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

26:31Insulin resistance would be here, and the other hand would be impaired beta cell function. So if you are insulin resistant and your beta cells work well, they know how to read the insulin resistance, they'll make enough insulin you won't become diabetic. The hyperinsulinemia can damage you in other ways, but you won't become diabetic. But what happens is if you're insulin resistant, particularly if you have a genetic predisposition, if your beta cells have to continuously pour out insulin, they start to exhaust. And insulin resistance is a disaster for someone who has a genetic predisposition is going to bring out the diabetes.

27:07Incellant resistance, in my opinion, is intimately related to cardiovascular disease. That is why when you see a diabetic patient, 10 % of them, you walk in, you have diabetes, first time I see you, 10 % -15 % of the people already have a clinically significant cardiovascular disease. And if you look carefully, virtually 100 % of them do. And sorry Ralph, do you think that that is a result of the hyperinsulinemia or the untreated or poorly treated hyperglycemia? All of the above. More importantly, what we showed, and we were again the first people to show this. And the cardiologists, they're hemodynamically oriented, they're looking at vessels.

27:47Stinosis, yeah. But if you look at the insulin signaling pathway, insulin has got a bind to its receptor. And then there's a signaling pathway. I can tell you all the molecules in there, which I'm not. And then glucose gets transported in the cell. We were the first people to show in humans that that pathway doesn't work normally. In some way, buying to the receptor, it will activate the receptor. But the next molecule, IRS -1, PI -3, all those molecules don't get activated, so glucose doesn't get into the cell. That's diabetes. That same pathway activates nitric oxide synthase, and that generates nitric oxide.

28:25nitric oxide is the most potent vasodilator in the human body. It's the most potent anti -athrogenic molecule in the human body. So this defect that's in muscle and it's in cardiac muscle and it's in skeletal muscle, this is all human data that I'm talking about, not the animal data. When you get a defect in that insulin signaling pathway, that's going to cause diabetes and it's gonna promote cardiovascular disease. And that is why you can never separate cardiovascular disease from diabetes. Now, as you pointed out, rightfully so, I believe that high levels of insulin are also atherogenic. I don't want people saying Dr.

29:08DeFranco said you shouldn't be giving insulin to people who needed it. Of course, if people need insulin, you need to give them insulin. But our beta cells make 35 units of insulin per day. So we showed this many years ago and actually was at Yale that if you were to take a type one patient and they were lean, they would only need 35 or 40 units of insulin to get their glucose control to assume you gave the doses at the right time. But we have a lot of people who are taking 100 units of insulin, both type ones and type dos. So three X physiologic? Yes. That kind of hyper -insulinemia, I think there's evidence to support that's pathogenic.

29:47But now we have a problem. Can you have the glucose remain high? Yeah, it's a question of do you want to die quickly or slowly? But we have very good drugs. Yes, yes, yes. But if you were only doing this with insulin, it's an awful tradeoff. It's you're going to die very quickly from hyperglycemia if you're left untreated. But if we overdo it with insulin to maintain normal glycemia, we're going to kill you slowly. De Quagma, you're stuck. Yeah. You have to treat. But you also know that when you're giving these big doses of insulin, there may be some side effects. This is something, Ralph, I don't think that has been necessarily appreciated by the medical community.

30:21Absolutely not. There has generally been an ethos of when I've talked to patients with type 2 diabetes, what they've been told is I'm told to cover with as much insulin as is necessary to maintain my glucose levels in this range. And it means I can eat whatever I want. It's okay if I have all the pasta and bread and sugar in the world because as long as I'm covering it with insulin, I'm okay. And then you find out, wow, you're taking 150 units of insulin a day in all of its forms, the short acting, the long acting, etc. But I didn't actually realize that what we would consider physiologic is 35.

30:59I may have known that at one point in a sense forgotten, but that's a great reference. So basically if there's a person with type 2 diabetes listening to us today and they're taking 75 units of insulin, one of the takeaways should be, what do I need to do with my nutrition and other pharmacologic activities plus exercise, plus everything that's under my control to maybe get that down to 35, where I would be at a physiologic level? There are things as you already insinuated weight loss if you get people to do it, exercise, and then we can add medications combinations in combination with insulin, insulin sensitizes or some drugs to help you lose weight that will also allow you to get that dose of insulin reduced.

31:44The other thing we showed in this study doctor Del Prado, who's past president of the European Diabetes Association, we took normal healthy lean kids 18, 25 years of age. And we put them on the clinical research center for three days and we gave them a very, very low dose of insulin infusion. And we raise their fasting insulin from eight, which is what a normal person would be to 20, which is really quite low. And within 48 to 72 hours, they were as insulin resistant as a type two diabetic patient. So hyperinsulinemia induces insulin resistance. Wait a second. Why is that the case? So, what insulin does is it down regulates the insulin signaling transduction system.

