And so given that that's both a very important and very common pathway towards insulin resistance, bringing it back to PPAR gamma. PPAR gamma is part of the pathway. It's part of the IRS 1 PPAR gamma PI 3K GLUT 4 bring the glucose in the cell. In other words, if people don't want to get mired down in this, which is totally understandable, insulin hits a receptor, that receptor kicks off a cascade that ultimately results in a little tube, like a little straw, that goes into the cell surface that allows glucose to freely flow in. In its gradient.

Remember, that same pathway also activates nitric oxide synthase.

That's right.

Generates nitric oxide.

And that's why we see in patients with insulin resistance, even if glucose is controlled, cardiovascular disease is still up.

A very important.

Yeah, very important point. So back to actose.

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 edematist. And so people associate fluid retention and edema with heart failure. 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. Myocardial insulin sensitivity with PET and fluorodeoxyglucose and improved by 75%. Your heart, we showed this before, is severely insulin resistant. I came pretty damn close to normalizing insulin sensitivity in your heart. Now, since we're doing the insulin clamp.

With tritiated glucose, you can track it.

74% improvement in skeletal muscle insulin sensitivity.

The same.

Exactly the same. 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.

It's a victim of maybe not so nuanced thinking about the drug. Now, the critic would push back and say, okay, Ralph, but don't we have better drugs?

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.

So let's talk about metformin. Everybody wants to know if metformin is zero protective, but let's just remind people metformin inhibits complex 1 of the electron transport chain. Is that a given?

Yes. 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 is the belief that metformin's efficacy in diabetes is through reducing hepatic glucose output.

That is 100% true.

Okay, and what's the mechanism by which it reduces hepatic glucose output, 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 ion transporter doesn't exist in muscle. It can't possibly be an insulin sensitizer in muscle. You're asking the drug to do something that's impossible.

Does it get into muscle mitochondria?

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

Why does lactate go up when people are taking metformin?

Level of the liver, it's interfering with aerobic metabolism. There's a block.

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

No, no.

And you're saying, Peter, it's all in the body. It's not possible. It can't get into skeletal muscle.

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. 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. 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, a biguanide as well. But it had a powerful effect.

Yeah, Phenformin was much more powerful.

Yes.

And when you say high dose, I mean is 2 grams a day of metformin. No, no, no, the normal dose.

That's the normal dose.

Okay, so metformin has the following going for it. It's free.

Yes, it's basically free.

Yeah, it's free. Absolutely. And it does a pretty good job at reducing hepatic glucose output.

Yeah.

And it has no myotoxicity, frankly, any toxicity.

Gi.

Yeah, the gi. But you can usually overcome that with a slow ramp up.

Yeah. 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 3 kilogram weight loss with metformin. And when you lose weight, you can improve insulin sensitivity. 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 leaf of pharmaceuticals. We did insulin clamps, many of them. We never could show metformin improve insulin sensitivity using the gold standard with radioisotopes.

Do you think many people. I feel like I'm asking you this question a lot and it's getting a little old, but do you get the sense that most people are still thinking what I think?

Yes.

Metformin gets into the muscle.

Yes.

Metformin is an insulin sensitizer.

Absolutely.

And it's an insulin sensitizer by getting into the muscle and inhibiting complex one.

Absolutely. People have done pet studies 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 3, 4, 5, 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 ten minutes, you see it in the bladder. And that's the only place where you see 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.

Is there a downside to using metformin in combination with the other three drugs?

No. The classic study, which we'll talk about, which to me should change the entire approach to treating diabetes is called the Edict study. And in the edict study, what we did is we used triple therapy right from the beginning. And my point of the banting lecture, the ominous octet. If you have eight problems, I'm sure 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. 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 GLP1.

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 interceptide, but you have to start somewhere, right? Yeah.

Let's pay it its dues as being the Gen1 OG version of that drug, without which we might not have. We wouldn't have semaglutide or tirzepatite.

