The Peter Attia Drive - #337 - Insulin resistance masterclass： The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment

00:00:00.000 Hey, everyone. Welcome to the Drive podcast. I'm your host, Peter Atiyah. This podcast,

00:00:16.540 my website, and my weekly newsletter all focus on the goal of translating the science of longevity

00:00:21.520 into something accessible for everyone. Our goal is to provide the best content in health and

00:00:26.720 wellness, and we've established a great team of analysts to make this happen. It is extremely

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00:00:53.200 of the subscription. If you want to learn more about the benefits of our premium membership,

00:00:58.000 head over to peteratiyahmd.com forward slash subscribe. My guest this week is Dr. Ralph

00:01:06.360 DeFranzo. Ralph is a distinguished diabetes researcher and clinician known for his pivotal

00:01:11.760 work in advancing the understanding and treatment of type 2 diabetes. He's widely recognized for his

00:01:17.680 groundbreaking contribution to the concept of insulin resistance, which has reshaped the understanding

00:01:22.420 of type 2 diabetes and its progression. He played a very important role in bringing metformin to the

00:01:27.320 United States as a standard treatment for the disease nearly 40 years ago, along with the

00:01:32.780 discovery and development of SGLT2 inhibitor, a class of drugs you have no doubt heard me discuss

00:01:38.660 many times before. With over five decades of research in the field, Dr. DeFranzo has received numerous

00:01:46.000 prestigious accolades, including the Banting and Claude Bernard Awards, the highest honors that can be

00:01:51.900 given to a diabetologist. This episode with Ralph is really a masterclass in the organ-specific aspects,

00:02:00.160 the pharmacology, the diagnosis of type 2 diabetes, and it draws from his vast experience. Now, if you

00:02:06.500 listen to my conversation with Jerry Shulman a few years ago on insulin resistance, what amazed me was how

00:02:13.140 little overlap there was, not because the information is not congruent, but because of how much we were able

00:02:19.740 to go into different topics. So the discussion with Jerry Shulman, which I would encourage everyone to

00:02:24.480 listen to if they have not, really focused on one of the areas that insulin resistance manifests itself,

00:02:31.700 which is in the muscle. What we talk about here is about all of the other organs. Spoiler alert, there are

00:02:38.060 seven that are impacted by this condition, and therefore we go into much greater detail. They're in addition

00:02:45.300 to the pharmacologic interventions, and I just have to say I learned more in this podcast than I do in

00:02:53.060 most podcasts. It's one of the few that I had to immediately go back and listen to, and my notes

00:02:59.860 from this podcast are so voluminous that they even provided substrate for internal meetings with our team

00:03:07.500 in the practice. In short, there are many things that I've taken away from this that will directly impact

00:03:12.500 my patients. Just as far as some of the other things we discuss, we get into details about how

00:03:18.440 insulin resistance impacts liver. We do talk about muscle, but we talk more about fat cells. We talk

00:03:24.520 about his development of the euglycemic clamp, something that some of you have probably heard of

00:03:28.520 as the gold standard for measuring insulin resistance. Again, we talk about the pharmacology,

00:03:33.040 not just the SEL22 inhibitors, but the GLP-1 agonists, metformin, and another class of drug that we

00:03:39.840 don't talk about that often that, frankly, for me was a real eye-opener. There's a lot more I can say,

00:03:45.220 but I think at the end of the day, you just kind of got to listen to this one maybe twice.

00:03:48.280 So without further delay, please enjoy my conversation with Dr. Ralph DeFranza.

00:03:57.640 Ralph, thank you so much for coming down to, I guess, up to Austin from San Antonio. Very excited to sit

00:04:04.180 down with you and talk about potentially one of the most important subject matters in all of health.

00:04:09.980 People who listen to me all the time hear and are familiar with me talking about these four horsemen,

00:04:14.480 cardiovascular disease and cerebrovascular disease, cancer, neurodegenerative and dementing diseases.

00:04:19.560 And then there's this fourth horseman that I talk about, and it's in many ways the squishiest

00:04:23.860 because it's not the one that shows up on the most death certificates, but in many ways it's the

00:04:28.920 foundational one that is amplifying the risk of all of those other causes of death. And I refer to it

00:04:35.380 as metabolic disease spanning the spectrum from hyperinsulinemia to insulin resistance to fatty

00:04:42.360 liver disease all the way out to type 2 diabetes. So given how much I speak about that, it seems very

00:04:49.660 important that we should have a really thorough discussion of that foundational metabolic disease and

00:04:56.180 no one better than you to have that discussion. So let's start a little bit with just telling

00:05:01.460 folks briefly about what you're doing at UT San Antonio and why you've spent the last 40 plus,

00:05:06.480 almost 50 years now working on this problem. Yeah, more than 50 years. I actually have been

00:05:10.600 in this field of metabolic disease for a long time. I think I'm the longest consecutively funded 53

00:05:17.980 years NIDDK investigator. I actually started even long before that when I was a medical student at

00:05:25.560 Harvard, I had this fantastic teacher, Professor Cahill, who gave us all of the lectures on

00:05:31.300 intermediary metabolism. And I decided this is what I wanted to do. And I worked each summer with Professor

00:05:38.940 Cahill. And sometimes in life, you meet the right person, the right opportunity, it changes everything

00:05:44.020 you do. And basically what I do now, I contribute directly to George. And when I gave the Banting lecture

00:05:51.280 in 2008, people usually put a picture of their mother and father and children. And I love my

00:05:57.040 mother and father and children, but I only showed one picture and that was Professor Cahill because

00:06:01.800 he's really the person who's ended up directing me to where I am today.

00:06:07.260 People who are listening, who are particularly astute might recall, I've referenced a number of

00:06:11.600 Cahill's papers, but one of the more interesting studies he did, which it's possible he did while you

00:06:16.520 were even a student there, was the 40-day starvation study. Now, you might've not been quite at Harvard

00:06:22.120 yet because this was, if I recall, in the mid-60s, maybe 66, 67. And it was probably a group of medical

00:06:28.740 students that actually volunteered, if not medical students, undergrads. They did a water-only fast

00:06:33.260 for 40 days. And the study basically just followed all of the metabolites, what happened to glucose

00:06:40.220 levels, obviously insulin, beta-hydroxybutyrydocetoacetate. Anyway, it was very fascinating stuff.

00:06:44.860 One of the things that was most interesting to me in that study was even under a period of such

00:06:50.580 extreme starvation, the brain never gave up its dependency on glucose. So even though ketone bodies

00:06:57.380 began to service the brain by about day seven to 10 as the majority of the fuel, even at three and

00:07:04.900 four weeks of starvation, glucose was, if my memory serves me correctly, still providing about a third

00:07:10.780 of the brain's energy. Your memory is very good. The brain did switch over to ketone metabolism.

00:07:16.440 And believe it or not, I didn't do the 40-day fast, but I was one of the people who fasted for

00:07:22.440 five to seven days. If you fasted for three days, you could get paid $50. And I thought I was the

00:07:30.120 richest guy in the world from this study. I can assure you that the physical specimens in this study

00:07:36.000 were phenomenal. What did the 40-day fasting students get? I don't know, but I'm sure he paid

00:07:41.620 them a lot of money. That's amazing. In order to do that. The interesting thing about that is you

00:07:45.980 realize that we have so much energy stored in the human body. Who would have thought that you're a

00:07:51.300 lean type person, you can fast for 40 days. But the real problem is at some point, you start to break

00:07:57.520 down muscle. And then if you start to break down cardiac muscle, then prolonged fasting at that point

00:08:03.240 becomes a problem. But you have a lot of energy stored in fat and you can starve for a long time.

00:08:08.820 And obese people easily can go for three, four months with all the reserves that are in the body.

00:08:14.700 Let's maybe talk a little bit about what insulin resistance is. We'll get into what causes it,

00:08:20.840 but let's just maybe define for people this term that gets thrown around constantly. And let's

00:08:26.400 explain what it is from a technical standpoint. Basically, every time you eat a meal and your blood sugar

00:08:31.840 level goes up, you're going to release insulin. And insulin is sort of a master regulator for all

00:08:37.520 biochemical processes in the body. One of the things that insulin is going to do is going to

00:08:42.220 talk to your muscles. They're going to say, take up glucose and burn that glucose. What we need to know

00:08:47.840 is in a normal person, when I infuse insulin, how much of the glucose is taken up by the muscle.

00:08:54.480 And then we could look at someone who is, say, overweight, or we could look at someone who's

00:08:58.620 diabetic. And I actually developed the gold standard technique, which is the insulin clamp

00:09:03.400 technique to look at this. So we could take an obese person or a diabetic or a normal person,

00:09:08.440 we raise the insulin. And then I'm using muscle as an example, how much glucose is taken up,

00:09:14.000 disposed of by the muscle. And then I can compare if you're overweight compared to the lean person.

00:09:20.880 Obese people are very insulin resistant in terms of muscle glucose uptake. I could look at the

00:09:25.220 diabetic. They're even more insulin resistant. But there are many processes that insulin control.

00:09:31.800 So insulin regulates how much fat is released from your fat cells. And obese people, unfortunately,

00:09:39.420 insulin keeps the fat in your fat cell. But in obese people, insulin doesn't work so well.

00:09:45.800 So instead of keeping the fat in the fat cell, even though your insulin is high,

00:09:49.300 you're breaking down the fat. So you have to look at each individual process that insulin

00:09:54.740 is controlling. And so for that process, we know this is what a normal person should respond like.

00:10:01.840 This is what a diabetic responds like. And the diabetic is much, much more insulin resistant.

00:10:07.500 They're not responding. In a certain way, it's a general term because insulin controls so many

00:10:14.120 things. Protein metabolism. Insulin is very important in helping you to build protein.

00:10:19.020 So I could infuse insulin. And we've done this using carbon labeled leucine. And we can define

00:10:25.560 how insulin promotes protein metabolism in a normal, healthy person. And then I could do the

00:10:31.580 same kind of study in an obese person. And we know that the obese people don't respond to the

00:10:36.760 insulin as well in terms of aggregating protein metabolism. So it's kind of a general term.

00:10:42.480 Does that translate not just to structural proteins such as enzymes or cellular structural

00:10:48.620 proteins, but also macro structural proteins such as muscle?

00:10:51.980 Absolutely. So I can look at specific enzymes within the cell. I can look at certain genes within

00:10:58.820 the cell that are turned on or off. Or I can look at muscle in terms of muscle as a bulk. So there are

00:11:05.180 many ways in which you could define insulin resistance. But basically, whatever the particular process

00:11:11.080 you're looking at, you're comparing what would be the normal response in a normal, healthy person

00:11:16.660 compared to what might happen in a diabetic person or an obese individual.

00:11:21.840 So one of the challenges with the term insulin resistance is, as you said, it's a vague term and

00:11:26.660 it's nonspecific because the actions of insulin are so many. It has an action in the liver. It has an

00:11:33.160 action in the muscles. It has an action with response to glucose. It has an action with response to

00:11:37.840 amino acids. And it has an action with response to fat, both in the liberation of fat, lipolysis,

00:11:44.500 and presumably in response to oxidation.

00:11:47.120 Absolutely.

00:11:47.920 We'll go through all of these. But let's maybe start with how the euglycemic clamp test is done.

00:11:55.140 Let's assume that I'm a healthy enough individual that we can use me as a proxy. I come into your

00:12:01.040 clinic. What are we going to do? How do you run this test?

00:12:04.340 Let me bring you back in time when I was a fellow because at that time, we didn't really have a good

00:12:09.920 measure of insulin sensitivity. So what people would do is you do an oral glucose tolerance test

00:12:15.860 and the insulin level would go up. Some people would say, I'll look at how much insulin comes out

00:12:21.220 compared to the rise in glucose. And that's a measure of beta cell function. And then someone

00:12:25.960 would just turn it around and say, look, I'm going to see how much the rise in glucose was per insulin.

00:12:31.800 And that's a measure of insulin resistance. And it was very clear to me, well, this is insane.

00:12:37.060 You can't take two variables and then just depending upon how you want to look at them,

00:12:41.360 switch denominator and numerator. So I said, we need to develop something that is really more specific.

00:12:48.740 Just to be clear, Ralph, I mean, unfortunately, we as clinicians are not able to do euglycemic clamps.

00:12:54.900 Correct.

00:12:55.160 We are still looking at oral glycemic tolerance tests. We are still giving people

00:13:00.440 oral glucose and sampling glucose and insulin every 30 minutes and trying to impute what we can,

00:13:08.960 which I'd love to come back and talk about interpretation, but carry on with the limitation.

00:13:13.140 We actually have done a lot of work on how you interpret that. So what we said is,

00:13:17.300 why don't we develop a serious way? And so we developed a technique where I could take a hundred

00:13:22.480 people and I would infuse insulin initially as a primary dose and then just clamp the insulin

00:13:27.800 level. So I give a prime continuous insulin infusion. I can take a hundred people and all

00:13:33.180 hundred people, I can raise your insulin level by a hundred micro units per ml. And I can do that

00:13:38.320 for two hours. And now I know that the stimulus, the insulin stimulus, whether you're lean, whether

00:13:44.900 you're obese, or whether you're diabetic, whatever particular process that I want to look at.

00:13:49.740 So maybe I wanted to look at how insulin shut down hepatoclucose production. And actually we were

00:13:55.720 the first people to ever use radioisotopes to trace this and show that in normal people, insulin

00:14:01.980 shut down glucose production by the liver very quickly. But obese people and diabetics were very,

00:14:07.460 very resistant to the insulin. And then we said, we wanted to know, look, everybody now has got the

00:14:12.080 same insulin level. How effectively does that insulin stimulate muscle glucose uptake? And again,

00:14:18.400 what we showed, and these actually were the very first unequivocal demonstration that diabetic people

00:14:25.020 type two were insulin resistant. Before this, there was a lot of controversy. Dr. Reven, who is a father

00:14:32.080 of insulin resistance, I like to think I'm the son of Dr. Reven. He's a great idol of mine. He really

00:14:38.440 was one of the very first people to insinuate that diabetics were insulin resistant. With the insulin

00:14:44.960 clamp, we showed this very definitively. And we also know we use the label glycerol and free fatty

00:14:51.660 acids, and we could show the ability of insulin to shut down release of lipid from the fat cell was

00:14:58.720 markedly impaired. So three of the major organs, all of this work originally was done by us when I was

00:15:06.720 back at Yale. Let's summarize those again. We're talking about this in an insulin sensitive person,

00:15:11.520 right out of the gate. Insulin is going to shut down hepatic glucose output. Absolutely.

00:15:16.600 Which again, all of this kind of makes sense if you think through the pathway. Our liver is constantly

00:15:21.040 putting glucose into circulation because the muscles can't put glucose into circulation. So

00:15:27.100 something has to feed the brain. If insulin is high, it suggests glucose is already sufficiently high.

00:15:34.080 So let's not create more glucose toxicity. Let's shut that. Second thing it's going to do

00:15:39.160 is it's going to take that excess glucose and put it in the place where we have the largest capacity

00:15:44.720 to store it, which is muscle. So point two is we increase muscle uptake of glucose. And then point

00:15:51.620 three you said was it's going to shut down lipolysis. It's going to shut down the release of triglycerides

00:16:00.100 and or free fatty acids from the adipose tissue. That's very critical. We also, when we did these

00:16:05.860 studies, we would put a catheter in the hepatic vein and in a femoral artery and a femoral vein. So we

00:16:11.340 could look at the individual tissues. And what we showed is that when you infuse insulin, say 80 or 90

00:16:16.800 percent of the glucose is going to be taken up in muscle. Only 10 percent is going to be taken up in

00:16:21.900 the adipocyte and stored. How much in the liver? Basically none. Under euglycemic conditions, and we

00:16:28.520 were the first to show this conclusively as well, there's no glucose uptake in the liver by insulin.

00:16:33.500 Just explain to people what a euglycemic condition is.

00:16:36.840 Euglycemic means you're fasting glucose when you wake up in the morning is 80. Now you're euglycemic.

00:16:43.440 That means when we do the studies, we keep your fasting glucose of 80. We don't let the glucose

00:16:48.140 change. All we're going to do is raise the insulin. And that means you're giving glucose.

00:16:52.700 Of course, because if we didn't give glucose, then your blood sugar level would drop and then you'd

00:16:58.160 release cortisol, you release epinephrine. I just want to make sure people understand that. I was going to

00:17:02.980 come back to that. I wanted you to finish that point. So let's make sure we go back to the test

00:17:06.420 because it's very counterintuitive. So I've got a catheter in each arm. I walk in off the street.

00:17:11.420 I've been fasting. My blood sugar is 80 or 90, whatever milligrams per deciliter it is.

00:17:16.520 You are going to have to infuse both insulin and glucose into each of my arms. And the reason is

00:17:22.480 when you said a moment ago, you're going to steadily increase my insulin and take it to a steady state

00:17:28.340 of 100 IU per mil. That's a staggeringly high insulin level.

00:17:35.200 Not so high. In your life, after a meal, it would be maybe 60. Obese people very commonly get to 100.

00:17:40.920 Sure, sure. For a healthy person, you would never see an insulin level that high. And if you were not

00:17:46.680 simultaneously running glucose into them, you would kill them within minutes.

00:17:51.880 Hopefully not.

00:17:52.700 Yeah. But to get to the point, they would become so profoundly hypoglycemic that they would cease to

00:17:57.380 exist. And it should be obvious that if you're very sensitive to insulin, I have to infuse a lot

00:18:02.720 of glucose. But the other beauty of it, as I said, when I was a young guy at Yale, there was a physician

00:18:09.660 in New York, Dr. Altshuler. He was the first one to use trigated glucose to trace metabolic pathways.

00:18:16.240 And I said, this is astounding. So I actually went to visit Dr. Altshuler and learned how he did it.

00:18:21.680 So all of the insulin clamp studies that we did, we were the first people to use trigated glucose

00:18:26.560 in humans. And to show that the ability of insulin to shut down the release of glucose from the liver

00:18:33.940 was markedly impaired.

00:18:36.020 Sorry to interrupt, but just to make sure that people are following us, the reason you wanted

00:18:39.340 to use trigated glucose there was not to quantify the total amount of glucose disposal. You could do

00:18:45.880 that on mass balance. You wanted to determine the ultimate fate of glucose. How much became hepatic

00:18:52.120 glycogen, if any? Sounds like the answer is none. How much became muscle glycogen? Sounds like you said

00:18:57.620 about 90%. And how much ultimately got converted through de novo lipogenesis into adipocyte or free

00:19:05.200 fatty acid? Sounds like that's about 10% under the euglycemic condition. Is that correct?

00:19:10.740 Yeah. In general, that's correct. Except in the muscle, remember,

00:19:13.200 some of the glucose is going to be oxidized. So if you look at the glucose, once it gets into the

00:19:19.260 cell, one third would go through the glycolytic pathway and be oxidized.

00:19:23.700 Right away?

00:19:24.280 Yes. And the other two thirds would be stored as glycogen.

00:19:27.680 I mean, presumably you're doing this test and a person is sedentary.

00:19:30.620 Yes.

00:19:31.200 Is muscle that metabolically active at rest? I guess it is.

00:19:34.020 Yes.

00:19:34.400 Yeah. So that's really interesting. Does that mean you're increasing energy expenditure under these

00:19:38.640 conditions?