32:32So, that insulin when it binds to its receptor and then it activates iris -1 and p -i -3 kinase and AKT. That system is down regulated by hyperinslenemia. All of this that I'm telling you about, it's all published, these are all studies done in humans. And this also been shown in rodent models as well. So, this is another reason why we don't want people to be hyperinslenemic. You have to explain that to me again, Ralph. That is mind -boggling. I would never have predicted that. So let me say it back to you because I feel like I missed it when I was writing something down. You took normal volunteers who had a fasting insulin of eight.

33:08Yep. And they're lean healthy. Okay. And simply infused insulin in them, presumably with glucose. Oh, yes, of course. On the clinical research center, we can monitor, keep the glucose perfectly constant. We're not letting the glucose change. Person shows up, insulin eight, glucose is 90. You do a Euglycemic clamp where you bring insulin up only by one and a half per, one and a half ax. Much less than would be when you eat a meal. Exactly, not even a post -prandial bump, but now it's constitutively sitting there at 20. And you've obviously had to bring glucose. You had to infuse glucose to maintain Euglycemia.

33:43Correct. Did you save it in four days? 48 to 72 hours, these people are insulin resistant as type 2 diabetics. Okay. Again, very, very counterintuitive because if our model is that insulin resistance, which is the hallmark factor contributing to type 2 diabetes in the combination of beta -cell fatigue, is driven by lipotoxicity, which we're going to come to. It's an important one. These people didn't have any of that. These people didn't have any of the intramiosellular lipid that we talked about with your colleague, Jerry Reven, as a predisposing factor. It's the direct effect of insulin down regulating the insulin signaling system and probably other distal metabolic within the cell as well.

34:32So then when you turn the clamps off, let's just say we ran this for 72 hours, we've made them functionally diabetic. Turn the clamps off. How many hours or days? I would predict probably within 24 to 48 hours they would return to normal because we did this securely. Now, if we were able to do this for several months, then I would anticipate that the insulin resistance would remain for a long period of time. And remember, when we treat type 1 diabetics, we're always giving the insulin into the periphery. And you or I, when you ingest the meal, where does the insulin go? It goes into the portal vein.

35:14So the liver is seeing a high level of insulin. That's good. It says, stop making glucose. But now it removes half of the insulin. So how much insulin gets into the periphery? Half of what you secreted. Why? Because we don't want the insulin in the periphery over insulinizing the periphery because it would make the muscle tissue very insulin resistant. So the pancreas secreting insulin into the portal circulation limer sees the insulin good stop making glucose, but it also takes up half of the insulin So let's insulin get enough to nourish the muscle enough to shut down the fat producing free fatty acids But not enough to hyperinsunize the system and in a certain way If you're a diabetic and you are insulin resistant or an obese person and you are insulin resistant and you are hyper secreting insulin It's kind of working against you because it's a reverberating system that's making the insulin resistance Aggravated so one of the big things that we've forgotten is that insulin I told you there are two problems in diabetes one is you know, Megan of insulin the other is your insulin resistant You need to attack both problems and the paper that I recently Published which is a perspective and Lancet diabetes and a chronology was to bring people back to look But we're focusing on obesity and weight loss, and we should.

36:36But we need to remember that we still have a genetic cause for the insulin resistance. You go back to 1950, the incidence of diabetes was 2%. I've seen even data that says it was 1%, as recent as 1970. It's very low. But these people were all lean, and they're insulin resistant. So there's a genetic cause of the insulin resistance. And you think Ralph that the greater genetic effect is on the insulin resistance side or on the beta -selfateg side. Both. Okay. So let's tackle each. Since you started with insulin resistance, let's go there. Let's talk about what we know about the genetics of insulin resistance.

37:17That's easy. Nothing. Truly nothing. I joke. Let's say 20 years ago, we got involved in one of the biggest genetics that is called the Vegas study, Veterans Administration, Genetic Epidemiologic Study. And we were convinced that we were one of the people to do the first GWAS studies, that we would define all the genes that are responsible. Well, we were not very successful. Even if you took the subset of people with type 2 diabetes who were lean and you compared them to people who were lean and non -diabetic versus obese and diabetic, a GWAS was not able to identify a signal in those three cohorts?

37:57We identified several and remember their associations. Of course. And they're in non -coding regions. The TCF7LT2 gene. We found that. But that had already been described by Dr. Michael Stern in San Antonio many years before. So we repeated with Michael Schoen. And other people have shown that. So there are a number of associations. Again, if you ask me how many genes have And we truly established that are really important in terms of causing type two diabetes. I would say very, very few. I know the genetics people out there probably hate this and they'll say that we can put together a genetic score.

38:37But when they talk about a genetic score, it's not that they causably associated a gene with that. It's an association. It's an association. We have a whole different approach if you want. I can tell you what we're doing that may give some insight. And then people started to think about rare diseases that maybe the problem is in one family you have this particular genetic mutation. Another family you have a different genetic mutation, a third family a different genetic mutation. And then when you do the GWAS study, you got this mixture of individual genes. What about the phenotype? That's the answer.