Yes, it's kind of an old timer. And pioglitazone, that was the triple therapy. And then we said every diabetic patient, there are 315 people in this study. They're having insulin clamps, hyperglycemia clamps, muscle bibs. No one in the world can do this study. 315 people follow for six years. So we said this is what we believe is the appropriate therapy. Then we said we'll use the ADA approach. The ADA approach is you start on metformin and when you fail, even though 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. And that if your A1C rose above six and a half either on R 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.

Yep. 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 6.5. Six years later with our approach, 70% of the people have an A1C. That's less than 6.5. Why? Insulin clamp. Huge improvement with our therapy. Okay. This is the ED 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? 0 beta cell function. You have almost a normal beta cell.

Ralph, why the disconnect between what you're seeing in the EDICT study and what the ADA is promoting?

You have to Ask the ada, what's.

Their answer if I'm a patient or if I'm a physician who's treating these patients. And I'm saying, guys, I'm confused. I'm looking at the literature, I'm seeing this, I'm looking at your. And by the way, I see this with the aha and cardiovascular guidance. So I'm not singling out you. But is this simply a question of the pace at which medicine moves is so glacial?

That's part of it. Plus remember, if to do 315 people follow them for 16 years and do all the stuff we did, it's unequivocal.

And why has there not been political pressure? Because the cost of insulin is enormous. Your approach is going to be less expensive.

They finally said in 2022, this is 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 on people. 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 beta cell 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. 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 you not think that's the best therapy? And now on the other side, I have this metformin suit insulin and 71% of the people have failed. There's zero improvement in insulin sensitivity, zero improvement in beta cell function. Why 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 great 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 studies showed this in 1990. Stephen Karn 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 Kahn 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.

You had to fail on metformin to get into the study.

Okay, so you failed in metformin. Then you enter the study. Then we go single agent.

They wanted 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 sulfonylnuria 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.

Well, they stop working.

Yeah. I mean basically they kick the can down the road without addressing the pathophysiology.

I like that way. Other drug, DPP4 inhibitor, tell people how those work. Yep. So a DPP4 inhibitor increases your GLP1 and your GIP level endogenously. It makes your gastrointestinal cells the K and the L cells that secrete the GLP1 and GIP makes them make more GLP1 and GIP. But it doesn't increase the GLP1 and GIP enough to really give you a knockout punch. I give you an injection, you all people are out there. Mounjaro or Semaglutide. That's the knockout punch. When I give you the DPP4 inhibitors, they do increase GLP1 and GIP a little bit, but not powerful enough to give you a long lasting effect. So first year A1C comes down. Shh. A1C goes up. Third drug. This was very surprising to me. This was liraglutide. This is one of the earlier GLP1 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 it out and then they failed. So five years later, all four of those regimens added to metformin failed. Triple therapy, exenatide, an old time GLP1, piolitazone, which people don't appreciate. The only true insulin sensitizer. And metformin. Six years later, 70% of the people have an A1C less than 7.

And let's just go back. Metformin is free. The Gen 1 Exeter Tide.

Basically free.

Is basically free.

Now Pio Litazone is five dollars a month.

Okay, so we have three free drugs that work better.

Correct.

Now it's interesting when you talk about today's triple therapy, which is way more efficacious. Two of those three drugs are very expensive. Yes, the SGLT2 inhibitors are very expensive in the modern day Gen 3, Gen 4, and soon we'll have a Gen 5 GLP1. They're very pricey.

$1,000 a month. Now, are they great drugs? Of course.

I guess the question is, do you need to be on those drugs if your old version of triple therapy, our.

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

And the reason is patients are frustrated with the fact that they're retaining water.

No gain weight.

How much weight do they gain typically? 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 2 or 2 and a half kilos at the 15 and 30 milligram dose. Okay. But their A1C is controlled.