00:19:39.160 Well, of course, in a certain way you are, but it's not like when you go out and you exercise and you

00:19:44.880 run a mile or two. So I would say you are turning on a number of cycles, which are, of course,

00:19:52.380 going to increase energy expenditure. You're generating ATP. So there is a certain increase

00:19:57.700 in energy expenditure. But if I really want to increase energy expenditure, I'd get you to go jog

00:20:02.620 five miles or so because exercise is really the thing that really increases energy expenditure.

00:20:07.660 And Ralph, just for a sense of amount, if you're doing this in, say, somebody my size who's

00:20:13.120 insulin sensitive, how many actual grams of glucose would you be able to get into the person

00:20:18.740 within the hour whilst keeping insulin clamped?

00:20:23.600 So I'm going to do it first in terms of rates, the way we express it, and then I'll translate that.

00:20:29.880 Under basal conditions, you wake up in the morning and your liver is producing and your tissues

00:20:35.680 are taking up about two milligram per kilogram body weight per minute.

00:20:39.540 Liver is producing, that's hepatic glucose output.

00:20:42.400 That's hepatic glucose output, two milligram per kilogram body weight per minute. And we were the

00:20:47.920 first to actually show this many years ago, and this is humans. Mice are very, very different,

00:20:52.600 totally different. And that's why extrapolating from mice to humans can be a problem.

00:20:56.520 Let's just reflect on that for a second. People who listen to this podcast are probably sick of me

00:21:00.800 saying this, but I'm sorry. I just can't stop saying it. The liver never ceases to amaze me.

00:21:06.220 It's an incredible organ.

00:21:07.280 It's an unbelievable organ. And again, I come back to this idea. It's the only major organ for

00:21:13.020 which we don't have extracorporeal support. If your heart, if you went into cardiogenic shock

00:21:18.540 and we felt we could reverse it in time, we could put an intra-aortic balloon pump in you. We could put

00:21:23.740 an IABP in you. We could put a left ventricular device in you to stem you over until we get you out of

00:21:29.560 there. If your kidneys are destroyed, we can transiently dialyze you. Even if your brain is

00:21:35.460 experiencing swelling, we can, you know, put enough steroids in you or decompress your skull

00:21:40.220 to give you the time to recover and keep you alive otherwise. Go through all the major organs. If

00:21:45.340 your spleen is dinged, take it out. Even if you lost your small bowel, we could at least transiently

00:21:50.640 keep you alive with TPN or something like that. None of this is true with the liver.

00:21:54.940 You know, in the old days, they actually used to use pig liver perfusion.

00:22:00.520 I know.

00:22:01.220 But that was in the old days. We don't do that anymore.

00:22:04.020 And baboon as well.

00:22:05.200 They have baboons. Yeah.

00:22:06.620 So the fact that the liver can titrate this amount is remarkable. So two milligrams per kilogram

00:22:11.460 per minute. So you take an individual who weighs a hundred kilograms, you're putting 200 milligrams

00:22:18.080 per minute of glucose into circulation. Then you can multiply that by however minutes you want to

00:22:26.520 look. So that's a gram every five minutes. That's 12 grams of glucose every hour that the liver is

00:22:35.060 putting out. But now when I do an insulin clamp, depending on how much I raise the insulin and over

00:22:41.120 the years, we've done a dose response curve. And I can come back to this because your fat is

00:22:46.820 exquisitely sensitive to insulin. If I raise the insulin just by 10 micro units per ml, the fat

00:22:52.960 stops producing free fatty acids and glycerol. You inhibit lipolysis literally completely. The liver,

00:22:59.660 you need to get the insulin up to about 50 micro units per ml to really get it shut down.

00:23:05.600 Sorry. And the fat you had to get how high?

00:23:06.940 10. A rise of 10.

00:23:09.060 Tell me, these people, when they come in unhealthy, they're what, they're at 5 to 10 faster?

00:23:12.700 Yeah, they're at 5 to 10. So I'm going to raise them from 5 to 10 to maybe 15 or 20.

00:23:17.140 And that's going to, in large part, shut down lipolysis. In fact, all of this sort of work

00:23:22.780 was work that we originally did many, many years ago. Now, at the level of the liver,

00:23:27.300 you really need to get up to about 50 micro units per ml. So maybe at 10, I'm going to bring you up

00:23:32.780 to 50. And that's in large part going to shut off glucose production by the liver. Now, that's

00:23:38.780 critical because you wake up in the morning and your liver's producing glucose. Now, if you eat a

00:23:44.920 meal, glucose is coming in from the gastrointestinal tract. You can't have glucose coming in from the

00:23:50.280 liver at the same time. Otherwise, you get very hyperglycemic. So when you eat a meal and that

00:23:55.240 insulin comes out, it really needs to shut down a pad of glucose production. Now, what's replacing the

00:24:00.940 liver is what's coming from the meal. But then after you absorbed all of the meal, the liver needs

00:24:05.320 to turn back on. So understanding how the liver is responding to insulin is really very important.

00:24:11.600 And then if I want to look at what's going on in the muscle, the reason why we go to 100

00:24:16.100 micro units per ml, which is above physiologic, but it's still within the physiologic range.

00:24:21.740 If you really want to stimulate muscle glucose uptake completely in a normal healthy person,

00:24:26.720 you'd probably have to get the plasma insulin to about 200 micro units per ml.

00:24:32.680 At 200, what happens?

00:24:34.340 You have now maximized muscle glucose uptake. In reality-

00:24:38.300 Even in an insulin sensitive person?

00:24:40.400 Yes.

00:24:40.860 Just to make sure I understand what you're saying, you're saying that if you took an insulin

00:24:43.980 sensitive individual at 100 units of insulin versus 200, you will actually drive more glucose

00:24:52.600 uptake. You haven't saturated the GLUT4 transporter at 100.

00:24:56.620 Probably about 25% more uptake as you go from 100 to 200.

00:25:00.500 Wow.

00:25:01.040 And these are all early studies that we did. So when we talk about insulin resistance, that's why I said

00:25:06.960 you need to know which tissue you're talking about and which metabolic pathway. And if you want to talk

00:25:12.720 about enzymes, you need to talk at what specific enzyme because insulin resistance needs to be

00:25:18.940 related to the tissue you're talking about and the process within the tissue that you're talking

00:25:24.220 about. So insulin resistance is a very important concept, but you all have to be a little bit more

00:25:30.420 specific about what aspect you want to address. So you can have insulin resistance in the fat cell.

00:25:36.620 You can have insulin resistance in the liver. You can have insulin resistance in the muscle. And then

00:25:41.060 something that's now pretty exciting, you may have insulin resistance in the brain.

00:25:45.000 And the suggestions now, and there are many insulin receptors in the brain. Jesse Roth,

00:25:51.000 very famous diabetes person, maybe 50 or 60 years ago was the first to describe insulin receptors in

00:25:57.320 the brain. And this is an area that's now starting to unfold. It may have some relationship to

00:26:02.740 neurodegenerative disease, Alzheimer's disease. Some people say that Alzheimer's disease is diabetes type

00:26:09.200 three. Brain diabetes. Yes. So insulin resistance is a very important concept. Let's say we're going

00:26:16.940 to talk about diabetes. Even though there's an ominous octet that I developed that's used everywhere in

00:26:22.720 the world for the pathophysiology of type 2 diabetes, if we really wanted to solidify it and say,

00:26:28.820 what are the two big concepts? Insulin resistance would be here. On the other hand,

00:26:33.620 would be impaired beta cell function. So if you are insulin resistant and your beta cells work well,

00:26:40.560 they know how to read the insulin resistance. They'll make enough insulin. You won't become

00:26:45.200 diabetic. Hyperinsulinemia can damage you in other ways, but you won't become diabetic. But what happens

00:26:51.380 is if you're insulin resistant, particularly if you have a genetic predisposition, if your beta cells

00:26:56.580 have to continuously pour out insulin, they start to exhaust. And insulin resistance is a disaster for

00:27:03.040 someone who has a genetic predisposition, it's going to bring out the diabetes. Insulin resistance,

00:27:08.720 in my opinion, is intimately related to cardiovascular disease. That is why when you see a diabetic patient,

00:27:15.720 10% of them, you walk in, you have diabetes, first time I see you, 10%, 15% of the people already have

00:27:21.780 clinically significant cardiovascular disease. And if you look carefully, virtually 100% of them do.

00:27:27.980 And sorry, Ralph, do you think that that is a result of the hyperinsulinemia or the untreated

00:27:33.760 or poorly treated hyperglycemia? All of the above. More importantly, what we showed, and we were,

00:27:39.620 again, the first people to show this, and the cardiologists, they're hemodynamically oriented,

00:27:45.400 they're looking at vessels. Stenosis, yeah.

00:27:48.740 But if you look at the insulin signaling pathway, insulin has got to bind to its receptor. And then

00:27:54.400 there's a signaling pathway. I can tell you all the molecules in there, which I'm not. And then

00:27:58.600 glucose gets transported in the cell. We were the first people to show in humans that that pathway

00:28:04.420 doesn't work normally. Insulin will bind to the receptor. It will activate the receptor. But the

00:28:10.240 next molecule, IRS1, PI3 kinase, all those molecules don't get activated. So glucose doesn't

00:28:16.180 get into the cell. That's diabetes. That same pathway activates nitric oxide synthase.

00:28:22.340 And that generates nitric oxide. Nitric oxide is the most potent vasodilator in the human body.

00:28:30.680 It's the most potent anti-arthrogenic molecule in the human body. So this defect that's in muscle,

00:28:37.940 and it's in cardiac muscle, and it's in skeletal muscle, this is all human data that I'm talking

00:28:42.920 about, not animal data. When you get a defect in that insulin signaling pathway, that's going to cause

00:28:49.080 diabetes. And it's going to promote cardiovascular disease. And that is why you can never separate

00:28:55.420 cardiovascular disease from diabetes. Now, as you pointed out, rightfully so, I believe that

00:29:02.820 high levels of insulin are also atherogenic. I don't want people saying Dr. DeFranco said you

00:29:09.360 shouldn't be giving insulin to people who need it. Of course, if people need insulin, you need to give

00:29:14.360 them insulin. But our beta cells make 35 units of insulin per day. So we showed this many years ago

00:29:21.000 when I actually was at Yale, that if you were to take a type 1 patient and they were lean, they would

00:29:27.480 only need 35 or 40 units of insulin to get their glucose controlled, assuming you gave the doses at

00:29:33.560 the right time. But we have a lot of people who are taking 100 units of insulin, both type 1s and type 2s.

00:29:39.220 So 3x physiologic. Yes. That kind of hyperinsulinemia, I think there's evidence to support

00:29:45.880 that's atherogenic. But now we have a problem. Can you have the glucose remain high? Yeah. It's a

00:29:50.820 question of, do you want to die quickly or slowly? But we have really good drugs. Yes, yes, yes. But

00:29:54.900 if you were only doing this with insulin, it's an awful trade-off. You're going to die very quickly

00:30:00.460 from hyperglycemia if you're left untreated. But if we overdo it with insulin to maintain normal

00:30:07.060 glycemia, we're going to kill you slowly. To quagma, you're stuck. Yeah. You have to treat,

00:30:11.100 but you also know that when you're giving these big doses of insulin, there may be some side effects.

00:30:16.580 This is something, Ralph, I don't think that has been necessarily appreciated by the medical

00:30:20.840 community. Absolutely not. There has generally been an ethos of, when I've talked to patients with

00:30:26.900 type 2 diabetes, what they've been told is, I'm told to cover with as much insulin as is necessary

00:30:33.160 to maintain my glucose levels in this range. And it means I can eat whatever I want. It's okay if I

00:30:40.940 have all the pasta and bread and sugar in the world, because as long as I'm covering it with insulin,

00:30:47.100 I'm okay. And then you find out, wow, you're taking 150 units of insulin a day in all of its forms,

00:30:53.680 the short acting, the long acting, et cetera. But I didn't actually realize that what we would

00:30:57.520 consider physiologic is 35. I may have known that at one point and I've since forgotten, but that's a

00:31:02.160 great reference. So basically, if there's a person with type 2 diabetes listening to us today

00:31:06.820 and they're taking 75 units of insulin, one of the takeaways should be, what do I need to do with

00:31:16.420 my nutrition and other pharmacologic activities, plus exercise, plus everything that's under my control

00:31:22.180 to maybe get that down to 35, where I would be at a physiologic level?

00:31:26.320 There are things as you already insinuated, weight loss, if you can get people to do it,

00:31:30.560 exercise. And then we can add medications in combination with insulin, insulin sensitizers or

00:31:36.720 some drugs to help you lose weight that will all also allow you to get that dose of insulin reduced.

00:31:44.140 The other thing we showed in this study, Dr. Del Prado, who's past president of the European

00:31:49.900 Diabetes Association, we took normal healthy lean kids, 18, 25 years of age. And we put them on the

00:31:57.460 clinical research center for three days and we gave them a very, very low dose of insulin infusion.

00:32:05.020 And we raised their fasting insulin from eight, which is what a normal person would be, to 20,

00:32:11.760 which is really quite low. And within 48 to 72 hours, they were as insulin resistant as a type 2

00:32:18.920 diabetic patient. So hyperinsulinemia induces insulin resistance.

00:32:25.200 Wait a second, why is that the case?

00:32:26.760 So what insulin does is it down-regulates the insulin signaling transduction system.

00:32:32.500 So that insulin, when it binds to its receptor and then it activates IRS-1 and PI3 kinase and AKT,

00:32:38.960 that system is down-regulated by hyperinsulinemia. All of this that I'm telling you about,

00:32:44.020 it's all published. These are all studies done in humans. And this has also been shown in

00:32:48.660 rodent models as well. So this is another reason why we don't want people to be hyperinsulinemic.

00:32:55.220 You have to explain that to me again, Ralph. That is mind-boggling. I would never have predicted

00:32:59.120 that. So let me say it back to you because I feel like I missed it when I was writing something down.

00:33:03.700 You took normal volunteers who had a fasting insulin of eight.

00:33:08.260 Yep. And they're lean, healthy.

00:33:10.100 Okay. And simply infused insulin in them, presumably with glucose.

00:33:15.580 Oh yes, of course. On the clinical research center, we can monitor and keep the glucose

00:33:19.240 perfectly constant. We're not letting the glucose change.

00:33:21.780 Person shows up, insulin eight, glucose is 90. You do a euglycemic clamp where you bring insulin up

00:33:28.560 only by one and a half per, one and a half X. Much less than would be when you eat a meal.

00:33:33.640 Exactly. Not even a postprandial bump, but now it's constitutively sitting there at 20.

00:33:39.420 And you've obviously had to bring glucose. You had to infuse glucose to maintain euglycemia.

00:33:43.760 Correct.

00:33:44.400 Did you say that in four days?

00:33:46.400 48 to 72 hours. These people are as insulin resistant as type two diabetics.

00:33:51.160 Okay. Again, very, very counterintuitive because if our model is that insulin resistance,

00:33:59.940 which is the hallmark factor contributing to type two diabetes in the combination of

00:34:05.480 beta cell fatigue is driven by lipotoxicity, which we're going to come to.

00:34:10.940 It's an important one.

00:34:11.800 Yes. These people didn't have any of that. These people didn't have any of the intramyocellular

00:34:17.300 lipid that we talked about with your colleague, Jerry Riven, as a predisposing factor.

00:34:23.080 It's the direct effect of insulin down-regulating the insulin signaling system and probably other

00:34:29.040 distal metabolic within the cell as well.

00:34:32.600 So then when you turn the clamps off, let's just say we ran this for 72 hours,

00:34:37.220 we've made them functionally diabetic. Turn the clamps off, how many hours or days?

00:34:43.140 We didn't do that.

00:34:44.200 What would you predict?

00:34:45.020 I would predict probably within 24 to 48 hours, they would return to normal because we did this

00:34:50.820 acutely. Now, if we were able to do this for several months, then I would anticipate that the

00:34:58.640 insulin resistance would remain for a long period of time. And remember, when we treat type one

00:35:03.840 diabetics, we're always giving the insulin into the periphery. And you or I, when you ingest the meal,

00:35:10.620 where does the insulin go? It goes into the portal vein. So the liver is seeing a high level of

00:35:16.940 insulin. That's good. It says stop making glucose. But now it removes half of the insulin. So how much

00:35:24.160 insulin gets into the periphery? Half of what you secreted. Why? Because we don't want the insulin in

00:35:30.420 the periphery over insulinizing the periphery because it would make the muscle tissue very insulin

00:35:35.620 resistant. So the pancreas secreting insulin into the portal circulation. Liver sees the insulin.

00:35:41.700 Good. Stop making glucose. But it also takes up half of the insulin. So less insulin get enough to

00:35:47.720 nourish the muscle, enough to shut down the fat producing free fatty acids, but not enough to

00:35:53.480 hyperinsulinize the system. And in a certain way, if you're a diabetic and you are insulin resistant,

00:36:00.080 or an obese person, and you are insulin resistant, and you're hyper secreting insulin, it's kind of

00:36:06.180 working against you because it's a reverberating system that's making the insulin resistance

00:36:11.100 aggravated. So one of the big things that we've forgotten is that insulin, I told you, there are

00:36:17.360 two problems in diabetes. One is you don't make enough insulin. The other is you're insulin resistant.

00:36:21.960 You need to attack both problems. And the paper that I recently published, which is a perspective in

00:36:29.020 Lancet Diabetes Endocrinology, was to bring people back to, look, we're focusing on obesity and weight

00:36:35.780 loss, and we should, but we need to remember that we still have a genetic cause for the insulin

00:36:41.940 resistance. You go back to 1950, the incidence of diabetes was 2%. I've seen even data that says it

00:36:48.440 was 1% as recent as 1970. It's very low. Yeah. But these people were all lean and they're insulin

00:36:55.700 resistant. So there's a genetic cause of the insulin resistance. And you think, Ralph, that the greater

00:37:02.320 genetic effect is on the insulin resistance side or on the beta cell fatigue side? Both. Okay. So

00:37:08.600 let's tackle each. Since you started with insulin resistance, let's go there. Let's talk about what

00:37:13.280 we know about the genetics of insulin resistance. That's easy. Nothing. Truly nothing. I joke.

00:37:21.420 Well, let's say 20 years ago, we got involved in one of the biggest genetic studies called the

00:37:27.420 VEGAS study, Veterans Administration Genetic Epidemiologic Study. And we were convinced that

00:37:33.740 we were one of the people to do the first GWAS studies, that we would define all the genes that

00:37:37.920 are responsible. Well, we were not very successful. Even if you took the subset of people with type 2

00:37:44.680 diabetes who were lean and you compared them to people who were lean and non-diabetic versus obese

00:37:52.120 and diabetic, a GWAS was not able to identify a signal in those three cohorts? We identified several

00:37:59.300 and remember their associations. Of course. And they're in non-coding regions. The TCF7LT2 gene,

00:38:07.000 we found that, but that had already been described by Dr. Michael Stern in San Antonio many years before.

00:38:13.060 So we repeated what Michael showed. And other people have shown that. So there are a number

00:38:18.320 of associations. Again, if you ask me how many genes have we truly established that are really

00:38:26.060 important in terms of causing type 2 diabetes, I would say very, very few. I know the genetics

00:38:31.340 people out there probably hate this. And they'll say that we can put together a genetic score.