39:13I've taken care of a couple of patients with type 2 diabetes who are very lean. including one patient whose body fat by Dexa was about 8 % for people listening that is insanely lean. So you take an individual whose body fat is 8 % and yet they have type 2 diabetes. The first thing that comes to my mind is a lipidistrophy. Is this an individual whose adipose tissue is the problem? In able to assimilate enough excess nutrient i .e. glucose into the fat cell. And so they're undergoing the toxicity associated with an insufficient reservoir. Is that what could be the causal, not that I can tell you what's causing the lipidistrophy, but is the lipidistrophy, the issue that's driving the diabetes?

40:09The answer to that is it's very clear that lipidistrophy can cause diabetes. This, I would say, a very, very rare and unusual cause, but well -established. But you're saying that's not what would explain one percent of diabetes. No, no. Jerry Schoeman has done some beautiful work in this area. So it's unequivocal that lipodistrophic people, because their fat cells can't take up the fat. It ends up in your macarium, cause heart disease. It ends up in the beta cells. It's in your beta cell in the muscle. But that's a very, very small percentage. So the basic genetic ideology of the insulin resistance, the P -PAR GAMER gene has been associated.

40:49There are about seven or eight genes. There's a recent study, I think it's in Nature Genetics by Brown where they've identified eight, and again, their associations, except I would say the P -PAR GAMER gene that is pretty clear, that's a causal. Did Michelazar do some of this work? He's worked in this area, but again... The long list of folks at the point. Yes. The number of genes that have been described, the other thing people said, well, maybe there are 20 genes involved each giving a small component and that's why it's so difficult. Well, all of these hypotheses have been difficult to prove in the simple fact is we don't understand the genetic basis.

41:27In part because diabetes in my opinion is a very poor phenotype. Diabetes is a very heterogeneous disease. So, when we talk about diabetes, if that's your phenotype, it's not surprising to me that it's going to be difficult to define genes that are related to diabetes. So what I'm going to tell you about, I don't want to take the credit for this. So one of the people in my division, Dr. Luke Norton, working with Steve Parker at Michigan, I'm involved because I'm doing the insulin clamp studies. We're taking as a phenotype muscle insulin resistance. This is a very, very specific phenotype. This is not diabetes.

42:10The ominous octet, my pathophysiology. That's eight problems. Okay, this is muscle insulin resistance. I'm going to do an insulin clamp now. And then I'm going to do a muscle biopsy before I do the insulin clamp. And I'm going to do a muscle biopsy at the end of the insulin clamp. And what happens? During the insulin clamp, I know exactly how sensitive of our resistance you are to insulin. I've got the most definitive phenotype in the world. No one gets this kind of phenotype. And now what do I see? An enormous amount of chromatin opens up. This is the epigenetic component. Genes in the chromatin area that you're never ever going to see in the basal state.

42:52And that's why we think this is hypothesis now that why it's been so difficult with all of these GWAS studies to identify genes that are associated with diabetes. And now we're starting to see diabetic people and non -diabetic people. We're starting to see some associations which we think now are causal and we can relate to the insulin resistance with the clamp. Let's just pause there for a second, Ralph. I want to make sure everybody's following what you're saying. You're saying, look, one of the challenges of having a disease that isn't perfectly, perfectly, clearly defined where every single member of the class that has the disease looks exactly the same, the word for that is heterogeneous.

43:34So let's take an example where the disease is very heterogeneous. Sickle cell anemia. Correct. Everybody who has sickle cell anemia from a pathophysiology standpoint is identical. Correct. And guess what? There's a single mutation that defines the disease. Because you have a single gene that defines the disease, one gene, mutated, produces one change and one base pair that changes, one amino acid that changes the property of the hemoglobin molecule and everybody looks the same. But you're saying Peter, it's totally different. With type 2 diabetes, we have some people that are thin, some people that are fat, some people that have lots of insulin resistance in the muscle, some people that don't seem to have much, but it's all in the liver.

44:15I want to make sure we define the octet, the ominous talk, Tet. But if that's the case, why would you ever expect to find a simple genetic answer? You're right. Definition. It's going to be a mess. Absolutely. And so if you don't have a very definitive phenotype, it's going to be difficult. But the implication, by the way, is any physician who approaches a patient with type 2 diabetes as a single entity is going to be providing suboptimal care. Yes. I've been fighting for 20 years to convince people you need to start with combination therapy from the beginning. Finally, 2022, the American Diabetes Association has made a comment.

44:52And for the first time, suggest that you should consider starting with combination therapy. We can talk about the therapies in detail. But yes, you have to take a precision medicine approach to type two diabetes, which begins by trying to identify which phenotype your patient is. Before we continue, I just want to make sure that everybody understands it's loop, Norton in Steve Parker and they're the rain child. I'm involved. I understand the disease. We're doing the insulin clamps We're giving them the phenotype and they're doing single cell. It turns out there are 10 12 different types of cells within the muscle So we tend to think the muscle.