If you give PO plus a modern day GLP1, don't you offset the weight gain?

Oh, you lose all the weight you go lose with the GLP1 receptor.

So if a patient is willing to go down the path of a modern day GLP1, that's my treatment. Completely eliminate.

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 in the proactive. I'll come back. So in the proactive study, this was done long time ago, you have to Show Cardiovascular Safety. 5,238 people. To get into the study, you had to have an MI stroke or something bad. 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. And so when I talk to cardiologists, I like to say, what was the one thing in the pioglitazone 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 gonna pick? I think I go for being a.

Little bit chubby, but now that's not even a necessary comparison. You don't even need to make that trade off with a modern day GLP1 agonist.

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 ones. They're incredible drugs, but that's not what I'm gonna 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. 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. 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 in the people who get into these studies who already have cardiac disease? So if you have a cardiac problem, I put you on the SGLT2 inhibitor, you're less likely to have MI, stroke, et cetera. 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 a thousand people. You probably have to take 20,000 people newly diagnosed and then 10,000 go on SGLT 2 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.

Yeah, that's never going to happen. But I also don't think it needs to happen in the same way that.

I agree with you, in the same.

Way that we saw, for example, PCSK9 inhibitors reduced mace in people with secondary prevention. Take people who had already suffered mace, put em on a PCSK9 inhibitor, secondary prevention, reduce subsequent. Well, of course everybody's using these for primary prevention now. That's effectively what you're saying. Sure, we already know the SGLT2 works for secondary prevention. That may never get approval for primary prevention, but it probably justifies its use.

I agree with you 100%.

So just to make sure I'm synthesizing what you're saying, Ralph, if you only get one drug and your price. Agnostic GLP1 agonist.

Yeah.

If you get to add a second drug, you're going to add PO.

Yep.

If you get a third drug, especially if you care about your heart. SGLT2.

Yeah, SGLT2.

And what's amazing is metformin didn't even make the top three in your list.

But it's number four.

So here's my question. Given that metformin is free, should we just be adding it the second we put on the GLP1?

I don't have any problem with that. Yep. And also we have to be cognizant of the fact these newer GLP1s so potent, but they're a thousand dollars a month.

Yeah. I want to ask you about that. So just again, for the listeners. Right. Semaglutide is gen 3, tirzepatide is gen 4. Retatrutride is coming out. Assuming the phase 3 goes according to.

Plan and cargi Sema is the new Nova 1.

Yeah. Let's go back to retatrutride, GLP1, GIP and glucagon. Glucagon. Can you explain that in the context of the octet where glucagon is going up?

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 GLP1 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 glugagon effect to drive hepatic glucose production will be totally blunted by the insulin secretory effect. This is the other thing that bothers me about these GLP1s. 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 GLP1. And the GIP people have stopped talking about this effect on the beta cell. I told you. If you want to look at type 2 diabetes, big problems, beta cell failure, insulin resistance, these GLP1s, they're saving your beta cell. We've forgotten about. 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. 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 glugon's 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 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. 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.

Yeah, I would be surprised if they're going to see a clinically meaningful increase in involuntary energy expenditure.

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 GLP1 studies. Cardiovascular. What's the reduction in cardiovascular events? Almost uniformly 20%. Old dudes, exenatide, etc. Liraglutide, new dudes, 20%. Even though the weight loss with the.

Newer ones is much greater.

Much greater. 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. And also, if you look at the A1C, yes, Manjaro does drop the A1C a little bit more than semaglutide, but they're both pretty powerful. Rituatide does a little bit more. And does cargi sema 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 at three?

So you're saying if a person shows up with a hemoglobin A1C of 9 1/2 percent. This is a person who hasn't come to medical attention soon enough.

And I'm going to give you the answer definitively. But I'm going to let you ask the question.

You're happy if they only go from 9.5% to 7%. If they only had a 2.5% drop, you wouldn't try to get them down to 6%.