00:38:36.900 But when they talk about a genetic score, it's not that they've causably associated a gene with

00:38:42.760 diabetes. It's an association. It's an association. We have a whole different approach. If you want,

00:38:47.660 I can tell you what we're doing that may give some insight. And then people have started to think

00:38:52.700 about rare diseases. That maybe the problem is in one family, you have this particular genetic

00:38:58.980 mutation. Another family, you have a different genetic mutation. A third family, a different

00:39:03.860 genetic mutation. And then when you do the GWAS study, you got this mixture of individual genes.

00:39:10.320 What about the phenotype? That's the answer. I've taken care of a couple of patients with type 2

00:39:16.480 diabetes who are very lean, including one patient whose body fat by DEXA was about 8%. For people

00:39:26.740 listening, that is insanely lean. Very lean. So you take an individual whose body fat is 8%

00:39:33.440 and yet they have type 2 diabetes. The first thing that comes to my mind is a lipodystrophy.

00:39:40.180 Is this an individual whose adipose tissue is the problem? In other words, they're not able to

00:39:48.700 assimilate enough excess nutrient, i.e. glucose, into the fat cell. And so they're undergoing the toxicity

00:39:57.020 associated with an insufficient reservoir. Is that what could be the causal, not that I can tell you

00:40:04.120 what's causing the lipodystrophy, but is the lipodystrophy the issue that's driving the diabetes?

00:40:09.760 The answer to that is it's very clear that lipodystrophy can cause diabetes. This is, I would say,

00:40:16.260 a very, very rare and unusual cause, but well-established.

00:40:20.420 But you're saying that's not what would explain 1% of diabetics?

00:40:24.040 No, no. Jerry Shulman has done some beautiful work in this area. So it's unequivocal that

00:40:29.800 lipodystrophic people, because their fat cells can't take up the fat, it ends up in your myocardium,

00:40:36.040 cause heart disease.

00:40:36.960 Ends up in the beta cells.

00:40:38.120 Ends up in your beta cell in the muscle. But that's a very, very small percentage. So the basic

00:40:44.240 genetic etiology of the insulin resistance, the PPAR gamma gene has been associated. There are about

00:40:49.840 seven or eight genes. There's a recent study, I think it's in Nature Genetics by Brown,

00:40:56.000 where they've identified eight. And again, they're associations, except I would say the

00:41:00.600 PPAR gamma gene, that is pretty clear. That's a causal.

00:41:03.900 Did Mitch Lazar do some of this work?

00:41:05.620 He's worked in this area, but again-

00:41:08.500 It's a long list of folks at this point.

00:41:10.300 Yes. The number of genes that have been described. The other thing people said,

00:41:14.320 well, maybe there are 20 genes involved, each giving a small component. And that's why it's so

00:41:19.020 difficult. Well, all of these hypotheses have been difficult to prove. And the simple fact is,

00:41:25.220 we don't understand the genetic basis. In part, because diabetes, in my opinion,

00:41:30.740 is a very poor phenotype. Diabetes is a very heterogeneous disease. So when we talk about diabetes,

00:41:37.660 if that's your phenotype, it's not surprising to me that it's going to be difficult to define genes

00:41:44.980 that are related to diabetes. So what I'm going to tell you about, I don't want to take the credit

00:41:50.160 for this. So one of the people in my division, Dr. Luke Norton, working with Steve Parker at

00:41:55.800 Michigan, I'm involved because I'm doing the insulin clamp studies. We're taking as a phenotype,

00:42:02.520 muscle insulin resistance. This is a very, very specific phenotype. This is not diabetes.

00:42:09.820 The ominous octet, my pathophysiology. That's eight problems. Okay. This is muscle insulin

00:42:17.300 resistance. I'm going to do an insulin clamp now. And then I'm going to do a muscle biopsy

00:42:22.820 before I do the insulin clamp. And I'm going to do a muscle biopsy at the end of the insulin clamp.

00:42:29.200 And what happens? During the insulin clamp, I know exactly how sensitive or resistant you are to insulin.

00:42:35.620 I've got the most definitive phenotype in the world. No one get this kind of phenotype.

00:42:40.920 And now what do I see? An enormous amount of chromatin opens up. This is the epigenetic

00:42:46.620 component. Genes in a chromatin area that you're never, ever going to see in the basal state.

00:42:52.780 And that's why we think this is a hypothesis now that why it's been so difficult with all of these

00:42:59.340 GWAS studies to identify genes that are associated with diabetes. And now we're starting to see

00:43:05.500 diabetic people and non-diabetic people. We're starting to see some associations which we think

00:43:11.740 now are causal and we can relate to the insulin resistance with the clamp.

00:43:16.080 Let's just pause there for a second, Ralph. I want to make sure everybody's following what you're

00:43:19.400 saying. You're saying, look, one of the challenges of having a disease that isn't perfectly, perfectly,

00:43:25.200 clearly defined where every single member of the class that has the disease looks exactly the

00:43:31.260 same. The word for that is heterogeneous. So let's take an example where the disease is very

00:43:36.400 heterogeneous. Sickle cell anemia. Correct. Everybody who has sickle cell anemia from a

00:43:42.220 pathophysiology standpoint is identical. Correct. And guess what? There's a single mutation that

00:43:48.480 defines the disease. Because you have a single gene that defines the disease, one gene mutated produces

00:43:55.620 one change in one base pair that changes, one amino acid that changes the property of the hemoglobin

00:44:01.680 molecule, and everybody looks the same. But you're saying, Peter, it's totally different.

00:44:06.340 With type 2 diabetes, we have some people that are thin, some people that are fat, some people that

00:44:10.700 have lots of insulin resistance in the muscle, some people that don't seem to have much, but it's all

00:44:14.600 in the liver. I want to make sure we define the octet, the ominous octet. But if that's the case,

00:44:20.060 why would you ever expect to find a simple genetic answer? You got it.

00:44:23.400 Definition. Perfect. It's going to be a mess. Absolutely. And so if you don't have a very

00:44:28.100 definitive phenotype, it's going to be difficult. But the implication, by the way, is any physician

00:44:33.900 who approaches a patient with type 2 diabetes as a single entity is going to be providing suboptimal

00:44:39.620 care. Yes. I've been fighting for 20 years to convince people you need to start with combination

00:44:45.080 therapy from the beginning. Finally, 2022, the American Diabetes Association has made a comment.

00:44:52.340 And for the first time, suggest that you should consider starting with combination therapy. We

00:44:57.580 can talk about that. We're going to talk about the therapies in detail. But yes, you have to take a

00:45:01.400 precision medicine approach to type 2 diabetes, which begins by trying to identify which phenotype

00:45:06.600 your patient is. Before we clean it, I just want to make sure that everybody understands it's Luke

00:45:11.280 Norton and Steve Parker, and they're the brain child. I'm involved. I understand the disease. We're doing

00:45:17.280 the insulin clamps. We're giving them the phenotype, and they're doing single cell. It turns out there

00:45:22.340 are 10, 12 different types of cells within the muscle. So we tend to think the muscle, oh, there's

00:45:27.460 a myocyte. That's the problem. But it's probably cells also talking to each other, making it even

00:45:32.180 more complex. So we're at an early stage in the development, but we're enthusiastic. We really have

00:45:39.580 not discovered these genes. So we think that epigenetics are important, and this is part of the

00:45:44.660 epigenetic phenomenon. We'll see where it takes us, but we're pretty excited about these findings.

00:45:50.140 Let's go back to the ominous octet, make sure I have that defined and all our listeners do.

00:45:55.000 So in 2008 at the Banting Lecture at the American Diabetes Association, the title of the Banting Lecture

00:46:02.100 was From the Triumvirate to the Ominous Octet. So what was the triumvirate? I got the Young

00:46:08.140 Investigator Award, the Lilly Award from the ADA in 1987. So the triumvirate was very simple.

00:46:14.660 The beta cell, it fails. Insulin resistance in the muscle, when you ingested a meal, the

00:46:20.460 muscle didn't take up the glucose because you're insulin resistant, and insulin resistance

00:46:24.980 in the liver. When you ate a meal, insulin didn't shut down the liver. So that was the triumvirate.

00:46:31.280 So from the triumvirate to the ominous octet, we needed to add five more players. So who were

00:46:38.680 the new five players? So number four on the list was the fat cell and a very deserving

00:46:44.860 guy. So the fat cell is your friend initially. You overeat, you take in excess calories, you

00:46:51.920 store them in the fat cell that can't hurt you there. But if you keep expanding those fat

00:46:56.080 cells, the fat cells become very, very resistant to the antilipolytic effects of insulin. And

00:47:02.000 now you start to pour fat out into the bloodstream. We've shown this as a big interest to Jim.

00:47:07.220 Very counterintuitive.

00:47:08.560 Counterintuitive.

00:47:09.480 Not that we should mire ourselves in teleologic things. Do you have a sense of why?

00:47:14.800 Yeah. So the insulin signaling system in multiple early steps become severely impaired. And when

00:47:20.900 you get insulin resistance in the glucose metabolic pathway, there are changes that alter the cell

00:47:25.900 metabolism. So you become very resistant to insulin's antilipolytic effect. And so now,

00:47:32.120 if you look at people who are obese or people who have type 2 diabetes, their plasma FFA levels are

00:47:37.920 very, very high. And those FFA levels, and this is lipotoxicity, and we've got a long history of

00:47:44.840 studying this, high FFA levels impair insulin secretion. High FFA levels cause insulin resistance

00:47:51.600 in the muscle. High FFA levels cause insulin resistance in the liver. High FFA levels impair

00:47:59.920 the insulin signaling transduction system. And in fact, one of my previous fellows who's now back

00:48:05.320 with me here at UT, Dr. Belfort, was the first author on this paper showing that just physiologic

00:48:11.500 rises in the plasma FFA literally obliterate the insulin signal transduction system, which is the first

00:48:18.140 step in glucose metabolism. I always thought that the reason we saw high free fatty acids in people

00:48:26.780 with type 2 diabetes was not because the fat cells were undergoing more lipolysis, but because the fat

00:48:35.040 cells were themselves becoming resistant to insulin and not able to take up fat. So same net effect,

00:48:44.360 but I was kind of drawing the arrow of causality in the other direction.

00:48:47.240 The arrow is more on the other side. The fat is pouring out fat. And you can show that the

00:48:52.420 lipolytic enzymes are all resistant to insulin. We've shown this. Other people have shown it.

00:48:57.100 So these elevated FFA levels are a disaster. So the fat cell initially is your friend.

00:49:02.200 Because he's your friend and goes to foe.

00:49:03.540 Then it becomes a bad guy. So that's number four. Number five is the gastrointestinal trap.

00:49:09.560 And of course, we'll, I'm sure, talk more about this when we talk about treatment. But when you eat a meal,

00:49:13.980 you release two incretin hormones, GLP-1 and GIP, glucon-like peptide 1 and glucose-dependent

00:49:21.160 insulin trophic polypeptide. Those two incretin hormones, when you eat a meal, account for about

00:49:27.700 70% of the insulin that's released in response to the meal. So now, what is the problem? Is the problem

00:49:35.100 that you don't release enough GLP-1 and GIP? Or is it that your beta cell is refractory to the GLP-1

00:49:44.240 and GIP? Well, it's the later. Let's say that again, Ralph. I want to make sure people understand

00:49:48.140 this. And the reason it's important is, obviously, everybody listening to us right now is very

00:49:52.140 familiar with drugs like semaglutide and trzepatide. But I want people to understand why those drugs

00:49:58.620 were developed. And of course, semaglutide's already probably what the third generation of it anyway.

00:50:03.780 So when we go back in time, we'll understand why people try to develop these drugs. But just say

00:50:08.020 that again. So you eat your meal, GIP, GLP-1 are increased. And they come out normally.

00:50:13.820 Yep. That's not the problem. And they're telling the beta cell,

00:50:16.560 hey, make more insulin. Beta cell's deaf, not listening. It's resistant to the GLP-1 and GIP.

00:50:21.800 And he should be responding to 70% of his input should come from that signal.

00:50:27.140 70% of the insulin that's going to come out is dependent on that GLP-1 and GIP. So you can imagine

00:50:32.600 that that's a huge problem at the level of the beta cell in terms of the defect in insulin

00:50:37.320 secretion. And tell me, why is it mechanistically that the beta cell becomes deaf to GLP-1 and GIP?

00:50:45.160 I don't know that we know the answer to that.

00:50:47.880 So it's just another horrible piece of this puzzle where everything starts to work against

00:50:53.100 the patient. So this is an area, of course, intense investigation. But the clinical counterpart

00:50:58.000 of this, as you've already mentioned, the drugs that are out there, the GLP-1 receptor agonist,

00:51:03.020 what I'm doing is I'm giving you a pharmacologic dose of GLP-1. And I'm overcoming the resistance

00:51:08.940 at the level of the beta cell. Now, there's another component to this that we'll get to,

00:51:15.060 and that's glucotoxicity. And these were studies that were done by Jens Toltz and the group in Denmark.

00:51:20.680 They took people and they infused GIP. We're talking about GIP. And you don't respond to

00:51:27.200 the GIP. These are type 2 diabetics. And then they intensively treated them with insulin and

00:51:31.920 lowered their glucose. And then when they come back with the GIP, you release a normal amount

00:51:37.600 of insulin. So this is a glucotoxic effect. So you asked me mechanism. So we know that at least

00:51:45.160 for the GIP, the glucotoxicity is impairing the ability of the beta cell to respond to the GIP.

00:51:52.680 But not necessarily GLP-1.

00:51:54.380 No, no. And that doesn't correct the GLP-1 problem. So there's true resistance still,

00:52:01.000 even though I normalize the glucose in terms of GLP-1. So this incretin axis, the gut,

00:52:07.420 is a very important endocrine organ. And that's number 5 in the ominous octet. Number 6 in the

00:52:14.220 ominous octet is the alpha cell. I would say the father of hyperglucagonemia, this is Dr. Roger

00:52:21.100 Unger in Dallas. He was one of the very first people to show that diabetics had very high glugon

00:52:27.020 levels. And glucagon drives- Tell people what glucagon does.

00:52:30.000 Yeah. Glugon, it drives hepatic glucose production. So if your glucose gets too low,

00:52:35.620 your alpha cells will release glucagon. So the alpha cell can sense the glucose. And so if you're

00:52:41.280 hypoglycemic, this is an important defense mechanism. You release glucagon, that stimulates

00:52:47.060 your liver and the glucose production goes up. It returns your glucose to normal. But a diabetic

00:52:52.940 already has a high glucose. We don't want high glugon levels. So paradoxically, there's very high

00:53:00.000 glugon levels in the diabetic. And those high glugon levels are very important contributor to the

00:53:07.380 hepatic insulin resistance because they're driving the liver to make glucose.

00:53:12.420 And sorry, just to make sure, I'm embarrassed to say I forget this from biochemistry. Is it driving

00:53:16.760 the liver to make glucose out of, for example, glycerol, amino acids, or other things?

00:53:21.140 Gluconeogenic pathway and glycogenolysis. Acutely, so if I acutely give you glucagon,

00:53:26.900 the first thing that happens, you break down glycogen. But very quickly, you get rid of all the glycogen

00:53:31.860 that's in the liver. And so chronically, now you're running on gluconeogenesis. But glugon

00:53:36.760 stimulates both pathways.

00:53:38.560 And does it also drive hepatic glucose output? Or does it just drive the creation of glucose?

00:53:43.220 No, no, no. Absolute terms.

00:53:45.160 It increases hepatic glucose output as well as gluconeogenesis.

00:53:48.420 Yes. And that's an important reason why you have fasting hyperglycemia. So when you wake up in

00:53:55.400 the morning...

00:53:55.780 Yeah, and your blood sugar is 110 milligrams per deciliter.

00:53:58.020 That's the liver. And part of that is because your liver is intrinsically resistant to insulin.

00:54:03.140 Part of it is because the liver is now responding to the glucagon and producing an excess amount of

00:54:09.500 glucose, both through gluconeogenesis and through glycogenolysis. Although I would say the major

00:54:16.140 contributor is the gluconeogenic pathway. Now, that gluconeogenic pathway is also turned on because

00:54:22.980 fat is coming from the fat cell. Remember I told you the FFA is high.

00:54:26.980 Yes.

00:54:27.640 Glycerol is coming from the fat cell.

00:54:29.040 Yes.

00:54:29.660 We talked about some of the work that Jerry did. This is Jerry's work,

00:54:32.720 showing that glycerol coming from the fat cell is an important driver of gluconeogenesis.

00:54:38.000 And then hepatic fatty acyl-CoA levels are up because you have all this fat pouring in,

00:54:42.720 and that's activating the enzymes, pyruvate carboxylase, that are driving the gluconeogenic

00:54:48.160 pathway. So the metabolic, the actual pathways, I think, are very well worked out. So glugon,

00:54:54.380 alpha cell, bad guy.

00:54:55.720 And so is the alpha cell overproducing glucagon in this state?

00:54:59.440 Yes, absolutely. Absolutely. And this is really Roger Unger and Dallas's.

00:55:03.880 And again, why is it overproducing it? Why is it doing something that doesn't make any sense

00:55:08.700 in the context of what's happening?

00:55:10.520 In a certain way, this is also insulin resistance because hyperinsulinemia shuts down glucagon.

00:55:16.160 And we have very high fasting insulin levels in the diabetic. Okay. Now, what is it? What's the

00:55:22.640 sensing mechanism within? It's counterintuitive. Usually when things go wrong,

00:55:26.860 they get attenuated, right? Like it makes sense that the beta cell eventually fatigues because

00:55:32.260 that's an attenuation of doing something that it's getting tired of doing. The alpha cell

00:55:37.460 ramping up is a little less intuitive.

00:55:40.300 You're going to see it gets even worse when we talk about the kidney, which is number seven on the list.

00:55:44.140 All right. Let's go to number seven.

00:55:46.180 Okay. So people don't know I'm also board certified in nephrology. In the old days,

00:55:50.940 I trained as a micropuncturist. I used to sit with a microscope. I would draw my little pipettes

00:55:57.600 out the night before and put the little micropipette in the tubules and I collect tubular fluid.

00:56:03.380 What I was interested in, and this is when I was a renal fellow at the University of Pennsylvania,

00:56:08.240 I was interested in glucose and phosphate transport. And I published a series of,

00:56:12.520 I'd say they're pretty elegant papers in the JCI looking at how glucose and what regulated glucose

00:56:18.980 in phosphate transport. And I knew that there was a molecule called fluorosin that blocked glucose

00:56:24.700 transport in the kidney. And so I took this molecule called fluorosin and it blocks glucose

00:56:30.860 transporters. There are two transporters in the kidney, SGLT2 and SGLT1. SGLT2 takes back 90%

00:56:38.660 of the glucose. If it does its job, SGLT1 takes back the other 10%. And then in your eye,

00:56:46.520 even though we filter 180 grams of glucose per day, no glucose appears in the urine. But what I showed

00:56:52.900 is that fluorosin, it blocked both SGLT2 and SGLT1. It blocked glucose transport and it also blocked

00:57:01.040 phosphate transport. And I showed that glucose and phosphate transport were coupled. When I was

00:57:07.080 doing these studies, even though I was a nephrology fellow, I had previously done my endocrine

00:57:12.940 fellowship at the NIH in Baltimore City Hospitals. I had an interest in diabetes and I said, this would

00:57:18.300 be a great way to treat diabetes. So in the old days, we did things for science and I published

00:57:25.300 a series of four papers in the JCI. And I never even thought of, to be honest with you, of patenting

00:57:32.440 this. I have a significant other who said to me one day, she said, Ralph, you're one of the smartest

00:57:37.440 guys I ever met. And I said, yeah, I know that. And she said, you're probably the stupidest guy I ever

00:57:42.100 met. And I said, why? She said, you could have patented this drug. So I actually worked with

00:57:49.040 Bristol-Myers Squibb and then AstraZeneca. And that eventually led to that glyphosin coming to the

00:57:55.400 market. But what we showed, and this is human biopsy.