45:26Oh, there's a myocyte. That's the problem But it's probably cells also talking to each other making it even more complex So we're at an early stage in the development, but we're enthusiastic that we really have not discovered these genes. So we think that epigenetics are important, and this is part of the epigenetic phenomenon. We'll see where it takes us, but we're pretty excited about these findings. Let's go back to the ominous octet. Make sure I have that defined, and all our listeners do. So in 2008 at the Banting Lecture at the American Diabetes Association, the title of the Banting Lecture was from the triumbrate to the ominous octet.

46:05So what was the triumbrate? I got the young investigator award, the Lilly Award from the ADA 1987. So the triumvirate was very simple. The beta cell, it fails. Insulin resistance in the muscle. When you ingested a meal, the muscle didn't take up the glucose because you're insulin resistant and insulin resistance in the liver. When you ate a meal, insulin didn't shut down the liver. So that was the triumvirate. So, from the tram break to the ominous octet, we needed to add five more players. So who were the new five players? So number four on the list was the fat cell, and a very deserving guy.

46:45So the fat cell is your friend initially. You, over e, you take in excess calories, you store them in the fat cell that can't hurt you there. But if you keep expanding those fat cells, the fat cells become very, very resistant to the anti -liplytic effects of insulin. And now you start to pour fat out into the blood stream. We've shown this as a big interest to Jerry. Very counterintuitive. counterintuitive. Not that we should mire ourselves in teleologic things. Do you have a sense of why? Yeah. So the insulin signaling system and multiple early steps become severely impaired. And when you get insulin resistance in the glucose metabolic pathway, there are changes that alter the cell metabolism so you become very resistant to insulin's anti -lipolitic effect.

47:31And so now, if you look at people who are obese or people who have type 2 diabetes, their plasma FFA levels are very, very high. And those FFA levels, and this is lipotoxicity, and we've got a long history of studying this, high FFA levels, impair insulin secretion, high FFA levels cause insulin resistance in the muscle, high FFA levels cause insulin resistance in the liver high FFA levels impair the insulin signaling transduction system and in fact one of my previous fellows who's now back with me here at UT Dr. Belfart was the first author on this paper showing that just physiologic rises in the plasma FFA literally obliterate the insulin signal transduction system which is the first step in glucose metabolism.

48:20I always thought that the reason we saw high free fatty acids in people with type 2 diabetes was not because the fat cells were undergoing more lipolises, but because the fat cells were themselves becoming resistant to insulin and not able to take up fat. So same net effect, but I was kind of drawing the arrow of causality in the other direction. The arrow is more on the other side. The fat is pouring out fat. And you can show that the lipolytic enzymes are all resistant insulin. We've shown this other people are showing it. So these elevated FFA levels are a disaster. So the fat cell initially is your friend.

49:02It is your friend who goes to foe. That's from the bed. That's from the bed. That guy. So that's number four. Number five is the gastrointestinal trap. And of course, I'm sure I talked more about this when we talked about it. about treatment, but when you eat a meal, you release two Inquitin hormones, GLP1 and GIP, glucon -like peptide, one, glucose -dependent, insulin -trophilic, polypeptide. Those two Inquitin hormones, when you eat a meal, account for about 70 % of the insulin that's released in response to the meal. So now, what is the problem? Is the problem that you don't release enough GLP1 and GIP?

49:39or is it that your beta cell is refractory to the GLP1 in JIP? What's the later? Let's say that again, Rob. I want to make sure people understand this, and the reason it's important is obviously everybody listening to us right now is very familiar with drugs like semi -glutide and trozepatide. But I want people to understand why those drugs were developed. And of course, semi -glutides already probably what the third generation of it anyway. So when we go back in time, we'll understand why people try to develop these drugs. but just say that again. So you eat your meal. GIP, GLP1 are increased.

50:12And they come out normally. Yep. That's not the problem. And they're telling the beta cell, hey, make more insulin. Beta cell's deaf, not listening. It's resistant to the GLP1 and GIP. And he should be responding to 70 % of his input should come from that signal. 70 % of the insulin that's going to come out is dependent on that GLP1 and GIP. So you can imagine that that's a huge problem at the level of the beta cell in terms of the defect an insulin secretion. And tell me why is it mechanistically that the beta cell becomes deaf to GLP1 and GIP? I don't know that we know the answer to that. So it's just another horrible piece of this puzzle where everything starts to work against the patient.

50:54So this is an area of course intense investigation, but the clinical counterpart of this is you've already mentioned the drugs that are out there. The GLP1 receptor agonist. What I'm doing is I'm giving you a pharmacologic dose of GLP1 and I'm overcoming the resistance at the level of the beta cell. Now there's another component to this that we'll get to and that's glucose toxicity. And these are studies that were done by Jens Toll and the group in Denmark. They took people and they infused GIP. We're talking about GIP and you don't respond to the GIP. These are type 2 diabetics. and then they intensively treated them with insulin in lower their glucose.

51:33And then when they come back with the GIP, you reach a normal amount of insulin. So this is a glucose toxic effect. So you asked me mechanism. So we know that at least for the GIP, the glucose toxicity is impairing the ability of the beta cell to response to the GIP. But not necessarily GLP1? No, no. And that doesn't correct the GLP1 problem. So there's true resistance still even though I normalized the glucose in terms of GLP1. So this Inquitin axis the gut is a very important endocrine organ and that's number five in the ominous octet. Number six in the ominous octet is the alpha cell. I would say the father of hyperglue gonemia this Dr.