I would. And we've done the study. Old time, guys. All 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. 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, cell phoneuria, 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. 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 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. We said, well, that may or may not be true. So we said, well, half of these people who 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 exetatide and piolitazone, one that people don't like to use. Three years later, the A1C in the group with the mixed split insulin regimen is 7.1% and we are 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 will just look at the people who are symptomatic. The starting A1C is 12.2. Three years later, their A1C is 6.1.

From 12, 12.2 symptomatic on which combination ezenatide 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 pioglitazone.

This is almost impossible for me to imagine.

I can send you all the papers, it's all published.

I hope every single family medicine internist, everyone who ever takes care of somebody with diabetes is listening. I hope so too, because you're basically saying we can take these two old cheap drugs and take someone from the most brittle type 2 diabetes. I mean, a hemoglobin A1C of 12, pretty bad. You're knocking on death's door.

Correct.

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

These numbers that I'm telling you, they're right from the paper and it's a lot. It's over 200 people and in a.

Couple of years on two old cheap drugs, you're normal.

Yep. What makes these studies so solid is we have very sophisticated pathophysiologic measurements. No one can do what we do.

So the only pushback is those patients are going to have to gain a couple of kilograms. But of course, if you're willing to now spend a bit more money and switch them from Gen1 to Gen3 or Gen4, GLP1 agonist and GIP, then all of a sudden you ameliorate that and you get all the benefits.

This becomes a non issue. Put cost aside.

I would wonder if you add metformin, you almost cancel out the weight, gain a little bit because you might get, get a little bit of the GI improvement and you get the 2 to 3 kilos of weight loss there.

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.

Which was that study?

This is called the Qatar. It was done in Qatar.

Qatar, the country.

The country. And I need to give credit to Dr. Muhammad Abdul Ghani, who's been sort of my co worker in all of these studies and Mohammed's on the faculty at UT in our Diabetes division.

Can we at least assume that the Gulf states are paying attention to this? A, the study was done in Qatar. B, the Gulf states are disproportionately ravaged by type 2 diabetes.

Yep.

Is it at least being heeded there?

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 Dasmin 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. 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 GLP1 goes up and that secretes insulin. So now when you eat a meal, there are already three stimuli. And now you're looking for a gene or a set of genes that might be associated with beta cell failure. When you have three stimuli, now that's 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 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. And then after that, now I'm going to give you GLP1 infusion and I'm gonna see how much insulin comes out. And then after that I'm gonna give you an balanced amino acid infusion. I'm gonna see how much insulin comes up.

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, 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 these hits and clamp studies and these kind of measurements are not easy to do, that was published when, let's see, I would say the one and a half year data were probably about 20, 18 and the three year data I would say 20, 21, 22, something like that. I can send you all the references.

Yeah, we'll link to all of these in our show notes for Folks, just simply phenomenal. Let me ask you a question. If you take an individual with type 2 diabetes or insulin resistance and you presumably collecting urinary C peptide for 24 hours is the best surrogate for total insulin secretion?

No, it's an index.

If you could quantify total area under the curve of insulin for a person and then you gave them a GLP1 agonist, is total insulin going up or down?

Depends, 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.

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. 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, maybe just tell folks I.

Threw out C peptide as though everybody knew what it is. That's a mistake. Tell people what C peptide is and what its relationship is to insulin.

Yeah, 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. So everything that comes out you see in the circulation. So when we want to know how much insulin was secreted, we actually don't measure the insulin. We measure the C peptide, and that's the true measure. Now, the other confounding feature here is, and we 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. 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. 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, you get hypoglycemic. How does your beta cell recognize that? 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. 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 K. Developed with Daniel Port many, many years ago. So simply looking, as I said, as insulin or trying to do an OGTT and come up and say, you know how the beta cell is working, that's not so good. And that's why I say in the Qatar study, in the Edict study we are doing such sophisticated measures of insulin sensitivity and beta cell function, you drew 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, 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 Gerry Shulman 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.