00:57:57.920 Which is the first SGLT2 inhibitor.

00:57:59.800 That's correct. Yes.

00:58:01.080 Brand name on that one?

00:58:03.060 Forsyget.

00:58:03.780 Forsyget, right. Canagaflozin was next?

00:58:06.600 Ampigliflozin, yeah. And then canagliflozin, ertogliflozin, we have a bunch of them.

00:58:10.540 They're all very good, basically do the same thing. But what we showed was the SGLT2 transporter

00:58:16.140 was markedly upregulated in the kidney.

00:58:18.920 Let's just wrap our heads around that. Again, this is so counterintuitive.

00:58:22.800 I know.

00:58:23.480 Okay, this does not make any sense. I want to just bring it back to people

00:58:27.660 listening so they understand what we're talking about here. The kidney is this massive

00:58:31.560 filtration, another remarkable organ. No offense to the nephrologist, not as remarkable as the

00:58:36.260 liver, but every bit as remarkable in terms of-

00:58:39.360 I think it's more remarkable than the liver, guys. So that's okay.

00:58:43.120 Everything that's floating through our plasma, our kidneys, by the way, they take 25% of our

00:58:48.420 cardiac output.

00:58:49.220 Huge, yes.

00:58:49.940 So it's massive. This organ weighs 2% of our weight and takes 25% of our cardiac output. Why?

00:58:56.320 Because we have to take everything that is in our circulation and dump it out. And then the kidney

00:59:02.400 has to selectively bring back in what's normal. This was explained to me, I still remember in medical

00:59:06.960 school, as a brilliant trick of evolution. Evolution was never going to be able to predict

00:59:13.120 every toxic thing we might encounter and therefore teaching the kidney how to spot toxic things and

00:59:19.440 get rid of them would have been a failed mission. Rather, it was better to teach the kidney what

00:59:24.780 was absolutely necessary and to discard all other things. So-

00:59:28.940 Pretty simple way.

00:59:29.760 Yep. So it's the take everything out of your drawer and dump it out and only bring back the socks and

00:59:35.500 underwear that you need. So glucose, potassium, sodium, you name it, chloride, phosphate,

00:59:42.180 all of these things get dumped along with everything else. And then it knows I need this

00:59:47.040 much glucose. I need this much sodium. I need this much potassium. So SGLT2 does the lion's share of

00:59:53.380 this.

00:59:53.780 It takes back 90% of the glucose. And now, so here's a diabetic with a very high glucose.

01:00:00.220 Right. So my point was SGLT2, if it had a brain, would say, oh, you have too much glucose.

01:00:06.820 Turn off.

01:00:07.380 Turn it off. How about we just stop reabsorbing all this glucose? But you said it's the opposite.

01:00:11.820 I told you earlier, it's going to get worse.

01:00:14.080 It ramps up SGLT2.

01:00:16.500 So as a doctor, I want the kidney to dump the glucose out in the urine.

01:00:20.480 Yeah.

01:00:20.840 But what is the kidney doing? It's doing the opposite. It's holding on to the glucose.

01:00:26.220 Even as a renal fellow, it became clear to me, this is such a simple way to treat diabetes.

01:00:32.460 And the fact is, it's so simple, no one thought about it. The only dumb thing that I did was I

01:00:36.780 didn't patent it, which I should have done. I'd probably never have to write another NIH grant for the

01:00:40.800 rest of my life. And then we went on to show, and in fact, this is the first definitive proof of the

01:00:46.940 glucotoxicity hypothesis. So we did all of these studies initially in animals, and this was all

01:00:53.860 published in the JCI. And Luciano Rossetti is one of the fellows at this time. Actually, Jerry Shulman

01:00:59.680 was a fellow on the papers as well. And what we showed was that you could take different types of

01:01:05.920 diabetic animal models, and you could show that they're reabsorbing excessive amounts of glucose.

01:01:11.760 And then if I treated them with fluorosin, because that's what was available, they simply

01:01:16.580 peed the glucose out in the urine. And now, all of a sudden, their beta cells started functioning

01:01:21.400 normally. Muscle insulin sensitivity improved. So, of course, that's wonderful if you're a mouse

01:01:27.340 or a rat. So we said, well, what about humans? And so the original studies actually were done.

01:01:33.560 There's kind of an interesting story behind this, but the initial studies were done with

01:01:38.480 dapogliflozin. And we showed with just 14 days of treatment with dapogliflozin, we markedly lowered

01:01:45.240 the fasting and postprandial glucose. We improved insulin sensitivity by 35%, and we made a major

01:01:52.240 improvement in beta cell function. Now, the beauty of this, SGLT2 inhibitors are only in the kidney.

01:01:59.540 They're not in your muscle. They're not in your beta cell. And the only thing that the SGLT2

01:02:04.720 inhibitors do makes you put glucose out in the urine. The only change in the plasma was the

01:02:09.680 glucose came down. And now insulin sensitivity improved, and muscle and beta cell function

01:02:14.640 improved. And this was the first, now in humans, even though the original studies were done in

01:02:19.560 animals, first studies to show an improvement in the reality of glucotoxicity. What was interesting

01:02:27.000 is that when we started to work on developing this with BMS and AstraZeneca, the company decided,

01:02:33.500 well, we should get some nephrologists in to see about this story. They said, look, if you listen

01:02:38.860 to what Dr. DeFranzo says, this will be a disaster. And they said, why? Because if you put glucose in the

01:02:44.440 urine, it will glycosylate the proteins, then you'll cause kidney damage. And they actually held up the

01:02:51.560 development of the SGLT2 inhibitors. And the way we finally convinced them to go ahead was that

01:02:57.500 there's a disease called familial renal glucosuria. From day one of their life, they're bringing out

01:03:02.880 tremendous amounts of glucose. They have perfectly normal kidney function.

01:03:06.640 How many grams of glucose can be differentially or extra secreted, basically, in the presence of an

01:03:14.000 SGLT2 inhibitor today? It kind of depends on what the level of your GFR is. But it could be anywhere

01:03:19.620 from 40 to 60 grams up to 120 grams of glucose. And the higher would be in somebody with a higher

01:03:25.980 gradient? Yeah, the higher the glucose. The higher the, yeah. Yes, because you filter more glucose,

01:03:30.580 then there's more glucose to be blocked at the level of the kidney. And these drugs are very,

01:03:36.260 very good. Now, I actually, in developing these drugs, as I said, I'm also a nephrologist.

01:03:42.640 Based on the Barry Brenner hypothesis, I predicted these drugs would save your kidneys,

01:03:48.100 according to the Brenner hypothesis. And that's all turned out to be correct. These drugs are

01:03:52.720 great for the kidney. What I never, ever envisioned is that these drugs were going to save your heart.

01:03:57.740 Good for the heart, yeah. I want to come back to that because I'm making notes of other things I

01:04:01.280 want to come back to. And so I want to come back to, just so you can hear me say it now and we

01:04:05.900 remember, I want to come back to combined inhibitors, the SGLT2, SGLT1 inhibitor. I think it was a new

01:04:11.880 drug. Sodoglyphlosia. Yeah, it does both. We'll just touch on that. And then I want to also come

01:04:15.500 back to the broader gyroprotective nature of the SGLT2s as documented by the ITP in mice and then also

01:04:23.020 in the human studies for cardioprotection. But before we do that- We need to finish the

01:04:26.400 homoshock day. Exactly. Let's go back to number eight.

01:04:28.580 The brain. So the brain plays a role in a somewhat indirect way. So every day you have your breakfast,

01:04:36.340 your lunch. I actually eat only once a day, but at some point you eat a meal. And at some time during the

01:04:41.240 meal, you'll say, okay, I'm hungry. I stopped eating. Why'd you ever think? Why does that happen?

01:04:46.140 Well, because there are certain hormones that are released or inhibited that tell you, okay,

01:04:50.420 you're satiated. Stop eating. Well, one of the very important ones is GLP1. That same thing that's

01:04:55.820 increasing insulin secretion. Your brain has become very resistant to GLP1. When you eat a meal,

01:05:02.000 amylin comes out. It comes out in a one-to-one ratio with insulin. Your brain has become

01:05:06.060 resistant to amylin. Your brain is resistant to leptin. So there are a lot of these interrectic

01:05:11.780 molecules that your brain has become resistant to. And these molecules, it's another area of

01:05:19.760 interest of mine. These, they work in the hedonic areas in the brain. So in the putamen,

01:05:25.280 the prefrontal cortex, and they tell you to stop eating. And unfortunately, and this is the big

01:05:31.460 unknown is what's going on in the brain. The neurocircuitry is clearly distorted. Not only

01:05:36.960 is the neurocircuitry distorted, one of the big things that we are interested in, Dr. Peter Fox and

01:05:42.520 myself at UT, is if you look at the gray matter in these areas, in the areas that are critically

01:05:48.680 important in regulating your appetite, there's shrinkage of the gray matter area, okay? And in

01:05:54.320 these areas, if you do an insulin clamp, the brain is insensitive to insulin in your eye. In obese

01:06:00.740 people, these areas in the brain where there's abnormal, marked increase in glucose uptake.

01:06:07.160 Incredible finding. Who would have thought? I'm sorry. You're saying that these are the few areas

01:06:12.860 in my brain and your brain that are actually default insulin insensitive. Yes. Don't take up glucose.

01:06:19.620 Correct. If I do an insulin clamp. So what is their fuel source? Lactate? Well,

01:06:24.380 in response to insulin, they don't take up more glucose. Oh, okay. I'm sorry. Got it.

01:06:28.280 Because remember, this is from the Cahill studies. As long as your glucose is about 50,

01:06:32.900 your brain is happy. So this is actually in the evolution of the human being, this is phenomenal.

01:06:38.720 Because in the old days, you may not eat. You may slaughter one of these beasts.

01:06:43.360 Yeah. You're not eating for days. You're not eating for days. So your glucose would drop. So if your

01:06:47.320 normal fasting was 80, if it dropped to 40, you're okay because your brain saturated at 40. If you got

01:06:53.100 below 40, you're in trouble. So you have a big buffer here. But now if I infuse insulin and your

01:06:58.980 glucose is 80, your brain doesn't take up more glucose. It's, quote, insulin insensitive in a

01:07:03.820 certain way. Now, of course, if you take people with mild cognitive impairment, there've been some

01:07:09.400 experiments that actually suggest in these people, insulin infusion can transiently improve glucose

01:07:14.500 uptake. But presumably, that's because they're insufficiently getting glucose in the disease state.

01:07:19.500 Yes. This has been postulated. This also suggests that there's brain insulin resistance,

01:07:25.560 which is, I'd say, an interesting concept and may play some role in this neurocognitive

01:07:30.720 dysfunction, Alzheimer's, whole different story that's in evolution. But to come back to the

01:07:36.160 ominous octet now, if you overeat, what happens? You gain weight. And when you gain weight, you become

01:07:41.660 insulin resistant, severely insulin resistant. That's lipotoxicity. And we've done studies in

01:07:48.440 both directions. I can put an IV and I can infuse an emulsion of free fatty acids. And I can show

01:07:56.420 within two to four hours, I induced severe insulin resistance in the muscle, in the liver, and I

01:08:03.360 markedly impaired beta cell function. And then we don't have this drug in the United States, but there's

01:08:09.500 a drug that's available in Europe, and I have an IND to use it. It's called the Cipamox. It inhibits

01:08:14.760 lipolysis. It's like SGLT2 inhibitor. The only thing to do is block glucose reabsorption in the

01:08:20.720 kidney. A Cipamox, all it does is do block lipolysis. It lowers your FFA level. And we've done this.

01:08:27.400 Does it result in any meaningful clinical increase in adiposity, or is it so subtle that you don't

01:08:32.780 notice it? Over 12 days, no change in adiposity, huge improvement in insulin sensitivity and muscle.

01:08:38.880 Why is it not approved in the U.S.?

01:08:40.760 I don't know the company that developed it in Europe ever tried to get it approved in the U.S.

01:08:46.480 It's, I would say, modestly effective in lowering triglycerides. And we have phenofibrates,

01:08:53.440 which are much more effective. So that may be the reason...

01:08:56.840 But the triglyceride and the FFA are not the same thing.

01:08:59.100 No. But that's the reason why it's approved in Europe. But if you lower the FFA, that's the

01:09:05.480 precursor for triglyceride synthesis. So it has an effect to lower the triglycerides.

01:09:10.760 But the key thing is if you lower the FFA, and we did this for 12 days, we did it in both

01:09:15.700 obese people and in diabetic. You markedly improve insulin sensitivity in the muscle. If using

01:09:22.040 MRI, you can measure muscle fat. It goes down dramatically and correlates with the improvement

01:09:26.980 in insulin sensitivity. We also measured ATP generation because there's this issue is...

01:09:33.500 There's clearly mitochondrial dysfunction if you're a diabetic. That's unequivocal.

01:09:37.320 The controversy is, is the mitochondrial dysfunction causing the insulin resistance or is the insulin

01:09:44.940 resistance causing the mitochondrial dysfunction? So in this study that we did, when we lowered the

01:09:51.680 FFA and lowered the muscle lipid content, we saw about a 50% improvement in ATP generation,

01:09:59.720 mitochondrial ATP generation. So at least this says that part of the mitochondrial dysfunction

01:10:05.700 is secondary to the lipotoxicity and insulin resistance. But this still remains, I would

01:10:12.200 say, a controversial topic. Clearly there's mitochondrial dysfunction. If you can improve

01:10:17.840 it, that's going to improve insulin sensitivity.

01:10:20.420 Is there anything that improves mitochondrial function more than aerobic exercise training?

01:10:25.240 P-oglitazone. The drug that I can't get people to use, which is a phenomenon. By activating PPAR

01:10:32.620 gamma, it does a lot of good things. And one of the important things that it does, it has a huge

01:10:38.100 effect to improve mitochondrial dysfunction. And it has direct effects. It works directly through

01:10:44.060 PPAR gamma to do this. And it also binds directly to the mitochondrial pyruvate carrier. And that influences

01:10:51.500 flux through the mitochondrial chain. Why don't people use this drug today?

01:10:57.680 Huge misconceptions. I guess we'll talk about therapy.

01:11:01.240 We'll come back to it.

01:11:02.660 As part of my triple therapy regimen, I use a GLP-1 receptor agonist. I use P-oglitazone.

01:11:09.960 And I use an SGLT2 inhibitor. There's a fourth good drug, and that's metformin. And you might ask,

01:11:16.560 well, why is metformin number four on my list of good drugs since I single-handedly brought metformin

01:11:22.120 to the United States in 1995? No other endocrinologist involved in this. 1995, metformin was a

01:11:30.060 revolutionary drug. Why? We had insulin and sulfonylureas. So now we had a drug that really could work.

01:11:36.600 It's still a very good drug. And of course, it's very cheap. It's $5 a month in the state of Texas.

01:11:41.860 But we have much better drugs. P-oglitazone causes weight gain. Now, here's the problem.

01:11:47.560 It'll become very obvious. We talk about these paradoxes. The more weight gain, the greater the

01:11:53.420 drop in A1C. The more weight gain, the greater the improvement in insulin sensitivity.

01:11:58.160 And is it fat gain specifically?

01:12:00.200 No. I'll come back to that in a second. It is fat weight gain, and I also believe muscle weight gain.

01:12:05.700 The more weight gain, the greater the improvement in beta cell function. The more weight gain,

01:12:09.420 the greater the drop in blood pressure. The more weight you gain, the greater the drop in

01:12:13.520 triglycerides. The more weight you gain, the greater the rise in HDL cholesterol. Sounds like

01:12:19.160 terrible drug. So here's another one of those paradoxes. Why? We know if you overeat and gain

01:12:24.680 weight, that's a disaster. But with P-oglitazone, the more weight you gain, everything gets better.

01:12:29.760 What P-oglitazone does is it shifts weight around in the body. In my opinion, it's the best drug for

01:12:35.740 treating NASH. No drug is going to beat P-oglitazone. The pharmaceutical companies,

01:12:40.200 if you had to go up against P-oglitazone, all these NASH drugs, I don't believe you can beat

01:12:44.580 P-oglitazone.

01:12:45.000 What's the brand name for P-oglitazone?

01:12:47.040 Actos. As I said, there's this paradox. So why do you gain weight? P-oglitazone,

01:12:53.400 it redistributes fat in the body. It gets it out of the muscle, puts it in subcutaneous tissue.

01:12:58.440 Gets it out of the liver, puts it in subcutaneous tissue. Gets it out of your beta cells,

01:13:02.340 put it in subcutaneous tissue. That's not going to make you gain weight. The richest density of

01:13:07.340 P-par gamma receptors in the hypothalamus. So when I activate these P-par gamma receptors in the

01:13:12.780 hypothalamus, you eat, okay? It makes you hungry. That's got nothing to do with redistributing the

01:13:18.900 fat in the body, except they parallel each other in association. And so you see the weight gain and

01:13:25.980 people say, oh, that's bad. But what's really doing the thing is this recycling and moving the fat around.

01:13:32.340 The other negative thing about P-oglitazone is it causes fluid retention. So people have

01:13:38.080 associated fluid retention with heart failure. Now, why do you get fluid retention? Again,

01:13:43.860 people do not understand. P-oglitazone, the only thing, the only drug that is a true insulin

01:13:51.240 sensitizer is P-oglitazone. Metformin is not a true insulin sensitizer. That's a total misconception.

01:13:55.860 P-oglitazone, that insulin signaling defect that I told you about, P-oglitazone corrects that defect.

01:14:03.500 It's incredible.

01:14:04.540 We kind of glossed over this. We're going to spare people the details, but it's probably worth just

01:14:08.660 reminding people. Insulin binds to the insulin receptor. That's outside the cell. That's a

01:14:14.360 kinase receptor, correct?

01:14:15.780 There are three tyrosine molecules, and they have to be phosphorylated. These are studies done,

01:14:20.920 Ron Kahn and other people in Boston. You mutate one of those tyrosines, you become a little insulin

01:14:25.640 resistant. You mutate two of them, you become moderately insulin resistant. You mutate three

01:14:30.440 of them, you're severely insulin resistant. Insulin binds to the receptor. Okay, that happens normally

01:14:35.840 in diabetics. We showed there's no problem there. Then IRS-1, insulin receptor substrate-1.

01:14:41.680 Which is inside the cell, comes up.

01:14:44.520 Yes. It interacts with the insulin receptor, and it gets phosphorylated on the same three

01:14:50.220 tyrosine molecules. Then you activate PI3 kinase, AKT. We could add some more molecules in here,

01:14:57.680 but this is the insulin signaling pathway. That's the pathway that the earliest defect that you can

01:15:03.500 show in diabetics is in that pathway.

01:15:05.340 And if I recall, isn't this where Jerry argued that the intramyacellular lipid was creating the

01:15:14.700 defect in that pathway? The accumulation of intramyacellular lipid?