52:20Roger Unger and Dallas. He was one of the very first people to show that diabetics had very high glucaun levels. And glucaun drives... Talk people what glucaun does. Yeah, glucaun, it drives a pedaglucose production. So if your glucaus gets too low, your alpha cells will release glucaun. So the alpha cell consents the glucose. And so if you're hypoglycemic, this is an important defense mechanism. You release glucaun, that stimulates your liver, and the glucose production goes up, a return to glucose to normal. But a diabetic already has a high glucose. We don't want high glue gun levels. So paradoxically, there's very high glue gun levels in the diabetic.

53:02And those high glue gun levels are very important contributor to the Epatic insulin resistance because they're driving the liver to make glucose. And so just to make sure that I'm embarrassed to say I forget this from biochemistry, is it driving the liver to make glucose out of, for example, glycerol amino acids or other? theogenic pathway in glycogenolysis acutely. So if I acutely give you a glugging on, the first thing that happens you break down glycogen, but very quickly you get rid of all the glycogen that's in the liver. And so chronically now you're running on gluconeogenesis, but glugun stimulates both pathways.

53:38And does it also drive hepatic glucose output? Or does it just drive the creation of glucose? No, no, no, it absolute terms. It increases hepatic glucose output as well as gluconeogenesis. Yes, and that's a important reason why you have fasting hyperglycemia. So when you wake up in the morning, and your blood sugar is 110 milligrams per decider, that's the liver. And part of that is because your liver is intrinsically resistant to insulin. Part of it is because the liver is now responding to the glucagon and producing an excess amount of glucose, both through gluconeogenesis and through glycogenoluses.

54:14Although I would say the major contributor is the gluconeogenic pathway. Now, that gluconeogenic pathway is also turned on because fat is coming from the fat cell. Remember I told you the FFA is eye. Yes. Glitterol is coming from the fat cell. Yes. We talked about some of the work that Jerry did. This is Jerry's work showing that glissorol coming from the fat cell is an important driver of gluconeogenesis. And then a paddock fatty acyl CoA levels are up because you have all this fat pouring in and that's activating the enzymes, pyruvate carboxylase that are driving the gluconeogenic pathway. So the metabolic, the actual pathways, I think, have very well worked out.

54:53So glugun, alpha cell, bad guy. And so is the alpha cell over producing glugun in this state? Yes, absolutely. Absolutely. And this is really rudge or anger in dialysis. And again, why is it over producing it? Why is it doing something that doesn't make any sense in the context of what's happening? And a certain way this is also insulin resistance because hyperinsulinemia shuts down Google gun and we have very high fasting insulin levels in the diabetic, okay? Now what is it? What's the sensing mechanism within? It's counterintuitive usually when things go wrong they get attenuated, right? Like it makes sense that the beta cell eventually fatigues because that's an attenuation of doing something that it's getting tired of doing.

55:36The the the the alpha cell ramping up is a little less intuitive. You're going to see it gets even worse when we talk about the kidney, which is number seven on the list. All right, let's go to number seven. Okay, so people don't know I'm also board certified in nephrology. In the old days, I trained as a micro punctureist. I used to sit with a microscope. I would draw my little pipettes out the night before and put the little micro pipette in the tubules and I collect tubular fluid. What I was interested in, and this is when I was a renal fellow at University of Pennsylvania, I was interested in glucose and phosphate transport.

56:11And I published the series, I had studied pretty elegant papers in the JCI, looking at how glucose and what regulated glucose in phosphate transport. And I knew that there was a molecule called fluorescent, that blocked glucose transport in the kidney. And so I took this molecule called fluorescent and it blocks glucose transporters. There are two transporters in the kidney. SGLT2 and SGLT1. SGLT2 takes back 90 % of the glucose. If it does its job, SGLT1 takes back the other 10%. And then in your eye, even though we filter 180 grams of glucose per day, no glucose appears in the urine. But what I showed is that fluorescent, it blocked both SGLT2 and SGLT1.

56:57It blocked glucose transport and it also blocked phosphate transport and I showed that glucose and phosphate transport were coupled. When I was doing these studies, even though I was in the phology fellow, I had previous done my Endocrine fellowship at the NIH in Baltimore City hospitals. I had an interest in diabetes and I said this would be a great way to treat diabetes. So in the old days, we did things for science and I published a series of four papers in the J .C. And I never even thought of, to be honest, with you of patting this. I have a significant other who said to me one day, she said, Ralph, you're one of the smartest guys I ever met.

57:38And I said, yeah, I know that. And she said, you're probably the stupidest guy I ever met. And I said, why? She said, you're going to pat in this drug. So I actually worked with Bristol, my squib, and then AstraZeneca. And that eventually led to the, that a guy closing coming to the market. But what we showed, and this is human body, which is the first SGLT2 inhibitor. That's correct. Yes. Brand name on that one. Forsega. Forsega, right. Kanagha Flosin was next. Ampuglyphlosin. And then Kanaglyphlosin, Urteglyphlosin, do we have a bunch of them? They're all very good, basically, to do the same thing.