Do you have any concerns with long term safety or anything other than simply the economics of the GLP1s in this current generation? Again, huge, huge leap forward between liraglutide and semaglutide. And I've discussed briefly elsewhere on the podcast what the roadmap looks like for how many of these drugs are in the pipeline. Oh, yeah, there seems to be no end in sight. And we're going to look back at semaglutide and say, God, that thing was pedestrian.

That's just going to happen.

Give us the bear case. What should we be concerned with? What should be at least looking out for?

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. 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 Y bypass. And the people lost, I think it was 33% of their body weight, and their lean body mass came down quite significantly. One of the problems is people 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 reasonable assumption muscle mass. So muscle mass came down. Why is that so bad?

How much did it come down? Because if total body mass came down by 33%, but three quarters of that mass was fat and only one quarter of that was lean, we would consider that acceptable.

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%.

Were these patients exercising during the period?

No.

No, no loss?

No, no, no, no. Then they said, let's express strength per weight loss 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 2 miles. And then say, 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?

Yeah, of course. Which is heavily dependent on weight as well.

Yeah, it all got better.

But in absolute terms, did VO2 max get better? Not necessarily. Yeah, the total VO2 not normalized per kilogram?

No, everything got better.

Okay, that's counterintuitive, by the way. Normally when you lose weight, VO2 max in liters per minute does not improve because you have less metabolic tissue.

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.

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. Why are you so worried about muscle mass? I look all these gloomy faces because they're all developing myostatin inhibitors or aventin. 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, 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. And they do have some concerns about these drugs, these mindset inhibitors that actually may have some negative effects on the heart. My suggestion is actually you may find a big improvement in myocardial function.

Where are myostatin inhibitors in their development? Phase two, of course. I think we've talked about myostatin before on the podcast. When you inhibit myostatin, you increase the expression of striated muscle, of which cardiac is striated.

It works through the Aventin 2A and 2B system.

Do you think that's a more promising pathway than the follistatin pathway? Where Follistatin.

Yes, I do.

Increasing follistatin inhibits myostatin, but this is a more direct way to go.

It's a more direct way to do it. So you can either have their antibodies by Magrubab to myostatin, or you can interfere with the signaling receptor itself.

And we think that this can still be effective in a fully developed and mature adult. I mean, clearly this would be effective during development. And we see that in the animal work. How effective Is it? A lot of the animal work is sort of a caricature stuff. It's knockouts. Right. They take myostatin knockouts and they look like bodybuilders. But if you take a mature chicken or a mouse that's two years old and you give it a myostatin antibody, how robust is the response?

Even more so. What about in a human? We don't know the answer to that.

So what, the phase two studies, obviously the toxicity passed in phase one?

Yes. 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 phases.

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. 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. Let's say I put you on a GLP1 receptor agonist and you lost 25% of your body weight and I put you on a myostatin inhibitor and that prevented the muscle loss, didn't increase it, but just prevented it.

But that would be ridiculous. I mean, if you took a 200 pound individual who's 30% body fat, they've got 60 pounds of adipose tissue on them. If you took 25% of their body weight off, you take them down to 150 pounds. But you're telling me potentially we prevent any deterioration of lean mass. That means they're down to 10 pounds of fat mass on a 150 pound frame.

I'm making an assumption.

Okay, this is remarkable.

Right? So let's say that happened. What would be the FDA's criteria? I'm gonna give you approval for this drug.

I think the FDA would ask that you've also improved function in some way. And the function would have to be determined through absolute strength, not relative strength would be my guess.

I don't know the answer to this.

Question because the way I think about these drugs is less about that situation, it's more in the sarcopenic adult.

This is the lean, particularly the older person.