01:15:18.260 So what Jerry has shown very elegantly is that there are certain lipids, DGAT, and it's a specific

01:15:24.520 DGAT. There are like several types of DGAT molecules, which has confused things. So he's shown

01:15:30.420 there's a specific one of the DGATs that activates these atypical PKC molecules, and that serine

01:15:36.940 phosphorylates the insulin receptor. When you serine phosphorylate the molecules in that pathway,

01:15:42.880 it inactivates them, okay? And so he's done these very nice elegant studies, both in peripheral muscle

01:15:48.320 and in the liver, showing that this plays a very, very important role in the insulin resistance.

01:15:53.760 This is part of the lipotoxicity. I don't believe that this is the genetic basis, the genetic

01:15:59.780 etiology. You get fat and you start putting fat everywhere. This is very important, critically

01:16:04.480 important. That was when he gave his Banting lecture, and I might say I am delighted that I

01:16:09.800 got to write his letter of nomination for the Banting lecture. He was incredibly deserving. He's

01:16:14.900 done phenomenal work in this area. But that was his Banting lecture, and you're right. Very,

01:16:20.100 very, very, very important mechanism of insulin resistance.

01:16:24.720 And so given that that's both a very important and very common pathway towards insulin resistance,

01:16:31.120 bringing it back to PPAR gamma, PPAR gamma is part of the pathway. It's part of the IRS-1,

01:16:38.180 PPAR gamma, PI3K, GLUT4, bring the glucose in the cell. In other words, if people don't want to get

01:16:45.520 mired down in this, which is totally understandable, insulin hits a receptor. That receptor kicks off a

01:16:51.260 cascade that ultimately results in a little tube, like a little straw that goes into the cell surface

01:16:57.040 that allows glucose to freely flow in, in its gradient. Remember, that same pathway also activates

01:17:03.820 nitric oxide synthase. That's right. Generates nitric oxide. And that's why we see in patients with

01:17:09.080 insulin resistance, even if glucose is controlled, cardiovascular disease is still up.

01:17:15.140 A very important.

01:17:16.160 Yeah, very important point. So back to Actos.

01:17:20.080 So what does it do? It activates that signaling pathway. You generate nitric oxide. Now you vasodilate.

01:17:27.980 That's why the blood pressure drops. When you vasodilate, so I'm a nephrologist. I understand this

01:17:32.980 very clearly. Anytime you end up refuse the kidney, you hold on to salt and water. You become an edematous.

01:17:39.940 And so people associate fluid retention and edema with heart failure. So we did the definitive

01:17:46.920 studies published in Diabetes Care in 2017. People just don't read. So we took people who had diabetes

01:17:53.560 and we treated them with pioglitazone. And then using NMR, very, very sophisticated techniques,

01:17:59.820 what we showed is pioglitazone markedly improved myocardial blood flow. Now, these numbers are

01:18:06.220 going to blow your mind away. Myocardial insulin sensitivity with PET and fluorodeoxyglucose

01:18:11.960 improved by 75%. Your heart, we showed this before, is severely insulin resistant. I came pretty damn

01:18:19.980 close to normalize insulin sensitivity in your heart. Now, since we're doing the insulin clamp with

01:18:24.400 tridioglucose... You can track it.

01:18:26.180 74% improvement in skeletal muscle insulin sensitivity.

01:18:29.440 It's the same.

01:18:30.120 Exactly the same. If you look at ejection fraction, it went up by 5% to 10%. Not down. It went up.

01:18:38.320 If you look at every measure of diastolic dysfunction, E over A, E over E prime, LV,

01:18:45.260 peak filling pressures, etc. Cardiology people understand this. The point is, whether you're

01:18:49.880 looking at systolic function or diastolic function, it all got better.

01:18:53.760 It's a victim of maybe not so nuanced thinking about the drug. Now, the critic would push back

01:19:00.520 and say, okay, Ralph, but don't we have better drugs? Like, I mean...

01:19:03.640 No drug that corrects insulin resistance. Metformin is not an insulin sensitizer. And people keep going

01:19:09.080 back to this. I brought metformin to the U.S. in 1995. I know this. I did all the mechanism of

01:19:15.060 action studies. What we showed was the insulin clamp. The drug absolutely does not improve insulin

01:19:21.060 sensitivity. So let's talk about metformin. Everybody wants to know if metformin is

01:19:24.600 gyroprotective. But let's just remind people, metformin inhibits complex one of the electron

01:19:29.280 transport chain. Is that a given?

01:19:31.440 Yes. I'd say this is still controversial. In high doses, for sure, yes. And the kind of doses you see

01:19:38.300 with giving metformin, I would say somewhat equivocal.

01:19:41.940 Is the belief that metformin's efficacy in diabetes is through reducing hepatic glucose output?

01:19:49.000 That is 100% true.

01:19:50.320 Okay. And what's the mechanism by which it reduces hepatic glucose output?

01:19:53.520 Inhibiting the mitochondrial chain and inhibiting gluconeogenesis. Well, for sure,

01:19:58.100 it inhibits gluconeogenesis. Metformin gets into cells through the organic cation transporter.

01:20:04.300 The organic cation ion transporter doesn't exist in muscle. It can't possibly be an insulin

01:20:10.260 sensitizer in muscle. You're asking the drug to do something that's impossible.

01:20:14.600 Does it get into muscle mitochondria?

01:20:16.520 No, it doesn't get into muscle at all.

01:20:18.100 Why does lactate go up when people are taking metformin?

01:20:21.460 Level of the liver. It's interfering with aerobic metabolism. There's a block.

01:20:26.900 This is very important. I have erroneously always believed, so I'm really happy to be corrected.

01:20:32.480 I love being proved wrong. I have always believed that the reason we saw an increase in fasting

01:20:40.040 lactate, even in healthy people, if they took metformin was because of the inhibition of the

01:20:47.900 ECT in skeletal muscle.

01:20:49.620 No, no.

01:20:49.960 And you're saying, Peter, that's not possible. It can't get into skeletal muscle?

01:20:54.180 Absolutely not. A single molecule in the world of metformin has ever gotten into

01:20:59.040 any skeletal muscle anywhere.

01:21:01.200 And tell me again why. What's the transporter?

01:21:03.080 The organic cation transporter. That's the transporter by which metformin enters cells.

01:21:09.840 It does not exist in skeletal muscle. It does not exist in cardiac muscle. So metformin cannot

01:21:16.420 get into these tissues. It's a huge, major misconception. It can, if you have very, very

01:21:24.100 high doses that can occur when you have very low GFR because metformin is excreted by the kidney,

01:21:29.980 if the metformin levels build up, you can get lactic acid doses. That's a very, very rare

01:21:35.060 complication. There's not a reason why you shouldn't be using the metformin. And I'm not

01:21:39.920 saying that metformin is not a good drug. It is a good drug. I don't think it's as good as the

01:21:44.380 other three drugs we talked about, but yes, it does at high doses increase the lactate level,

01:21:50.740 all in effect on the liver. And the old drug that caused all the problem was fenformin by guanide as

01:21:57.280 well, but it had a powerful effect. Yeah. Fenformin was much more powerful.

01:22:00.880 Yes. And when you say high dose, I mean, is two grams a day of metformin?

01:22:04.520 No, no, no, no. That's the normal dose.

01:22:06.120 That's the normal dose.

01:22:07.300 Okay. So metformin has the following going for it. It's free.

01:22:12.740 Yes. It's basically free.

01:22:13.900 Yeah. It's free.

01:22:14.320 Absolutely.

01:22:15.000 And it does a pretty good job at reducing hepatic glucose output.

01:22:19.320 Yeah.

01:22:19.480 Yeah. And it has no myotoxicity, frankly, any toxicity.

01:22:24.200 GI.

01:22:24.600 Yeah. The GI, but you can usually overcome that with a slow ramp up.

01:22:27.880 Yeah. See, this is the reason why some people thought it's an insulin sensitizer.

01:22:31.900 15 to 20% of people have significant GI side effects and they lose weight. And if you look

01:22:37.620 at the studies on average, there's about a three kilogram weight loss with metformin. And when you

01:22:44.040 lose weight, you can improve insulin sensitivity. So I think this is what's confused some of the old

01:22:49.960 literature to make people think that metformin was an insulin sensitizer. But when we developed

01:22:55.000 metformin and I did all of the work that went to the FDA, if you look at the New England Journal

01:23:00.580 of Medicine, article 1995, there are only two names on the paper, myself and a PhD oncology lady who was

01:23:09.700 the person from Leapha Pharmaceuticals. We did insulin clamps, many of them. We never could

01:23:15.580 show metformin to improve insulin sensitivity using the gold standard with radioisotopes.

01:23:20.780 Do you think many people, I feel like I'm asking you this question a lot and it's getting a little

01:23:24.940 old, but do you get the sense that most people are still thinking what I think?

01:23:28.880 Yes.

01:23:29.520 Metformin gets into the muscle.

01:23:30.900 Yes.

01:23:31.340 Metformin's an insulin sensitizer.

01:23:33.160 Absolutely.

01:23:33.740 And it's an insulin sensitizer by getting into the muscle and inhibiting complex one.

01:23:37.300 Absolutely. People have done PET studies. So you can label metformin and you give it. And then

01:23:42.660 where do you see? It's all accumulating in the liver in the first three, four, five,

01:23:47.540 10 minutes. And then what happens? You start to see it accumulating in the kidney. Why? Because

01:23:52.580 that's where it's excreted. And then wait another five or 10 minutes, you see the bladder. And that's

01:23:57.280 the only place where you see metformin. You never see it in the muscle. And that's even more

01:24:02.480 graphic demonstration that metformin is not getting into muscle. And it is definitely not

01:24:07.600 an insulin sensitizer.

01:24:08.720 Is there a downside to using metformin in combination with the other three drugs?

01:24:13.600 No. The classic study, which we'll talk about, which to me should change the entire approach to

01:24:18.800 treating diabetes, it's called the EDICS study. And in the EDICS study, what we did is we used triple

01:24:26.060 therapy right from the beginning. And my point of the Banting lecture, the ominous octet, if you have

01:24:32.520 eight problems, there I'm sure are going to be more to be found than I can give you a few more if you

01:24:36.940 want. But if you have eight problems, why in the world do you think one drug is going to correct

01:24:41.180 eight problems? It ain't going to happen in our lifetime. So the point was you need to use drugs in

01:24:46.560 combination. We said we're going to use what we think are the best drugs at the time. So we started

01:24:51.920 with metformin with exenotide, an old time GLP-1. This is not the kingpin.

01:24:58.180 This is the pre-liraglutide.

01:25:00.080 Yeah, exactly. Because that's what was available.

01:25:02.240 That drug was useless, wasn't it?

01:25:03.960 No, it's a good drug. Sure, it's not semaglutide or trezepatide, but you have to start somewhere,

01:25:09.140 right?

01:25:09.460 Yeah. Let's pay it its dues as being the Gen 1 OG version of that drug, without which we might not

01:25:14.400 have, we wouldn't have semaglutide or trezepatide.

01:25:17.120 Yes. It's kind of an old timer. In pioglitazone, that was the triple therapy.

01:25:21.080 And then we said, every diabetic patient, there are 315 people in this study. They're having insulin

01:25:27.320 clamps, hyperglycemic clamps, muscle biopsies. No one in the world can do this study. 315 people,

01:25:32.320 followed for six years. So we said, this is what we believe is the appropriate therapy.

01:25:38.180 Then we said, we'll use the ADA approach. The ADA approach is you start on metformin. And when you

01:25:43.660 fail, even not explicitly said, the next drug that's used is sulfonylureas. And then the third drug

01:25:50.500 that's added is insulin. And we said that the goal of therapy was an A1C of six and a half. Okay. And

01:25:58.920 that if your A1C rose above six and a half, either on R triple therapy or on the stepwise treat to fail

01:26:07.740 approach that the ADA says. ADA says, start metformin. You fail. You add sulfonylurea. You

01:26:13.160 fail. You add insulin. You titrate the insulin, basal insulin up to 60 units. And we said, 60 units is

01:26:19.880 really where we'll cap it. Yeah. You're already at 2x physiologic. Yeah. Now you have to split the

01:26:25.220 dose of insulin. You have to be adding rapid acting insulin. I think this is quite reasonable. Six years

01:26:30.840 later, 29% of the people with the ADA approach have failed. Their A1C is above six and a half. Six years

01:26:39.480 later with our approach, 70% of the people have an A1C. It's less than six and a half. Why? Insulin clamp.

01:26:47.920 Huge improvement with our therapy. Okay. This is the EDEK study. The three-year data published, the six-year

01:26:53.280 data we're writing it up. How much improvement in insulin sensitivity with the ADA approach? Zero.

01:26:57.940 Beta cell function. You have almost a normal beta cell. Ralph, why the disconnect between what you're

01:27:03.580 seeing in the EDEK study and what the ADA is promoting? You have to ask the ADA. What's their

01:27:09.200 answer? If I'm a patient or if I'm a physician who's treating these patients and I'm saying, guys,

01:27:14.360 I'm confused. I'm looking at the literature. I'm seeing this. I'm looking at your... And by the way,

01:27:18.040 I see this with the AHA and cardiovascular guidance, so I'm not singling out you. But is this simply a

01:27:23.820 question of the pace at which medicine moves is so glacial? That's part of it. Plus, remember,

01:27:29.680 if to do 315 people, follow them for 16 years and do all the stuff we did, it's unequivocal.

01:27:37.160 And why has there not been political pressure? Because the cost of insulin is enormous.

01:27:41.540 Your approach is going to be less expensive.

01:27:44.280 They finally said in 2022, there's a state, the ADA approach is not based on pathophysiology.

01:27:50.260 I view myself as a scientist as well as a clinician. As a good clinician, I've taken care

01:27:56.080 of hundreds of thousands of patients and at 850 publications. I do clinical research. I work in

01:28:02.160 people. When I do an insulin clamp study and I see an improvement in insulin sensitivity,

01:28:07.480 I do a hyperglycemic clamp and I see in 315 people your base self-function. I don't need 5,000 people.

01:28:14.040 I can't do this study in 5,000 people. No one can do this study. But the tools that we're

01:28:19.900 using are so powerful. Look, if I normalize your insulin sensitivity and I give you a normal beta

01:28:25.040 cell and your A1C is less than 6 and a half, well, it's half of the 315 people. Why do you not think

01:28:31.280 that's the best therapy? And now on the other side, I have this metformin SU insulin and 71%

01:28:38.320 of the people have failed. There's zero improvement in insulin sensitivity, zero improvement in beta

01:28:42.900 cell function. Why do you think that's such a good regimen? Now, above and beyond all that,

01:28:47.720 I didn't do this study. This is the GRADE study, G-R-A-D-E. It's sponsored by the National

01:28:54.420 Institutes of Health. And what the GRADE study said, and I have to say this is the third study

01:28:59.660 that's shown what I'm going to tell you. Dr. Robert Turner's United Kingdom Prospective Diabetes

01:29:04.340 Study showed this in 1990. Stephen Cairn showed this in the ADOPT study in year 2005. And now we have

01:29:12.440 the GRADE study, 2020. I call this the 15-year revelation. We saw what didn't work, 1990. Oh,

01:29:19.480 Stephen Cairn did it again. Oh, it didn't work in 2005. And now 2020, NIH did it. You know what?

01:29:26.620 I'll show the same thing. And this was a sequential approach.

01:29:30.040 You had to have failed on metformin to get into the study.

01:29:32.980 Okay. So you failed in metformin, then you enter the study, then we go single agent.

01:29:36.680 They want to know what's the best next drug to add to metformin. I can add a sulfonylurea. A1C went

01:29:42.860 down in year one, up straight. Tell folks how a sulfonylurea works.

01:29:47.820 Sulfonylureas are old-time drugs. They bind to the sulfonylurea receptor on the beta cell and they

01:29:52.880 kick out insulin. And they're very good drugs in the first year. And then they burn out the pancreas.

01:29:57.640 Well, they stop working. Yeah. I mean, basically,

01:30:00.180 they kick the can down the road without addressing the pathophysiology.

01:30:03.360 I like that way. Other drug, DPP-4 inhibitor.

01:30:06.840 Tell people how those work.

01:30:08.060 Yep. So a DPP-4 inhibitor increases your GLP-1 and your GIP level endogenously. It makes your

01:30:15.660 gastrointestinal cells, the K and the L cells that secrete the GLP-1 and GIP, makes them make more

01:30:21.820 GLP-1 and GIP. But it doesn't increase the GLP-1 and GIP enough to really give you a knockout punch.

01:30:27.900 I give you an injection, you all, people are out there, Monjaro or Semaglutide,

01:30:33.220 that's the knockout punch. When I give you the DPP-4 inhibitors, they do increase GLP-1 and GIP a

01:30:39.380 little bit, but not powerful enough to give you a long-lasting effect. So first year, A1C comes down,

01:30:45.320 A1C goes up. Third drug, this was very surprising to me. This was Liraglutide. This is one of the

01:30:52.040 earlier GLP-1 receptor agonists. I thought that was going to work the best. It failed. It worked

01:30:58.040 in the first year and then failed. And then the fourth drug was insulin. And the docs just didn't

01:31:04.100 titrate the insulin enough. So A1C down and then they failed. So five years later, all four of those

01:31:10.580 regimens added to metformin failed. Triple therapy, Exendatide, an old-time GLP-1,

01:31:16.940 P-oglitazone, which people don't appreciate, the only true insulin sensitizer, and metformin,

01:31:22.220 six years later, 70% of the people have an A1C less than seven.

01:31:27.560 And let's just go back. Metformin is free. The Gen 1...

01:31:31.280 Exendatide, basically free.

01:31:32.820 Is basically free now.

01:31:33.940 P-oglitazone is $5 a month.

01:31:35.780 Okay. So we have three free drugs that work better.

01:31:38.780 Correct.

01:31:39.160 Now it's interesting, when you talk about today's triple therapy, which is way more efficacious,

01:31:43.580 two of those three drugs are very expensive.

01:31:45.720 Yes.

01:31:46.260 The SGLT2 inhibitors are very expensive. In the modern day, Gen 3, Gen 4, and soon we'll

01:31:51.600 have a Gen 5, GLP-1, they're very pricey.

01:31:54.580 $1,000 a month. Now, are they great drugs? Of course.

01:31:58.480 I guess the question is, do you need to be on those drugs if your old version of triple

01:32:04.780 therapy...

01:32:05.660 Our old version is incredibly effective. The problem is you can't get people to use P-oglitazone.

01:32:11.440 And the reason is patients are frustrated with the fact that they're retaining water?

01:32:15.720 No. Gain weight.

01:32:16.760 How much weight do they gain, typically? How many kilos?

01:32:18.700 Depends on the dose. I don't go to the 45 milligram dose. So at the end of the year,

01:32:23.780 they may gain two or two and a half kilos at the 15 and 30 milligram dose. Okay? But their A1C

01:32:29.280 is controlled.

01:32:29.880 If you give PO plus a modern day GLP-1, don't you offset the weight gain?

01:32:38.200 Oh, you lose all the weight you lose with the GLP-1 receptor.

01:32:41.320 So if a patient is willing to go down the path of a modern day GLP-1...

01:32:45.780 That's my treatment.

01:32:46.340 ...doesn't that completely eliminate?