58:12But what we showed was the SGLT2 transporter was markedly up -regulated in the kidney. Let's just wrap our heads around that. This again. This is so counterintuitive. I know. Okay, this does not make any sense. I want to just bring it back to people listening so they understand what we're talking about here. The kidney is this massive filtration. Another remarkable organ. No offense to the nephrologist. Not as remarkable as the liver, but every bit is remarkable in terms of... I think it's more remarkable than the liver guys, so that's okay. Everything that's floating through our plasma, our kidneys by the way, they take 25 % of our cardiac output.

58:49But, huge. Yes. So it's massive. This organ weighs 2 % of our weight and takes 25 % of our cardiac output. Why? Because we have to take everything that is in our circulation and dump it out. And then the kidney has to selectively bring back in what's normal. This was explained to me, I still remember in medical school as the brilliant trick of evolution. Evolution was never going to be able to predict every toxic thing we might encounter. And therefore teaching the kidney, how to spot toxic things and get rid of them would have been a failed mission. Rather, it was better to teach the kidney what was absolutely necessary and to discard all other things.

59:28So... Recibel way. Yep. So it's the take everything out of your drawer and dump it out and only bring back the socks and underwear that you need. So, glucose, potassium, sodium, you name it, chloride, phosphate. All of these things get dumped along with everything else. And then it knows I need this much glucose. I need this much sodium. I need this much potassium Dada Dada Dada Dada Dada Dada Dada Dada. So SGLT2 does the lion's share of this. It takes back 90 % of the glucose and now So here's a diabetic with a very high glucose. Right. So my point was SGLT2 if it had a brain Would say oh you have too much glucose turn off turn it off How about we just stop reabsorbing all this glucose?

1:00:10But you said it's the opposite. I told you earlier. It's gonna get worse It ramps up SG -Oxi too. So as a doctor, I want the kidney to dump the glucose out in the urine. But what is the kidney doing? It's doing the opposite. It's holding on to the glucose. Even as the renal fellow, it became clear to me, this is such a simple way to treat diabetes. And the fact is, it's so simple, no one thought about it. The only dumb thing that I did was I didn't patent it, which I should have done. I probably never have to write another NIH grant for the rest of my life. And then we went on to show, and in fact, this is the first definitive proof of the glucose toxicity hypothesis.

1:00:49So we did all of these studies initially in animals, and this was all published in the JCI, and Luciano Rosetti is one of the fellows at this time. Actually, Jerry Schoeman was a fellow on the papers as well. And what we showed was that you could take different types of diabetic animal models, and you could show that they're reabsorbing excess amounts of glucose. And then if I treated them with fluorescent, because that's what was available, they simply peed the glucose out in the urine. And now all of a sudden their beta cell started functioning normally. Muscle insulin sensitivity improved. So, of course, that's wonderful if you're a mouse or a rat.

1:01:28So he said, well, what about humans? And so the original studies actually were done. This is kind of an interesting story behind this, but the initial studies were done with DAPAGLYPHLOZIN. And we showed with just 14 days of treatment with DAPAGLYPHLOZIN, we markedly lowered the fasting and post -prandial glucose. We improved insulin sensitivity by 35 % and we made a major improvement in beta -cell function. Now the beauty of this, SGLT2 inhibitors are only in the kidney. They're not in your muscle, they're not in your beta -cell. And the only thing that the SGLT2 inhibitors do makes you put glucose out in the urine.

1:02:07The only change in the plasma was the glucose came down. And now insulin sensitivity improved and muscle and beta -cell function improved. And this was the first, now in humans, even though the original studies were done in animals, first studies to show an improvement in the reality of glucotoxicity. What was interesting is that when we started to work on developing this with BMS in AstraZeneca, the company decided, well, we should get some nephrologists in the sea about this story. They said, look, if you listen to what Dr. DeFranco says, this will be a disaster. They said, why? Because you put glucose in the urine, it will glycosolate the proteins, then you'll cause kidney damage.

1:02:49And they actually held up the development of the SGLT2 inhibitors. And the way we finally convinced them to go ahead is that there's a disease called familial renal glucose urea from day one of their life, they're being out tremendous amounts of glucose. That perfectly normal kidney function. How many grams of glucose can be differentially or extra secreted basically in the presence of an SGLT2 inhibitor today? It kind of depends on what the level of GFR is, but it could be anywhere from 40 to 60 grams up to 120 grams of glucose. And the higher would be in somebody with a higher gradient? Yeah, the higher the glucose.

1:03:27So higher the, yes, because you'll filter more glucose than there's more glucose to be blocked at the level of the kidney. And these drugs are very, very good. Now I actually in developing these drugs, as I said, I'm also an aphrologist based on the Barry Brenner hypothesis. I predicted that these drugs would save your kidneys according to the better Brenner hypothesis. And that's all turned out to be correct. These drugs are great for the kidney. what I never ever envisioned at that these drugs were going to save your heart. I want to come back to that because I'm making notes of other things I want to come back to.