That's right. That's right. This is the elderly individual who's sarcopenic and whose fall risk is enormous. And Their risk of falling and morbidity and mortality is very high. And in that individual, I don't think the FDA will be satisfied with simply an increase in lean body mass unless it is accompanied by strength. Now, I think that some of the tests that are used here are silly. I think the six minute walk test should be folded up, discarded, put in the wastebasket and never discussed again. It is such a stupid test.

They do it all the time.

I know they do, and it just makes me want to scream. We need much more rigorous tests than a six minute walk test. We need a test that is actually more of a submaximal test. So if we're testing cardiorespiratory fitness or some sort of peak aerobic fitness, we have to do more than walking. And if we're testing strength, I much prefer grip strength, leg extension, bench press. Again, these can be done with machines. They can be done very safely. But we really need to test strength.

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.

There could be other functional benefits that exceed strength. For example, glucose disposal could be a functional benefit.

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.

Yeah, but I think that again, it's harder to tease out because there's more moving pieces. And they might argue there are easier ways to increase insulin sensitivity and glucose disposal. But one way to think about this is to go back to what if you did it the old fashioned way? What if you got in the gym and lifted a bunch of weights?

That's been done.

Yeah. And it increases insulin sensitivity and functional strength. And so the question is, can we replicate that pharmacologically?

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. 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. 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. 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 adult and your life expectancy will be significantly shorter and your quality of life will be significantly reduced.

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

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

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.

You could say potentially In San Antonio, one out of 20 teenagers, it's going.

To be very high. Gosh, that is 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 GLP1 agonists.

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

Just clinically. If you're in the clinic and you're using the best drugs you have available, you heard trouble. Why?

Because you can't get them controlled. Why they're so insulin resistant, much more so than adults. These are well published studies.

Is this really a selection bias where for someone to develop type 2 diabetes as a 16 year old, the underlying genetics and pathology are so severe that the current crop of drugs are the problem as opposed to when you take the current crop of drugs and you apply them to people who are young.

They don't work 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. 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.

What do you think? I mean, yes, we're gonna argue that these kids are. This is due to what they're eating. But what is it in the environment that is so obesogenic to these kids?

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 are Metformin's self. Your A1C is 9. You can put someone on Manjaro and they're gonna 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 9.

If you take that 16 year old with a hemoglobin on C of 9 and you give them Mounjaro, where are they in a year?

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 Fs, that person we know from the studies would be pretty well controlled.

What fraction of insured patients will have coverage on mounjaro if their A1C is 9?

I can't answer that.

Does CMS cover it? Does Medicaid cover that?

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? I didn't do anything else. It's almost like alcohol addiction. There are drugs that 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. Can we afford to treat 42% of the people in the US 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 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 stop 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. 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.

Yeah. Of course this begs the question, will the next generation of weight loss drugs be true uncoupling agents where you can basically eat as much as you want and they're going to create so much mitochondrial uncoupling and thermogenesis that you're truly going to see this increase in non voluntary energy expenditure and of course not have the GI side effects. But before we go on to the next thing I want to chat about and I just kind of bring it back to this question which everybody wants to understand this, which is what has changed so much in the last 30 years that has created this epidemic. And everybody has their favorite pet theory for what it is. It's the sugar, it's the carbs, it's the plastics, it's the video games, it's the Internet, it's the whatever, perhaps suggesting that it's many, many things. What is your best explanation for what's going on?

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 over subscribed to these stimuli, that's now initiated a process in the brain which is going to be a self fulfilling process. 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 keep your BMI of 25, do what you do during the day. But what is it that makes your BMI go to 35? That's all related to the hedonic areas in the brain, the putamin, the amygdala, the prefrontal cortex, et cetera. And then when you do structural mri, what you can show is that those areas in the brain, the gray matter, is shrunk down. 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 neural circuitry 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. And in concert with this. These are not, um, data, but these are data that are published in literature. And I think I mentioned this earlier. If you do an insulin clamp, okay, I told you that in uri, your brain doesn't respond by taking up glucose. But in people who are obese, actually almost in proportionate 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 PET radioisotope tracer we use in these areas, and that correlates inversely with the muscle insulin resistance.