01:32:47.920 Absolutely. And it also gets rid of the edema. And believe me, their A1Cs are down in the

01:32:53.100 normal range. Let me tell you this first thing about P-oglitazone and the proactive. I'll

01:32:57.480 come back. So in the proactive study, this was done a long time ago. You have to show cardiovascular

01:33:02.580 safety. 5,238 people to get into the study, you had to have an MI stroke or something bad.

01:33:08.880 Half people on P-oglitazone, half the people on placebo. Okay? And the MACE endpoint, major adverse

01:33:14.840 cardiovascular events, which is non-fatal MI, non-fatal stroke, cardiovascular mortality,

01:33:20.320 you have to show the benefit to get approval by the FDA. The MACE endpoint was positive. And so

01:33:25.400 when I talk to cardiologists, I like to say, what was the one thing in the P-oglitazone that predicted

01:33:32.680 that you would not die? They don't know. You know what the one thing that predicted that you wouldn't

01:33:37.860 die? Weight gain. So I jokingly say, look, you can either be a little fat and alive,

01:33:44.360 or you can be lean and dead. Which one you're going to pick? I think I go for being a little

01:33:48.400 bit chubby. But now that's not even a necessary comparison. You don't even need to make that

01:33:53.800 trade-off with a modern day GLP-1 agonist. Yes. And we've done this and we've published this.

01:33:58.300 If you tied my hands behind my back and said, Ralph, you can only pick one drug. I would pick

01:34:03.660 one of the newer GLP-1s. They're incredible drugs, but that's not what I'm going to do.

01:34:08.260 Even for a lean diabetic?

01:34:09.460 A little bit different story, but the answer is basically yes. Let me narrow that down a little

01:34:14.480 bit. If I had to pick two drugs, I would pick P-oglitazone with one of the newer drugs. And

01:34:22.040 for sure, if you had any kind of renal or cardiac disease, I'm going to pick an SGLT2 inhibitor.

01:34:28.920 But I would say, although this study will never be done, if you're a newly diagnosed diabetic and

01:34:34.120 you don't have any cardiac symptoms, why do you think that the SGLT2 inhibitor is not doing all

01:34:40.780 of the beneficial things in that newly diagnosed diabetic that it's doing in the people who get

01:34:46.500 into these studies who already have cardiac disease? So if you have a cardiac problem,

01:34:50.460 I put you on the SGLT2 inhibitor, you're less likely to have MI stroke, etc. It's doing good

01:34:55.300 things. It's doing, in my opinion, the exact same good thing in someone who I'm just diagnosing for

01:35:00.940 the first time when I put them on the SGLT2 inhibitor, but no one is ever going to do a

01:35:05.220 study. It's impossible. I'm going to take 1,000 people, you probably have to take 20,000 people

01:35:11.060 newly diagnosed, and then 10,000 go on SGLT2 and 10,000 on placebo. I'm going to follow them

01:35:18.900 for 20 years to see who's going to have their heart attack. No one's going to do that study

01:35:22.700 because they're going to get on all kinds of drugs. Yeah, that's never going to happen. But I also

01:35:27.080 don't think it needs to happen in the same way that... I agree with you.

01:35:30.680 In the same way that we saw, for example, PCSK9 inhibitors reduced MACE in people with secondary

01:35:37.440 prevention. Take people who had already suffered MACE, put them on a PCSK9 inhibitor, you secondary

01:35:43.420 prevention reduce subsequent. Well, of course, everybody's using these for primary prevention

01:35:48.260 now. That's effectively what you're saying is we already know the SGLT2 works for secondary

01:35:53.020 prevention. That may never get approval for primary prevention, but it probably justifies its use.

01:36:00.320 I agree with you a hundred percent. So just to make sure I'm synthesizing what you're saying,

01:36:04.480 Ralph, if you only get one drug and your price agnostic, GLP1 agonist. Yeah. If you get to add

01:36:10.840 a second drug, you're going to add PO. Yeah. If you get a third drug, especially if you care about

01:36:17.920 your heart, SGLT2. Yeah. SGLT2. And what's amazing is metformin didn't even make the top three in your

01:36:24.020 list. But it's number four, right? So here's my question. Given that metformin is free,

01:36:28.020 should we just be adding it the second we put on the GLP1? I don't have any problem with that.

01:36:32.820 Yeah. And also we have to be cognizant of the fact these newer GLP1s. So potent.

01:36:38.620 But they're a thousand dollars a month. Yeah. I want to ask you about that. So just again for

01:36:42.260 the listeners, right? Semiglutide is Gen 3. Trisepatide is Gen 4. Reditrutide is coming out,

01:36:48.400 assuming the phase three goes according to plan. And Kargi-Sema is the new NOVA one.

01:36:52.700 Yeah. Let's go back to Reditrutide. GLP1, GIP. And glucagon. Glucagon. Can you explain that in

01:36:59.000 the context of the octet where glucagon is going up? Yeah. I can, I think. It's not proven. So

01:37:06.780 remember I told you that insulin knocks down glucagon. So if I give you a GLP1 receptor agonist

01:37:14.220 and I kick out insulin and I get you well insulinized, any negative effect that might be related to

01:37:20.960 glucagon is going to be obviated. So that glucagon effect to drive hepatic glucose production

01:37:27.200 will be totally blunted by the insulin secretory effect. This is the other thing that bothers me

01:37:33.360 about these GLP1s. These are the best drugs in the world for losing weight. These are the best drugs

01:37:39.040 in the world for saving your beta cell. I told you that when you eat a meal, 70% of the insulin

01:37:43.940 that's secreted is coming from the GLP1 and the GIP. People have stopped talking about this effect on

01:37:49.620 the beta cell. I told you, if you want to look at type 2 diabetes, big problems, beta cell failure,

01:37:55.080 insulin resistance. These GLP1s, they're saving your beta cell. We've forgotten about it. We've

01:38:00.100 become so enamored with the weight loss. I don't want to downplay that at all because the weight

01:38:04.840 loss and the lipotoxicity, a huge problem that's causing insulin resistance. But people have forgotten

01:38:10.580 how powerful the drugs are on the beta cell. So when I give you this drug and they work on the

01:38:15.940 beta cell and they'll kick out insulin, any negative thing that glucagon's doing will be

01:38:19.660 totally negated. Now, you may see some good things that glucagon are doing that we couldn't

01:38:25.080 appreciate before. So what are the good things? Some people have suggested the increases thermogenesis

01:38:31.160 energy expenditure. I don't believe that. There are animal data. I don't believe this in humans.

01:38:36.820 I believe that it's exerting an interrectic effect in the central nervous system. That is,

01:38:42.200 I think, yet to be established. Pretty sure there are studies going on now at the Pennington Institute

01:38:47.820 and maybe also in Orlando where they have these chambers where you can-

01:38:52.440 A TRI.

01:38:53.140 Yeah. Yeah. So I think we'll get an answer about energy expenditure.

01:38:58.640 Yeah. I would be surprised if they're going to see a clinically meaningful increase in

01:39:02.540 involuntary energy expenditure.

01:39:04.020 I'm with you. I think it's all appetite. Here's another issue. It is very interesting. If you look

01:39:08.840 at all these big GLP-1 studies, cardiovascular, what's the reduction in cardiovascular events?

01:39:14.300 Almost uniformly 20%. Old dudes, exenatide, et cetera, liraglutide, new dudes, 20%. Even though

01:39:23.040 the weight loss with the newer ones-

01:39:25.400 Is much greater.

01:39:26.160 Much greater. I suspect in terms of cardiovascular benefit, there is a cap that once you've lost a

01:39:33.580 certain amount of weight and you've gotten a certain amount of lipotoxicity and all the good

01:39:38.520 things that these drugs are doing, you don't go beyond that. Even though you're losing more weight.

01:39:44.220 And also, if you look at the A1C, yes, Monjaro does drop the A1C a little bit more than semaglutide,

01:39:52.080 but they're both pretty powerful. Rituatide does a little bit more and does Cargisema do a little bit

01:39:57.780 more, but they don't do a lot more. So I also think there's also going to be somewhat of a cap

01:40:04.500 on how much you drop the A1C. You get two and a half percent drop. Do you need to drop at three?

01:40:10.440 So you're saying if a person shows up with hemoglobin A1C of nine and a half percent,

01:40:16.520 this is a person who hasn't come to medical attention soon enough.

01:40:19.840 And I'm going to give you the answer definitively, but I'm going to let you ask the question.

01:40:22.840 You're happy if they only go from nine and a half percent to seven percent. If they only had a two

01:40:27.740 and a half percent drop, you wouldn't try to get them down to six percent?

01:40:31.020 I would, and we've done the study. Old time guys, right? So this is called the Qatar study.

01:40:36.960 So there's this concept that's out there. And again, what drives me is science. If you understand

01:40:42.900 pathophysiology and there's an abnormality and you correct the abnormality, things get better.

01:40:47.020 So in the Qatar study, and there are 220 people or so in the study, to get into the Qatar study,

01:40:54.520 you had to be poorly controlled on metformin cell foliuria. So you had to have failed on this.

01:41:01.000 And the average A1C was about 10. And about a third of these people were symptomatic,

01:41:07.020 meaning they had polyuria, polydipsia, they were losing weight. And so the current concept is in those

01:41:13.060 people, you would put them on a mixed split insulin regimen. You would get rid of the glucotoxicity,

01:41:18.640 you get rid of the lipotoxicity, and you get their A1C down to six and a half. And then now you could

01:41:25.420 put them back on the oral medications or whatever. And now they respond because you got rid of the

01:41:29.800 glucotoxicity and lipotoxicity. We said, well, that may or may not be true. So we said, well,

01:41:35.060 half of these people are starting with an A1C above 10 will go on a mixed split insulin regimen

01:41:41.100 with a large union and rapid acting insulin. And the other half, I got to go on that old dude,

01:41:47.260 exenatide and pioglitazone, one that people don't like to use. Three years later, the A1C in the group

01:41:55.060 with the mixed split insulin regimen is 7.1%. And we're very good at insulin. Why couldn't we go

01:42:01.200 lower? Because we got into trouble with hypoglycemia. The A1C in the group treated with

01:42:07.520 exenatide and pioglitazone is 6.1%. Then we said, okay, look, we'll do a subgroup analysis. So

01:42:14.660 about one third of the people, we'll just look at the people who are symptomatic. The starting A1C is

01:42:20.280 12.2. Three years later, their A1C is 6.1. From 12? 12.2 symptomatic. On which combination?

01:42:29.680 Exenatide and pioglitazone. Without even metformin?

01:42:32.360 They had failed on metformin and SU to get into the study. So what we're saying, look,

01:42:37.760 if you have drugs that correct the insulin resistance, that's pioglitazone.

01:42:41.760 This is almost impossible for me to imagine.

01:42:44.860 I can send you all the papers. It's all published.

01:42:47.420 I hope every single family medicine internist, everyone who ever takes care of somebody with

01:42:55.780 diabetes is listening. I hope so too. Because you're basically saying we can take these two

01:43:02.000 old cheap drugs and take someone from the most brittle type 2 diabetes. I mean, a hemoglobin A1C

01:43:10.880 of 12? Pretty bad.

01:43:12.240 You're knocking on death's door. Correct.

01:43:14.280 You're going to go blind. You're going to have your toes amputated. You're not ever going to have

01:43:19.120 an erection again. And you're going to die of cardiovascular disease or kidney disease

01:43:23.620 or Alzheimer's disease quickly.

01:43:26.180 These numbers that I'm telling you, they're right from the paper and it's a large, over 200 people.

01:43:29.820 And in a couple of years on two old cheap drugs, you're normal.

01:43:34.680 Yep. What makes these studies so solid is we have very sophisticated pathophysiologic

01:43:41.800 measurements. No one can do what we do.

01:43:44.300 So the only pushback is those patients are going to have to gain a couple of kilograms.

01:43:48.440 But of course, if you're willing to now spend a bit more money and switch them from Gen 1 to Gen 3,

01:43:53.520 you're Gen 4, GLP-1 agonist and GIP, then all of a sudden you ameliorate that and you get all the

01:43:59.280 benefits.

01:43:59.700 This becomes a non-issue. Put cost aside.

01:44:02.560 I would wonder if you add metformin, you almost cancel out the weight gain a little bit because

01:44:07.320 you might get a little bit of the GI improvement and you get the two to three kilos of weight loss

01:44:12.000 there.

01:44:12.600 These drugs are so powerful when you put them with pioglitazone. I mean, you lose almost the same

01:44:17.180 amount of weight. They're huge in terms of getting you to lose weight.

01:44:20.660 Which was that study?

01:44:22.340 This is called the Qatar. It was done in Qatar.

01:44:25.080 Qatar, the country.

01:44:26.060 The country. And I need to give credit to Dr. Bahamut Ablugani, who's been sort of my

01:44:31.320 co-worker in all of these studies. And Bahamut's on the faculty at UT in our diabetes division.

01:44:38.460 Can we at least assume that the Gulf states are paying attention to this? A, the study was

01:44:43.100 done in Qatar. B, the Gulf states are disproportionately ravaged by type 2 diabetes.

01:44:48.080 Is it at least being heated there?

01:44:50.920 They are. And I can tell you we have a big program that's going on there as well as in

01:44:55.580 Kuwait. And we actually have a formal cooperative agreement with the Kuwaiti people. So at the

01:45:02.500 Dasmin Diabetes Institute, we have trained them. My people have been there, trained them how

01:45:09.020 to do these insulin clamps and sophisticated metabolic studies, and they take care of the

01:45:13.780 patients. So here's another thing that's pretty exciting that we're doing. And again, it's looking

01:45:18.600 for genes that cause diabetes. So you eat a meal, okay, you eat a meal, your glucose goes up.

01:45:24.740 That secretes insulin. There's amino acids in the meal. That secretes insulin. And GLP-1 goes up,

01:45:31.040 and that secretes insulin. So now, when you eat a meal, there are already three stimuli.

01:45:35.520 And now you're looking for a gene or a set of genes that might be associated with beta cell

01:45:41.980 failure when you have three stimuli. Now, that's going to be pretty confusing. So what we said,

01:45:47.580 maybe what we should do is that we should do a three-step hyperglycemic clamp. So we give you

01:45:53.680 three steps of glucose, and we can get beta cell sensitivity to glucose. From the slope,

01:46:00.040 I give you a little rise in glucose, another rise in glucose, another rise in glucose. I see how

01:46:04.200 much C-peptide comes up. The slope of that curve is, that's beta cell sensitivity to glucose.

01:46:08.740 And then the M value is where it hits the axis?

01:46:11.640 Then I can get glucose. But this is just, now I'm going to focus on the beta cell,

01:46:15.380 because the hyperglycemic clamp is just for beta cell function. And then after that,

01:46:19.620 now I'm going to give you GLP-1 infusion, and I'm going to see how much insulin comes out.

01:46:23.780 And then after that, I'm going to give you an balanced amino acid infusion. I'm going to see

01:46:27.980 how much insulin comes out.

01:46:29.260 So you can sequentially measure the different...

01:46:31.280 Three different stimuli. And now what we see is different loci. Some are associated with the

01:46:37.140 defect in glucose. Some are associated with the defect in amino acid. So again, the more you can

01:46:43.240 refine the phenotype, the more likely you are to identify defects that are there at the level of

01:46:49.660 the beta cell.

01:46:50.660 Let's go back to the Qatar study for a second. How many people were in that study?

01:46:53.380 About 220. Big study when you're doing... These insulin clamp studies and these kind of measurements

01:46:58.400 are not easy to do.

01:46:59.520 That was published when?

01:47:00.800 Let's see. I would say the one and a half year data were probably about 2018. And the three year

01:47:09.380 data, I would say 2021, 22, something like that. I can send you all the references.

01:47:14.840 Yeah. We'll link to all of these in our show notes for folks. Just simply phenomenal.

01:47:18.800 Let me ask you a question. If you take an individual with type 2 diabetes or insulin resistance,

01:47:24.100 and you presumably collecting urinary C-peptide for 24 hours is the best surrogate for total

01:47:29.840 insulin secretion?

01:47:31.220 No. It's an index.

01:47:33.760 If you could quantify total area under the curve of insulin for a person, and then you gave them

01:47:39.360 a GLP-1 agonist, is total insulin going up or down?

01:47:43.320 Depends. Because you have competing factors going on here. And I'm not trying to be elusive because

01:47:49.900 what I'm telling you is actually real. It's what happens. The drug is going to kick out insulin

01:47:54.720 and C-peptide is going to go up. And now the glucose is going to come down.

01:47:58.660 And then you need less insulin.

01:47:59.860 And then you need less. So depending upon the relationship, when you look in absolute terms,

01:48:07.000 the C-peptide and insulin levels actually may be lower. But now when you express how much C-peptide

01:48:13.580 comes up, per the rise in glucose, huge increase. So you always have to have something that you

01:48:19.940 compare it to, and that's the increment in glucose. And anytime you look at how much insulin comes out,

01:48:25.140 or C-peptide, which is another confusing factor, which I'll mention in a second,

01:48:29.280 you always have to relate it to the glucose area. When you do that, huge increase in beta cell function.

01:48:35.580 The other thing you have to be very careful about is you need to be measuring C-peptide,

01:48:39.240 not insulin. What we've shown, and this is a compensatory mechanism.

01:48:43.640 Maybe just tell folks, I threw out C-peptide as though everybody knew what it is. That's a mistake.

01:48:48.280 Tell people what C-peptide is and what its relationship is to insulin.

01:48:50.720 Yeah. So when you ingest a meal, there's a precursor that contains both C-peptide and pro-insulin.

01:48:57.380 And so you split off C-peptide and you split off insulin. And they both come out in a one-to-one

01:49:03.100 molar ratio. The problem is half of the insulin that comes out is taken up by the liver.

01:49:08.280 So you never see it in the circulating bloodstream. The C-peptide is not taken up by the liver.

01:49:13.800 So everything that comes out, you see in the circulation. So when we want to know how much

01:49:18.900 insulin was secreted, we actually don't measure the insulin. We measure the C-peptide.

01:49:23.880 And that's the true measure. Now, the other confounding feature here is, and we've shown this,

01:49:29.500 and this has now been reproduced by many other people, is that when you become insulin resistant

01:49:34.480 and diabetic, your beta cells don't secrete enough insulin. That's one of the big defects.

01:49:40.020 How do you compensate? You don't destroy the insulin that's secreted. So the degradation of

01:49:45.360 insulin becomes markedly impaired. So you can have a high insulin level, either because you secrete

01:49:51.600 too much insulin or because you don't destroy the insulin. So measuring the insulin level is not a good

01:49:57.820 measure of beta cell function. If you want to know about insulin secretion, measure the C-peptide

01:50:04.220 and express it per rise in glucose. It gets a little bit more clouded because your beta cell also

01:50:11.380 can recognize how insulin resistant you are. And so it knows, look, if you're this insulin resistant,

01:50:17.180 I need to secrete more insulin. If you're very insulin sensitive, like you're a lean person

01:50:21.680 with normal glucose tolerance, you don't want to secrete much insulin, you get hypoglycemic.