1:04:02And so I want to come back to just so you can hear me say it now and we remember, I want to come back to combined inhibitors, the SGLT2, SGLT1 inhibitor. I think there's a new drug. So to go like close. Yeah, it does both. We'll just touch on that. And then I want to also come back to the broader zero protective nature of the SGLT2s as documented by the ITP in mice and then also in the human studies for cardio protection. But before we do that, we need to finish the omniscientic. We gotta go exactly. Let's go back to number eight. The brain. So the brain plays a role in a somewhat indirect way.

1:04:33So every day you have your breakfast, your lunch, I actually eat only once a day, but at some point you eat a meal and at some time during the meal, I'll say, okay, I'm hungry. I start eating. Why'd you ever think? Why does that happen? Well, because there are certain hormones that are released or inhibited that tell you, okay, you're satiated, stop eating. Well, one of the very important ones is gel P1. That same thing that's increasing insulin secretion, your brain has become very resistant to gel P1. When you eat a meal, amlin comes out. It comes out in a one -to -one ratio with insulin. Your brain has become resistant to amlin.

1:05:07Your brain is resistant to leptin. So there are a lot of these anorectic molecules that your brain has become resistant to. And these molecules, it's another area of interest of mind. These, they work in the hedonic areas in the brain. So in the putamen, the profrontal cortex, and they tell you to stop eating. And unfortunately, and this is the big unknown is what's going on in the brain. The neurosurgery is clearly distorted. Not only is the neurosurgery distorted, one of the big things that we are interested in, Dr. Peter Fox and myself at UT, is if you look at the gray matter in these areas, in the areas that are critically important in regulating your appetite, there's shrinkage of the gray matter area, okay?

1:05:53And in these areas, if you do an insulin clip, the brain is insensitive to insulin in your eye. In obese people, these areas in the brain with this abnormal marked increase in glucose uptake. Incredible finding. Who would have thought? I'm sorry. You're saying that these are the few areas in my brain and your brain that are actually default insulin insensitive. Yes. Don't take up glucose. Correct. If I do an insulin clamp. So what is their fuel source? Lactate? Well, in response to insulin, they don't take up more glucose. Oh, okay. I'm sorry. Got it. Because remember, this is from the K -Hose studies.

1:06:30As long as your glucose is about 50, your brain is happy. So this is actually in the evolution of the human being. This is phenomenal. Because in the old days, you may not eat. You may slaughter one of these beasts. Yeah, you're not eating for days. You're not eating for days. So your glucose would drop. So if your normal fasting was 80, if it dropped to 40, you were okay because your brain saturated at your 40. You got below 40, you're in trouble. So you have a big buffer here. But now if I infuse insulin and your glucose is 80, your brain doesn't take enough more glucose. It's quote insulin insensitive in a certain way.

1:07:04Now, of course, if you take people with mild cognitive impairment, there have been some experiments that actually suggest in these people, insulin infusion can transiently improve glucose uptake, but presumably that's because they're insufficiently getting glucose in the disease state. Yes, this has been postulated. There's also suggest that there's brain insulin resistance, which is, I'd say an interesting concept and may play some role in this no -cognitive dysfunction all the time as whole different story that's in evolution. But to come back to the ominous octet, Now, if you overeat, what happens?

1:07:39You gain weight. And when you gain weight, you become insulin resistant, severely insulin resistant. That's lipotoxicity. And we've done studies in both directions. I can put an IV and I can infuse an emotion of free fatty acids. And I can show within two to four hours, I induced severe insulin resistance in the muscle, in the liver, and I markedly impaired beta cell function. And then we don't have this drug in the United States, but there's a drug that's available in Europe and I have an IND to use it. It's called a SIPPOMOX. It inhibits lipolosis. It's like SGLT2 inhibitor. The only thing to do is block glucose reabsorption in the kidney.

1:08:21A SIPPOMOX all it does is do block lipolosis. It lowers your FFA level. And we've done this. Does it result in any meaningful clinical increase in adiposity or is it so subtle that you don't notice it? Over 12 days, no change in adiposity, huge improvement in insulin sensitivity and muscle. Why is it not approved in the US? I don't know the company that developed it in Europe, ever tried to get it approved in the US. I would say modestly effective in lowering triglycerides. And we have phenofibrates which are much more effective. So that may be the reason... But the triglyceride in the FFA are not the same thing.

1:08:59No. But that's the reason why it's approved in Europe. But if you lower the FFA, that's the precursor for triglyceride synthesis. So it has an effect to lower the triglycerides. But the key thing is if you lower the FFA, and we did this for 12 days, we did it in both obese people and in diabetic. You markedly improve insulin sensitivity in the muscle. If using MRI, you can measure muscle fat, goes down dramatically and correlates with the improvement in insulin sensitivity. We also measured ATP generation because this issue is this clearly mitochondrial dysfunction if you're diabetic. That's unequivocal.