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

There is in the brain. Now, this is very interesting because what it's saying, there's a connection that somehow or another we believe that the brain is talking to the muscle or the muscle is talking to the brain, and that somehow or other, the brain is playing a very important role in the development of the insulin resistance. 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, what people have totally overlooked. You put fat in the kidney, you get kidney disease, fat in the heart. Yeah, yeah.

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

Almost instantaneously.

Even in kids?

Even in kids.

We can't blame video games, we can't blame social media, because that wasn't going on in the late 80s.

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 saying, oh, you're crazy. You don't see kids with type 2 diabetes. Believe me, I see them.

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

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

So, okay, what about in non Hispanic kids? Because if the Hispanic kids are genetically predisposed to this, then the question becomes, when did you begin to see this in African American kids and Caucasian kids?

Yes. So we don't have a large African American population here, but like in Philadelphia, there's a lady, Sylvia R. Slabian, 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.

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

No, I think it's both. 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 gonna develop type 2 diabetes. So we said, okay, in the Hispanic community it's very common to see mom and dad with diabetes, and it's very common to see a lot of children in these families. So we said, why don't we go look at the children and let's see 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 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 biopsy.

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?

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

Well established which enzyme in particular it.

Starts at the level of IRIS 1.

Starts at the first one, yeah. Oh, so it's not just one enzyme, though.

Well, no, it's Iris 1. You can't tyrosine phosphorylate it. You cannot activate pi3k.

So it starts at IRS 1.

Yeah.

Yep.

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. 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. 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.

Let's just make sure people understand this as we're kind of getting into some biochemistry here. When glucose enters the cell passively through.

The GLUT4 transporter, it gets free glucose in the cell.

Yes.

Then to metabolize it.

Yeah. The first step to that is hexokinase, which takes a phosphate off ATP and puts it on the sixth position, if I'm not mistaken.

And it's a specific type of hexokinase. So it's hexokinase 2 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 Is severely impaired.

Remind me what Jerry believes is wrong with the GLUT4 transporter.

That it doesn't work normally.

I thought it worked fine. It's just not getting the signal to work because of IRS 1.

That's where the controversy is. 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.

So you're saying it's possible that just having the IRS1 problem is enough. It's also possible that even if IRS1 is functioning reasonably, if GLUT4 is not getting up, that's the problem.

And there is evidence to support that.

And then it's also possible that even if all those things work, if you don't get hexokinase to phosphorylate glucose, you back up the whole system.

And I can show you that it's a primary defect in pyruvate dehydrogenase, in glycogen synthase. This comes back. I have an ominous octet for the insulin resistance. This is 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? 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. In diabetes metabolism reviews, I would say. Thirty 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. 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 8 or 9. 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. There's this. Phil Scherr will love me for saying this. He's the top guru in adipocyte metabolism up in Dallas. And it's Alstrom 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, I just postulated and said, here's a syndrome. And not only that, now that they defined 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 reproduce diabetes in the normal mouse model.

Ralph I want to close by bringing it back to something that people can do to help understand if they're at risk, either lean or otherwise. We talked about it at the outset but didn't go into it in detail, which is the ogtt, the oral glucose tolerance test. Now, again, none of us have the privilege of being able to use a euglycemic clamp, both clinically as physicians or as experience it as patients. So we're going to have to kind of rely on other things. We're going to have to rely on body fat. We're going to have to rely on triglycerides. We're going to have to rely on hemoglobin A1C, although I find that to be a particularly useless metric. Not that useless at the individual level, I find it very unhelpful. I think at the population level, it's great, and in deltas it's great. But, boy, the correlation between hemoglobin A1C and realized glucose levels, you're correct, it's pretty weak. But let's talk about the ogtt, because this is not a test that is done frequently. I believe it should be. And I'd love to have you walk us through the interpretation of the following. I'm going to give you a couple scenarios. So case one, I'm making this up as we go. You got a person who starts out. All these people are going to start out normal. They're going to start out with a glucose of 90 and an insulin of 6 at 30 minutes. This is after 75 grams of oral glucose, the insulin rises to 90.