01:50:26.440 How does your beta cell recognize that? Well, that's somewhat controversial. I can give you my

01:50:30.980 thoughts about it. But in either case, measuring beta cell function is not just simply measuring

01:50:36.360 insulin. That's probably bad. Measuring C-peptide is better. Measuring C-peptide per rise in glucose

01:50:41.480 is better. And then for some way or another, if you can express this all per insulin resistance,

01:50:46.320 this is called the disposition index, something that Dr. Stephen Kahn developed with Daniel Port

01:50:52.680 many, many years ago. So simply looking, as I said, as insulin or trying to do an OGTT and come up and

01:51:00.840 say, you know how the beta cell is working, that's not so good. And that's why I say in the Qatar study,

01:51:06.880 in the EDIC study, we're doing such sophisticated measures of insulin sensitivity and beta cell function,

01:51:12.600 you do 350 people, that's like doing one of these big cardiovascular studies with 5,000 people in it.

01:51:18.780 The pathophysiology will always tell you the truth, in my opinion. If you know what the problem is,

01:51:25.840 and you correct the problem, the A1C is going to get better. ADA does not emphasize pathophysiology.

01:51:32.940 You had Jerry Shulman on. I'm sure Jerry will tell you, he and I think very similarly. You understand

01:51:38.140 what causes a disease, and then you come with the treatment that will make it work.

01:51:42.600 Do you have any concerns with long-term safety or anything other than simply the economics of

01:51:50.060 the GLP-1s in this current generation? Again, huge, huge leap forward between

01:51:56.620 liraglutide and semaglutide. And I've discussed briefly elsewhere on the podcast what the roadmap

01:52:03.320 looks like for how many of these drugs are in the pipeline. There seems to be no end in sight.

01:52:09.100 And we're going to look back at semaglutide and say, God, that thing was pedestrian.

01:52:12.960 That's what's going to happen.

01:52:14.260 Give us the bear case. What should we be concerned with? What should we at least looking out for?

01:52:18.660 I would say overall at the present time, I would consider these drugs to be quite safe.

01:52:25.860 The major issue is you have to go slow because of the GI toxicity. Where is the controversy

01:52:31.060 involved? And it's something that I'm involved with myself. When you lose 20 or 30% of your body

01:52:38.880 weight, you lose muscle mass. Now, I just gave a talk on this to one of the pharmaceutical companies

01:52:44.480 that are involved in this area. I'm not going to name the name of the pharmaceutical company,

01:52:49.120 but I started off by saying, look, here is now a study with real data. This is a gastric bypass

01:52:55.840 surgery study, room-wide bypass. And the people lost, I think it was 33% of their body weight.

01:53:01.680 And their lean body mass came down quite significantly. One of the problems is people

01:53:06.020 measure lean body mass, and that's not a real measure of muscle mass. In fact, it can be a very

01:53:10.580 bad measure. You should measure muscle mass. But let's assume that the lean body mass largely reflects,

01:53:17.700 it's a reasonable assumption, muscle mass. So muscle mass came down. Why is that so bad?

01:53:22.580 How much did it come down? Because if total body mass came down by 33%, but three quarters of that

01:53:31.400 mass was fat, and only one quarter of that was lean, we would consider that acceptable.

01:53:38.700 And this is where the controversy is, because no one has really measured muscle mass. We're doing it.

01:53:43.700 We will have a definitive answer.

01:53:44.900 And you're doing that with MR?

01:53:46.540 MRI. It's gold standard. But now, I said, look, in this study,

01:53:51.920 they measured absolute strength. You can do grip strength or leg strength. And absolute strength

01:53:56.880 went down a little bit, maybe 25%.

01:53:59.720 Were these patients exercising during the period of their weight loss?

01:54:03.780 No, no, no. No, no, no. No. Then they said, let's express strength per weight loss.

01:54:08.940 Per weight, yeah.

01:54:09.540 Whew, up by 50%. Per appendicular, it goes up by 50%. And then they said, how far can they walk?

01:54:16.900 They went from walking 200 yards to two miles. And then they said, one of the things is how many

01:54:22.340 times can you get up out of a chair in a certain period of time? It increased like three or four

01:54:26.580 fold. They measured your VO2 max.

01:54:29.080 Yeah, of course, which is heavily dependent on weight as well.

01:54:31.240 Yeah, it all got better.

01:54:32.400 But in absolute terms, did VO2 max get better? Not necessarily.

01:54:35.320 Yeah.

01:54:35.540 The total VO2, not normalized per kilogram.

01:54:38.060 No, everything got better.

01:54:39.080 Okay. That's counterintuitive, by the way. Normally when you lose weight, VO2 max in liters

01:54:44.420 per minute does not improve because you have less metabolic tissue.

01:54:47.820 But here, for whatever the reasons are, maybe all of the fat that's pushing on your lungs so you

01:54:53.920 can't oxygenate, the epicardial fat that's not allowing your heart to contract, the fat that's

01:54:59.580 in the heart that's causing myocardial lipotoxicity, which I believe is real. These things are all

01:55:04.780 changing in a positive way. So again, it's a balance. Of course, they don't like this.

01:55:10.520 Why weren't they happy with these results?

01:55:12.380 Well, because now the companies are all looking at developing drugs that will preserve the muscle

01:55:17.080 mass or increase the muscle mass. But basically what I'm saying is that, look, it's lean body mass.

01:55:22.580 We have to say it's reflecting muscle mass. Everything gets better. The patient feels better.

01:55:27.800 They can walk better. They feel stronger, et cetera, et cetera. Why are you so worried about

01:55:31.140 muscle mass? I look all these gloomy faces because they're all developing myostatin inhibitors or

01:55:36.900 event. And then the next slide comes up and says, retort. Here's a good thing. So now if you lose all

01:55:43.920 of this body weight and you improve insulin sensitivity in muscle and you improve it in the heart and there

01:55:49.600 are cardiovascular benefits and you correct the improvement in all of the cardiovascular risk factors,

01:55:56.480 now even though you've lost muscle mass, if you've improved insulin sensitivity, there may be an

01:56:04.380 enormous benefit of seeing the improvement in the muscle insulin sensitivity even though you've lost

01:56:11.220 muscle mass. And they do have some concerns about these drugs, these myostatin inhibitors that actually

01:56:18.140 may have some negative effects in the heart. And my suggestion is actually you may find a big

01:56:22.920 improvement in myocardial function. Where are myostatin inhibitors in their development?

01:56:27.900 Phase two. Of course, I think we've talked about myostatin before on the podcast. When you inhibit

01:56:32.760 myostatin, you increase the expression of striated muscle of which cardiac is striated.

01:56:38.780 It works through the event in 2A and 2B system. Do you think that's a more promising pathway than the

01:56:44.280 folistatin pathway where folistatin... Yes, I do. Increasing folistatin inhibits myostatin,

01:56:48.960 but this is a more direct way to go about it. This is a more direct way to do it. So you can either have

01:56:52.840 their antibodies by Grubab to myostatin or you can interfere with the signaling receptor itself.

01:57:00.880 And we think that this can still be effective in a fully developed and mature adult. I mean,

01:57:05.180 clearly this would be effective during development. And we see that in the animal work. How effective

01:57:10.680 is it? A lot of the animal work is sort of a caricature stuff. It's knockouts, right? They take

01:57:14.780 myostatin knockouts and they look like bodybuilders. But if you take a mature chicken or a mouse that's

01:57:20.360 two years old and you give it a myostatin antibody, how robust is the response? Even more so,

01:57:26.060 what about in a human? We don't know the answer to that. So what the phase two studies,

01:57:30.460 obviously the toxicity passed in phase one. Yes. There doesn't seem to be any adverse effect

01:57:37.080 of these drugs or they wouldn't get through phase two. And there are actually some fairly large

01:57:42.280 phase two studies. What's the indication? Is it sarcopenia? I don't know. The FDA,

01:57:47.460 if you have a sarcopenic disease, there are criteria that the FDA has established if you

01:57:53.320 want to develop a drug that you have to meet certain criteria. I'm not an expert in this.

01:57:58.040 I can't tell you exactly what these criteria are, but they are pretty well established. Now for these

01:58:04.080 kind of people, and I'm going to come back, you asked me about lean people. I'll come back to that in a

01:58:07.560 second because this is really an issue. Let's say I put you on a GLP-1 receptor agonist and you lost

01:58:14.020 25% of your body weight. And I put you on a myostatin inhibitor and that prevented the muscle loss.

01:58:20.960 Didn't increase it, but just prevented it. But that would be ridiculous. I mean,

01:58:25.240 if you took a 200 pound individual who's 30% body fat, they've got 60 pounds of adipose tissue on them.

01:58:34.280 If you took 25% of their body weight off, you take them down to 150 pounds, but you're telling me

01:58:40.920 potentially we prevent any deterioration of lean mass. That means they're down to 10 pounds of fat

01:58:47.460 mass on 150 pound frame. I'm making an assumption. Okay. This is remarkable. Right. So let's say that

01:58:53.220 happened. What would be the FDA's criteria? I'm going to give you approval for this drug.

01:58:59.960 I think the FDA would ask that you've also improved function in some way. And the function

01:59:07.640 would have to be determined through absolute strength, not relative strength, would be my

01:59:12.160 guess. I don't know the answer to this question. Because the way I think about these drugs is less

01:59:17.960 about that situation. It's more in the sarcopenic adult. This is the lean, particularly the older

01:59:24.080 person. That's right. That's right. This is the elderly individual who's sarcopenic and whose fall

01:59:28.700 risk is enormous. And their risk of fall and morbidity and mortality is very high. And in that

01:59:36.300 individual, I don't think the FDA will be satisfied with simply an increase in lean body mass unless it

01:59:42.300 is accompanied by strength. Now, I think that some of the tests that are used here are silly. I think

01:59:48.460 the six-minute walk test should be folded up, discarded, put in the wastebasket, and never

01:59:53.360 discussed again. It is such a stupid test. They do it all the time. I know they do. And it just makes

01:59:59.540 me want to scream. Yeah. We need much more rigorous tests than a six-minute walk test. We need a test

02:00:05.740 that is actually more of a submaximal test. So if we're testing cardiorespiratory fitness or some sort

02:00:12.400 of peak aerobic fitness, we have to do more than walking. And if we're testing strength, I much prefer grip

02:00:18.040 strength, leg extension, bench press. Again, these can be done with machines. They can be done very

02:00:23.160 safely. But we really need to test strength. You see, you're raising very important and critical

02:00:28.680 issues because there are many, many companies that are going ahead with these drugs that increase

02:00:33.760 muscle mass. But to me, okay, increasing muscle mass, what does that mean? There needs to be some

02:00:39.760 functional translation of that. There could be other functional benefits that exceed strength. For

02:00:45.220 example, glucose disposal could be a functional benefit. Insulin sensitivity. That's the one I

02:00:49.260 put at the top of the list for them. Get rid of the insulin resistance. The FDA won't give them

02:00:53.360 credit for that, I don't think. Yeah. But I think that, again, it's harder to tease out because there's

02:00:57.600 more moving pieces and they might argue there are easier ways to increase insulin sensitivity and

02:01:01.560 glucose disposal. But one way to think about this is to go back to what if you did it the old-fashioned

02:01:06.500 way? What if you got in the gym and lifted a bunch of weights? That's been done. Yeah. And it

02:01:10.900 increases insulin sensitivity and functional strength. And so the question is, can we replicate

02:01:15.000 that pharmacologically? And that is actually exactly the way I ended my discussion to these

02:01:21.000 people. I showed them what resistance training did. And if you could show what resistance training did

02:01:26.760 with your muscle mass increase, then you'd have something. But you need to design the studies

02:01:32.360 appropriately. And as I said, and as you said, I don't know what the criteria are going to be that

02:01:37.800 the FDA uses to judge these things. They do have a sarcopenia set of criteria, but that's a very

02:01:43.960 different group of people that we're talking about. But this comes and hits home to one of the things

02:01:48.820 you asked me earlier. What about the lean person who's 80 years of age? Is this the right drug for

02:01:54.520 that person? I don't know. Maybe not. But now let's say you have a healthy 80-year-old person and

02:02:02.180 everybody in the family lives to be 105 and they have diabetes. Well, they're at risk to the toxic

02:02:08.580 effects of hyperglycemia. Would it be reasonable to treat that person? We know this powerful effects

02:02:14.700 on the beta cell. I would say it would be quite reasonable, but I think you need to monitor what's

02:02:18.940 happening to their weight and other features. Here's a bigger issue. Childhood obesity. You are

02:02:25.820 obese when you're four years of age. You're going to be obese when you're an adult.

02:02:29.220 And your life expectancy will be significantly shorter. Biggest. And your quality of life will

02:02:34.760 be significantly reduced. And you're going to get diabetes. Now, make it even better.

02:02:38.300 Adolescents, these young kids with diabetes, they don't respond to any of the drugs.

02:02:43.400 What is the prevalence of type 2 diabetes in under 18? It's increasing, but I would say maybe around

02:02:49.500 4 or 5%, something like that. One in 20 teenagers has type 2 diabetes?

02:02:55.900 I'm biased by San Antonio because we have more people with type 2 diabetes in our clinic.

02:03:01.600 You could say potentially in San Antonio, one out of 20 teenagers.

02:03:04.680 It's going to be very high.

02:03:05.620 Gosh, that is staggering.

02:03:07.620 And for sure, pre-diabetes. And I'll tell you about the pre-diabetes study that we did.

02:03:11.100 And we know these studies are out there. These kids and this big NIH-sponsored study,

02:03:17.020 they don't respond to metformin sulfonylureas. They don't respond to any drugs very well.

02:03:21.880 Even the GLP-1 agonists?

02:03:23.160 The first study has just come out. They respond better. It's a liraglutide study.

02:03:27.880 They don't have any of the two...

02:03:29.180 Just clinically, if you're in the clinic and you're using the best drugs you have available.

02:03:33.400 You're in trouble.

02:03:34.340 Why?

02:03:34.980 Because you can't get them controlled.

02:03:36.820 Why?

02:03:37.640 They're so insulin resistant, much more so than adults. These are well-published studies.

02:03:42.860 Is this really a selection bias where for someone to develop type 2 diabetes as a 16-year-old,

02:03:49.540 the underlying genetics and pathology are so severe that the current crop of drugs are the

02:03:55.460 problem? As opposed to when you take the current crop of drugs and you apply them to people who

02:04:00.840 are young, they don't work.

02:04:02.420 All three. Because I'm going to add one more. Genetic predisposition. So Hispanic population,

02:04:08.480 huge problem. Obesity. All of these kids are huge.

02:04:12.380 So you don't have the lean diabetic phenotype in this age?

02:04:15.680 No, not in these people. And then the drugs don't work very well. So all three of these

02:04:20.220 things. And what now has come, it's called the RISE study. And as these kids have been followed up,

02:04:25.840 they're starting to develop kidney disease. They're even, I'm told, a couple of people have had MIs in

02:04:30.000 their 20s. They're incredibly difficult to control.

02:04:33.860 What do you think? I mean, yes, we're going to argue that these kids are,

02:04:36.680 this is due to what they're eating, but what is it in the environment that is so obesogenic to these

02:04:43.540 kids?

02:04:44.400 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

02:04:50.080 don't met form and solve. Your A1C is nine. You're going to put someone on Manjaro and they're going to

02:04:55.020 have to take this for the rest of their life. Because as soon as you stop the drug. So this is

02:04:59.720 what I treat the person. Of course, I can't let the A1C nine.

02:05:03.220 If you take that 16-year-old with a hemoglobin A1C of nine and you give them Manjaro,

02:05:08.020 where are they in a year?

02:05:09.540 I think that if they can afford the drug and they stay on the drug, the three big ifs,

02:05:15.380 if the doctor knows what to do, I know what to do. If the patient will cooperate with you,

02:05:20.380 if you don't, they'll lose every time. And if they can afford, if you can satisfy those three Fs,

02:05:25.800 that person we know from the studies would be pretty well controlled.

02:05:28.700 What fraction of insured patients will have coverage on Manjaro if their A1C is nine?

02:05:35.440 I can't answer that.

02:05:36.520 Does CMS cover it? Does Medicaid cover that?

02:05:39.100 Yes, if you have diabetes. The Manjaro coverage I think is pretty good if you have diabetes.

02:05:43.560 If you have obesity without, that's a whole different issue. Should you be treating these

02:05:47.480 young kids? Obesity is a disease. They've got all kinds of problems. Should you put these young

02:05:52.420 kids on these newer drugs? And knowing that all I did is change you from food addiction to drug

02:05:58.240 addiction. I didn't do anything else. It's almost like alcohol addiction. There are drugs that things

02:06:04.240 I can give you that can help you, but they tend to relapse. Food addiction, I put you on the drug,

02:06:10.100 you lose weight. You stop the drug, you regain the weight. This is a huge public health concern.

02:06:15.260 It's almost way beyond my capacity because finances are involved here. Can we afford to treat 42%

02:06:23.020 of the people in the U.S. are obese? Or is there some way amongst the 42% we can define who are the

02:06:30.160 people who are insulin resistant? Who are the people who have the metabolic syndrome that we know

02:06:34.020 they're at risk, that we can treat them? My guess is that the great majority of that 42% of the people,

02:06:39.180 can we treat all of those people? And moreover, are they going to stay on the drug? We know on average

02:06:44.300 what the data is saying. I put you on the drug. We don't know all the reasons why,

02:06:49.480 but within a year, half of the people stopped the drug. Yeah. And it's probably a combination

02:06:53.040 of cost and side effects. Yeah. And my patients very commonly tell me,

02:06:57.820 I enjoy eating and I can't eat anymore. Some people just tell me they just want to eat. So I'm

02:07:04.120 going to get fat again. So I'm going to eat. Some is GI side effects and some is cost. $1,000 a month

02:07:10.100 is a lot of money for people. Yeah. Of course, this begs the question,

02:07:13.160 will the next generation of weight loss drugs be true uncoupling agents where you can basically eat

02:07:19.580 as much as you want and they're going to create so much mitochondrial uncoupling and thermogenesis

02:07:24.640 that you're truly going to see this increase in non-voluntary energy expenditure. And of course,

02:07:31.580 not have the GI side effects. But before we go on to the next thing I want to chat about,

02:07:36.500 and I just kind of bring it back to this question, which everybody wants to understand this,

02:07:40.680 which is what has changed so much in the last 30 years that has created this epidemic. And

02:07:47.740 everybody has their favorite pet theory for what it is. It's the sugar, it's the carbs,

02:07:53.200 it's the plastics, it's the video games, it's the internet, it's the whatever. Perhaps suggesting

02:07:59.080 that it's many, many things. What is your best explanation for what's going on?