I'm nervous.

Yep. The glucose rises to 130. At 60 minutes, the glucose is down to 100. The insulin is down to 60, and we'll just do one more check. At two hours, the glucose at this point is 60 and the insulin is 20.

As a prediabetic state, this is a very insulin resistant person. And two hour later, hypoglycemia is a reflection of the beta cells early infiltration. This is kind of a pre diabetic state.

Yeah, agree with you completely. And we see this all the time. This is a person, by the way, with a perfectly normal hemoglobin A1C. And this is a person who gets passed all the time as totally normal.

They're severely insulin resistant. The beta cell's doing a good job.

Your hemoglobin A1C is normal and your insulin is 6. Even if the doctor's checking insulin. But as you point out, the thing that trips you off is not their glucose. 90 to 130 to 100 is amazing. It's 90 was how high the insulin was at 30 seconds. And of course they overshot, which is why they become hypoglycemic.

Yes. Okay, well known.

Yep. Let's go another one. This person also starts at 90 and 6 at 30 minutes they go to 180. Insulin goes to 30. At 60 minutes they go to 200. Insulin is 40, they diabetic. But just to be clear, these are almost real cases, by the way. This is a person whose hemoglobin A1C is 5.6.

Got it. 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 botnia study where these people have been followed up. We were the first people to publish this. Oh, I'd say 7, 8, 9, 10 years ago. 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.

So if one hour glucose is more than 155, you're in trouble. And that's a great predictor of type 2 diabetes, regardless of all the other metrics.

Yes. And if you also happen to be hypoinsulemic, 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 Botanist study and also from our Vegas study.

Okay, next case. I'm not even going to give you the numbers. I'll just describe it. This is a person who has a delayed onset of insulin. So in other words, they start out normal at 90.

30 minute insulin is deficient. That's a predictor as well.

Yes. So what's going on in this person where 30 minute insulin does nothing? Glucose rises, and then at an hour and 90 minutes, the pancreas kicks on and starts to dispose of glucose. What's happening in that person?

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. 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 gonna 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. 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 TR.

We use the following numbers in our practice as what we consider what we want to see. Do you think we're being too aggressive? At time zero, we want to see you less than 90 and less than 6. At time 30 minutes, we want to see you less Than 140 and less than 40. At time 60 minutes, we want to see you Less than 1, 30, 90 minutes, we want to see you LESS than 110 and LESS than 20. Do you think we're being too hard?

Yeah, you might be being overly aggressive, but for sure, if they meet those numbers, you're probably safe.

Okay, Ralph, I don't know where the time went today, but it went. And this was a fascinating discussion. I could talk about this stuff all day long. It's interesting because someone listening to this podcast who heard the podcast with Jerry Schulman from probably three years ago, will be pleased because the overlap is virtually zero. I mean, that's what's amazing about a topic as rich as this is. You can talk to two of the world's experts and have two completely different conversations. Conversation with Jerry focused so much on the pathophysiology of insulin resistance. Here we focused much more on the actual organ specific aspect of type 2 diabetes. We got a masterclass in the pharmacology of it, and then I think, kind of brought it back to ways to diagnose it. If you're slumming it with those of us in the clinic who don't have clamps.

So maybe we should in the future we do one with both Jerry and.

I. I will 100% agree that in a few years we come back and we do a double version of this and we Fantastic.

Yeah, I sign up.

All right, Ralph, thank you so much. Not just obviously for this, but for your contribution to this field.

Okay. I appreciate it. This was wonderful.

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