02:08:04.120 I would say all of the above, processed foods, calorically dense foods, lack of exercise are

02:08:10.740 critical. But these are, I would say, the stimuli that has done something, that's changed the

02:08:17.560 neural circuitry in the brain. So yes, there's a stimulus. And because now you've been oversubscribed

02:08:24.120 to these stimuli, that's now initiated a process in the brain, which is going to be a self-fulfilling

02:08:30.040 process. This is something that I'm very interested in, Dr. Peter Fox and I at the Health Science

02:08:35.860 Center. But if you go through the literature, and we've published on this as well, in the areas of

02:08:41.820 the brain that control food intake, and I'm not talking about the hypothalamus, that kind of

02:08:46.240 regulates your basal energy intake, what you need to be, keep your BMI of 25, do what you do during the

02:08:52.660 day. But what is it that makes your BMI go to 35? That's all related to the hedonic areas in the brain,

02:08:59.100 the putamin, the amygdala, the prefrontal cortex, etc. And then when you do structural MRI, what you

02:09:07.040 can show is that those areas in the brain, the gray matter is shrunk down. And if you now map the

02:09:12.940 neural circuitry, which Peter Fox has been involved with, you can see that there's clear disruption using

02:09:19.500 functional MRI of the neural circuitry in the brain. We have a particular interest in defining

02:09:25.340 where this dysfunction occurs. And we have some ideas, which I'm not going to go into, but how we

02:09:33.040 might be able to sort of reprogram the brain. And in concert with this, these are not data, but these

02:09:40.360 are data that are published in the literature. And I think I mentioned this earlier. If you do an insulin

02:09:45.220 clamp, okay, I told you that in your eye, your brain doesn't respond by taking up glucose. But in people

02:09:52.360 who are obese, actually almost in proportion to how obese you are, in these areas in the brain,

02:09:58.800 the hedonic areas, there's a marked increase in, it's called fluorodeoxyglucose, which is the pet

02:10:04.380 radioisotope trace that we use in these areas. And that correlates inversely with the muscle insulin

02:10:10.180 resistance. The more insulin resistant they are in the muscle, the more FDG glucose uptake there is in

02:10:16.080 the brain. Now, this is very interesting, because what it's saying, there's a connection. That somehow

02:10:21.440 or another, we believe that the brain is talking to the muscle, or the muscle is talking to the brain,

02:10:26.840 and that somehow or other, the brain is playing a very important role in the development of the

02:10:32.960 insulin resistance. And that in large part, this deranged neurocircuitry, which is related to food

02:10:39.600 intake, is now making you overeat. And as you overeat, then all of the things that we know,

02:10:45.840 that we've studied, that other people have studied, that go with lipotoxicity, you put fat in the muscle,

02:10:51.800 you're insulin resistant. You put fat in the liver, you got NASH and NAFLD. What people have totally

02:10:56.440 overlooked, you put fat in the kidney, you get kidney disease.

02:10:59.420 Yeah. Fat in the heart.

02:11:00.320 Yeah.

02:11:00.700 Yeah.

02:11:01.200 So you've been in San Antonio since the late 80s. When did you really start to notice this was a

02:11:07.020 problem, at least in your community? Almost instantaneously.

02:11:10.080 Even in kids?

02:11:11.040 Even in kids.

02:11:12.140 We can't blame video games. We can't blame social media, because that wasn't going on in the late

02:11:16.780 80s. I never saw fat kids at Yale. I was on the faculty from 75 to 88. And I kind of thought back,

02:11:24.760 now I would say New Haven's not a large Hispanic, but it's more African-American. But I don't remember

02:11:30.720 seeing 12-year-old kids with type 2 diabetes. And when I came here, and I remember this very distinctly,

02:11:40.280 they're saying, oh, you're crazy. You don't see kids with type 2 diabetes. Believe me, I see them.

02:11:45.980 What did your colleagues at San Antonio tell you as far as when they started to notice that in the Hispanic kids?

02:11:53.520 I don't know that I can give you a specific time that they told me, except they knew it.

02:11:57.660 So, okay, what about in non-Hispanic kids? Because if the Hispanic kids are genetically

02:12:02.420 predisposed to this, then the question becomes, when did you begin to see this in African-American

02:12:08.500 kids and Caucasian kids?

02:12:09.820 So, we don't have a large African-American population here. But like in Philadelphia,

02:12:15.120 there's a lady, Sylva Arslavian, she sees the same thing. And she sees, I think it's a significant

02:12:21.540 African-American population. So, I think that in certain ethnic minorities, where the genes for

02:12:27.300 diabetes are enriched, those are the populations that are predisposed.

02:12:33.080 And do you think this is mostly an energy balance issue, and therefore, it's mostly a food environment

02:12:38.360 issue?

02:12:39.180 No, I think it's both. So, I told you I'd come back to the genetic study that we did.

02:12:43.340 An Italian fellow was with me, Giovanni Gulli, a long, long time ago here in San Antonio. We wanted

02:12:49.180 to know, what is the earliest defect that you can see in people who are going to develop type 2 diabetes?

02:12:55.700 So, he said, okay, in the Hispanic community, it's very common to see mom and dad with diabetes.

02:13:01.860 And it's very common to see a lot of children in these families. So, he said, why don't we go look

02:13:06.600 at the children? And let's see if we can define, because they're at high risk. And if you have mom

02:13:12.760 and dad with diabetes, you probably have a 70, 80% chance if you're Hispanic, if you're born in that

02:13:17.740 family developing diabetes. It was very easy to find the children. The problem was we couldn't find

02:13:22.340 lean children. So, it took us a while, because if you're obese, then you got the lipotoxicity.

02:13:28.380 So, we finally found them. This is a JCI paper, I believe. And so, we did an insulin clamp. They're

02:13:34.420 as resistant as their parents. They have normal glucose tolerance. Why? Because their insulin

02:13:38.980 levels are astronomical. And then we do a muscle biopsy.

02:13:41.620 How high, just for understanding?

02:13:43.280 Oh, they're like two times normal. Even higher sometimes. We do a muscle biopsy. The same

02:13:49.120 defect in the insulin signaling pathway.

02:13:52.220 How many of the tyrosine kinase defects do they have?

02:13:55.960 It starts at IRS-1. Insulin binding to the receptor is okay, just like their parents.

02:14:01.180 The ability to activate the insulin signaling pathway at the level of the IRS-1, it's already

02:14:07.000 well established.

02:14:08.840 Which enzyme in particular?

02:14:10.080 It starts at the level of IRS-1.

02:14:11.700 It starts at the first one.

02:14:12.400 Yeah.

02:14:12.860 Oh, so it's not just one enzyme, though.

02:14:14.340 Well, no. It's IRS-1. You can't tyrosine phosphorylate it. You cannot activate PI3 kinase.

02:14:19.500 Oh, I see. Okay. So, it starts at IRS-1.

02:14:21.240 Yeah.

02:14:21.460 Yep.

02:14:21.900 And then the other thing, Jerry and I have both done this in somewhat different ways. I'm

02:14:27.000 talking about Jerry Schulman. He uses NMR by looking at phosphate derivatives. Even though

02:14:33.580 I believe the primary defect is in the signaling pathway, there's clearly severe impairments

02:14:39.100 in glucose transport and phosphorylation. His work would suggest that the primary defect

02:14:43.480 is at the level of glucose transport. We developed a novel triple tracer technique using three

02:14:49.340 isotopes infused into the brachial artery. We believe that the primary defect is at the

02:14:54.320 level of hexokinase and phosphorylating glucose. We kind of agree to disagree because we can't

02:15:00.360 do the study. We'd have to do the MRI study at the same time we're doing the triple tracer

02:15:04.400 technique. In addition to the insulin signaling defect, there's a severe defect in glucose

02:15:09.560 transport and phosphorylation.

02:15:11.640 Let's just make sure people understand this as we're kind of getting into some biochemistry

02:15:14.820 here. When glucose enters the cell passively through the GLUT4 transporter.

02:15:20.240 It gets free glucose in the cell.

02:15:22.100 Yes.

02:15:22.640 Then to metabolize it.

02:15:24.240 Yeah. The first step to that is hexokinase, which takes a phosphate off ATP and puts it on

02:15:29.860 the sixth position if I'm not mistaken. And it's a specific type of hexokinase,

02:15:34.180 so it's hexokinase 2. Because there's a different one in the muscle and the liver,

02:15:37.980 correct? That is correct. So Jerry would say the primary defect is in GLUT4, the transporter.

02:15:45.020 I would say, yes, that is severely impaired. Remind me what Jerry believes is wrong with

02:15:49.580 the GLUT4 transporter? That it doesn't work normally.

02:15:52.580 I thought it worked fine. It's just not getting the signal to work because of IRS-1.

02:15:56.540 That's where the controversy is. We were the first to show this defect in muscle. In fact,

02:16:01.120 we're the only people I think that are showing this in human muscle. It's been shown in rats,

02:16:04.820 et cetera. To me, metabolism in rats and mice is so different. This is all people data.

02:16:10.740 So you're saying it's possible that just having the IRS-1 problem is enough. It's also possible

02:16:16.960 that even if IRS-1 is functioning reasonably, if GLUT4 is not getting up, that's the problem.

02:16:23.200 And there is evidence to support that.

02:16:24.660 And then it's also possible that even if all those things work, if you don't get hexakinase

02:16:28.920 to phosphorylate glucose, you back up the whole system.

02:16:33.260 And I can show you that there's a primary defect in pyruvate dehydrogenase and glycogen synthase.

02:16:38.700 This comes back. I have an ominous octet for the insulin resistance. That's why people don't

02:16:43.620 understand. Look, there are eight organ sort of things that are a problem. There are eight problems I

02:16:48.980 can show you within the muscle. Why do you think one drug is going to correct all these problems?

02:16:52.460 We need drugs to work on the beta cell. We need insulin sensitizers. We probably need different

02:16:57.280 types of insulin sensitizing drugs. We need drugs that reverse the lipotoxicity. And will we ever

02:17:03.580 have a single magic bullet that corrects all of these? Probably not until we discover the genetic

02:17:10.760 basis. And remember, I said that diabetes is a heterogeneous disease. In diabetes metabolism reviews,

02:17:17.360 I would say 30 years ago, I wrote a review article that said, I can put a defect in the muscle and

02:17:25.180 reproduce diabetes. I can put a defect in the liver and reproduce diabetes. I can put a defect in the

02:17:31.620 fat cell and reproduce diabetes. I can put a defect in the beta cell and reproduce diabetes. And I went

02:17:38.580 back and read that. And I said, I can put a defect that starts in the brain and reproduce diabetes.

02:17:44.020 So we see someone with an A1C of 8 or 9.

02:17:47.140 All these defects we've been talking about, they're already there.

02:17:50.320 So you put that defect in the fat cell, they can look lean.

02:17:53.640 There's a syndrome called Alstrom syndrome.

02:17:56.260 There's a specific defect.

02:17:58.340 This is white adipocyte.

02:18:00.060 There's this, Phil Scherer will love me for saying this.

02:18:02.180 He's the top guru in adipocyte metabolism up in Dallas.

02:18:06.560 And it's Alstrom syndrome.

02:18:08.900 There's a specific defect in the glucose transporter and white adipose tissue.

02:18:13.760 You know what happens?

02:18:14.980 You become diabetic.

02:18:16.260 You know what happens?

02:18:17.120 You gain weight.

02:18:18.000 You know what happens?

02:18:18.820 You get NASH.

02:18:20.240 So here's a defect that I said 30 years ago.

02:18:24.260 I just postulated and said, here's a syndrome.

02:18:27.620 And not only that, now that they define this in people in this paper,

02:18:32.400 they then went to the animal model and they knocked out the gene that's causing the defect

02:18:36.280 and they reproduce diabetes in the normal mouse model.

02:18:39.480 Ralph, I want to close by bringing it back to something that people can do

02:18:42.640 to help understand if they're at risk, either lean or otherwise.

02:18:46.780 We talked about it at the outset, but didn't go into it in detail, which is the OGTT,

02:18:51.000 the oral glucose tolerance test.

02:18:52.440 Now, again, none of us have the privilege of being able to use a euglycemic clamp,

02:18:56.080 both clinically as physicians or as experienced as patients.

02:19:00.800 So we're going to have to kind of rely on other things.

02:19:03.720 We're going to have to rely on body fat.

02:19:05.860 We're going to have to rely on triglycerides.

02:19:08.920 We're going to have to rely on hemoglobin A1C, although I find that to be a particularly

02:19:12.820 useless metric.

02:19:14.380 Not that useless.

02:19:15.100 At the individual level, I find it very unhelpful.

02:19:17.700 I think at the population level, it's great.

02:19:19.340 And in deltas, it's great.

02:19:20.800 But boy, the correlation between hemoglobin A1C and realized glucose levels is pretty weak.

02:19:27.140 But let's talk about the OGTT, because this is not a test that is done frequently.

02:19:31.760 I believe it should be.

02:19:33.320 And I'd love to have you walk us through the interpretation of the following.

02:19:37.340 I'm going to give you a couple scenarios.

02:19:38.840 So case one, I'm making this up as we go.

02:19:41.240 You got a person who starts out, all of these people are going to start out normal.

02:19:43.920 They're going to start out with a glucose of 90 and an insulin of six.

02:19:47.180 At 30 minutes, this is after 75 grams of oral glucose.

02:19:52.360 The insulin rises to 90.

02:19:56.140 I'm nervous.

02:19:56.940 Yep.

02:19:57.120 The glucose rises to 130.

02:20:00.140 At 60 minutes, the glucose is down to 100.

02:20:05.740 The insulin is down to 60.

02:20:08.780 And we'll just do one more check at two hours.

02:20:11.380 The glucose at this point is 60.

02:20:14.440 And the insulin is 20.

02:20:16.820 As a pre-diabetic state, this is a very insulin-resistant person.

02:20:21.960 And two hour later, hypoglycemia is a reflection of the beta cells' early insulin secretion.

02:20:29.520 This is kind of a pre-diabetic state.

02:20:31.560 Yeah.

02:20:31.920 Agree with you completely.

02:20:33.300 And we see this all the time.

02:20:35.620 This is a person, by the way, with a perfectly normal hemoglobin A1C.

02:20:38.940 And this is a person who gets passed all the time as totally normal.

02:20:43.580 They're severely insulin-resistant.

02:20:44.800 The beta cell's doing a good job.

02:20:46.800 Your hemoglobin A1C is normal and your insulin is 6, even if the doctor's checking insulin.

02:20:50.800 But as you point out, the thing that trips you off is not their glucose.

02:20:54.720 90 to 130 to 100 is amazing.

02:20:57.400 It's 90 was how high the insulin was at 30 seconds.

02:21:01.460 And of course, they overshot, which is why they become hypoglycemic.

02:21:04.340 Yes.

02:21:04.780 Okay.

02:21:05.120 Well known.

02:21:05.800 Yep.

02:21:06.360 Let's go another one.

02:21:07.120 This person also starts at 90 and 6.

02:21:08.840 At 30 minutes, they go to 180.

02:21:14.260 Insulin goes to 30.

02:21:16.780 At 60 minutes, they go to 200.

02:21:19.900 Insulin is 40.

02:21:21.000 They're diabetic.

02:21:22.020 But just to be clear, these are almost real cases, by the way.

02:21:24.760 This is a person whose hemoglobin A1C is 5.6.

02:21:27.120 Got it.

02:21:27.780 We already published this.

02:21:29.280 The best predictor of who's going to get diabetes is a one-hour glucose greater than 155.

02:21:34.160 And this is from prospective data from the San Antonio Heart Study, also from the Botnia

02:21:39.700 Study, where these people have been followed up.

02:21:42.340 We were the first people to publish this, oh, I'd say 7, 8, 9, 10 years ago.

02:21:46.740 There have been, I'd say, at least 15 to 20 studies that have reproduced what we showed

02:21:51.340 10 years ago.

02:21:52.660 I can send you all the references.

02:21:54.100 So if one-hour glucose is more than 155...

02:21:56.740 You're in trouble.

02:21:57.640 And that's a great predictor of type 2 diabetes, regardless of all the other metrics.

02:22:01.880 Yes.

02:22:02.060 And if you also happen to be hypoinsulemic, that adds more to the predictive value.

02:22:06.640 But just pick 155 without knowing the insulin.

02:22:09.920 That's a huge predictor of whether you're going to develop diabetes or not.

02:22:13.680 That's from the San Antonio Heart Study, and that's also from the Botnia Study, and also

02:22:18.820 from our Vegas Study.

02:22:20.040 Okay.

02:22:20.440 Next case.

02:22:20.980 I'm not even going to give you the numbers.

02:22:22.000 I'll just describe it.

02:22:22.900 This is a person who has a delayed onset of insulin.

02:22:26.660 So in other words, they start out normal at 90 years.

02:22:28.480 30-minute insulin is deficient.

02:22:30.280 That's a predictor as well.

02:22:31.440 Yes.

02:22:31.740 So what's going on in this person where 30-minute insulin does nothing, glucose rises, and then

02:22:37.540 at an hour and 90 minutes, the pancreas kicks on and starts to dispose of glucose.

02:22:42.040 What's happening in that person?

02:22:43.120 That's a primary beta cell defect.

02:22:45.400 And one of the earliest things you can detect in people who are predisposed to develop diabetes

02:22:50.080 is loss of first-phase insulin secretion.

02:22:52.920 Now, first-phase insulin secretion, strictly speaking, can only be measured with the hyperglycemic clamp

02:22:59.560 that we develop.

02:23:00.560 So when I acutely raise the glucose from, say, 90 and I raise it to 200, in the first 10 minutes,

02:23:07.440 there's a big spike of insulin that comes out.

02:23:09.720 That is typically lost in people who are going to develop type 2 diabetes.

02:23:13.920 And its counterpart during the OGTT is the insulin level at 30 minutes.

02:23:20.220 So when you ingest the glucose, of course, the rise in glucose is more gentle.

02:23:24.140 So when I acutely raise your glucose from 90 to 200, that big spike of glucose gives the

02:23:30.120 first phase.

02:23:31.180 But a low insulin response in the first 30 minutes is another predictor of who's going

02:23:36.740 to get into trouble.

02:23:38.160 We use the following numbers in our practice as what we consider what we want to see.

02:23:43.280 Do you think we're being too aggressive?

02:23:45.220 At time zero, we want to see you less than 90 and less than 6.

02:23:49.080 At time 30 minutes, we want to see you less than 140 and less than 40.

02:23:53.420 At time 60 minutes, we want to see you less than 130.

02:23:57.960 90 minutes, we want to see you less than 110 and less than 20.

02:24:01.300 Do you think we're being too hard?

02:24:02.880 Yeah, you might be being overly aggressive.

02:24:04.920 But for sure, if they meet those numbers, you're probably safe.

02:24:09.120 Okay.

02:24:09.740 Ralph, I don't know where the time went today, but it went.

02:24:12.740 And this was a fascinating discussion.

02:24:16.160 I could talk about this stuff all day long.

02:24:18.800 It's interesting because someone listening to this podcast who heard the podcast with

02:24:24.580 Jerry Shulman from probably three years ago will be pleased because the overlap is virtually

02:24:30.600 zero.

02:24:31.440 I mean, that's what's amazing about a topic as rich as this, is you can talk to two of the

02:24:36.080 world's experts and have two completely different conversations.

02:24:40.340 The conversation with Jerry focused so much on the pathophysiology of insulin resistance.

02:24:45.800 Here, we focused much more on the actual organ-specific aspect of type 2 diabetes.

02:24:52.300 We got a masterclass in the pharmacology of it.

02:24:55.680 And then I think kind of brought it back to ways to diagnose it if you're slumming it with

02:25:00.700 those of us in the clinic who don't have clamps.

02:25:03.060 So maybe we should, in the future, we do one with both Jerry and I.

02:25:05.920 I will 100% agree that in a few years, we come back and we do a double version of this

02:25:12.440 and that would be fantastic.

02:25:13.900 I sign up.

02:25:14.760 All right.

02:25:15.360 Ralph, thank you so much.

02:25:16.380 Not just obviously for this, but for your contribution to this field.

02:25:19.440 Okay.

02:25:19.860 I appreciate it.

02:25:20.540 This was wonderful.

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The Peter Attia Drive - February 24, 2025

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

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