1:09:37The controversy is the mitochondrial dysfunction causing the insulin resistance or is the insulin resistance causing the mitochondrial dysfunction. So in this study that we did when we lowered the FFA and lowered the muscle lipid content, we saw about a 50 % improvement in ATP generation mitochondrial ATP generation. So at least this says that part of the mitochondrial dysfunction is secondary to the lipotoxicity and insulin resistance. But this still remains, I would say, a controversial topic. Clearly, it is mitochondrial dysfunction. If you can improve it, that's going to improve insulin sensitivity.

1:10:20Is there anything that improves mitochondrial function more than a Robic exercise training? P .O. glittersome. The drug that I can't get people to use, which is a phenomena. By activating P -part gamma, it does a lot of good things. One of the important things that it does, it has a huge effect to improve mitochondrial dysfunction. It has direct effects. It works directly through P -part gamma to do this. It also binds directly to the mitochondrial pyruvate carrier. That influences flux through the mitochondrial chain. Why don't people use this drug today? Huge misconceptions. I guess we'll talk about therapy.

1:11:01We'll come back to it. As part of my triple therapy regimen, I use a GLP1 receptor agonist. I use PILGlytazone and I use an SGLT2 inhibitor. There's a fourth good drug and that's metformin. And you might ask, well, why is metformin number four in my list of good drugs since I single -handedly brought metformin to the United States in 1995? No other endocrinolous involved in this. 1995 made formant was a revolutionary drug. Why? We had insulin, cell phone, ures. So now we had a drug that really could work. It's still a very good drug. And of course it's very cheap. It's $5 a month in the state of Texas.

1:11:42But we have much better drugs. Pio -glidazone causes weight gain. Now, here's the problem. It'll become very obvious. We talk about these paradoxes. The more weight gain, the greater the drop in A1c. The more weight gain, the greater the improvement in insulin sensitivity. And is it fat gain specifically? No, I'll come back to that in a second. It is fat weight gain, and I also believe muscle weight gain. The more weight gain, the greater the improvement in better self -function. The more weight gain, the greater the drop in blood pressure. The more weight you gain, the greater the drop in triglycerides.

1:12:14The more weight you gain, the rise in, greater the rise in HDL cholesterol. Sounds like terrible drug. So here's another one of those paradoxes. Why we know a few overeat in game weight, that's a disaster. But with pale glitters on, the more weight you gain, everything gets better. What pale glitters on does is it shifts weight around in the body. In my opinion, it's the best drug for treating Nash. No drug is going to be pale glitters on. The pharmaceutical companies, if you had to go up against pale glitters on all these Nash drugs, I don't believe you can beat pale glitters on. What's the brand name for pale glitters on?

1:12:47Attoce. As I said, there's this paradox. So why do you game weight? Peel that is own, it redistributes fat in the body. It gets it out of the muscle, puts it in subcutaneous tissue. Gets it out of the liver, puts it in subcutaneous tissue. Gets it out of your beta cells, put it in subcutaneous tissue. That's not going to make you game weight. The richest density of pea par gamma receptors in the hypothalamus. So when I activate these pea par gamma receptors in the hypothalamus, you eat. Okay? Makes you hungry. That's got nothing to do with redistributing the fat in the body, except they parallel each other in association.

1:13:23And so you see the weight gain and people say, oh, that's bad. But what's really doing the thing is this recycling and moving the fat around. The other negative thing about paleolidazone is it causes fluid retention. So people have associated fluid retention with heart failure. Now why do you get fluid retention? Again, people do not understand. Pio -glitter zone, the only thing, the only drug that is a true insulin sensitizer is Pio -glitter zone. Metformin is not a true insulin sensitizer. That total misconception. Pio -glitter zone, that insulin signaling defect that I told you about, Pio -glitter zone corrects that defect.

1:14:03It's incredible. We kind of glossed over this. We're going to spare people the details, but it's probably worth just reminding people. insulin binds to the insulin receptor. That's outside the cell. That's a kinase receptor, correct? There are three tyrosine molecules and they have to be phosphorylated. These are studies that run kind of other people in Boston. You mutate one of those tyrosines. You come a little insulin resistant. You mutate two of them. You become moderately insulin resistant. You mutate three of them. You're severely insulin resistant. Insulin binds to the receptor. Okay, That happens normally in diabetics.

1:14:36We showed there's no problem there. Then IRS one, insulin receptor substrate one Which is inside the cell comes up. Yes. It interacts with the insulin receptor and it gets Foss -forilated on the same three tyrosine molecules and then you activate PI3 kinase AKT we could add some more molecules in here, but this is the insulin signaling pathway That's the pathway that the earliest defect that you can show in diabetics is in that pathway. And if I recall, isn't this where Jerry argued that the intramiosellular lipid was creating the defect in that pathway? The accumulation of intramiosellular lipid?

1:15:18So what Jerry's shown very elegantly is that there are certain lipids, de -gat, and it's a specific de -gat. There are several types of decat molecules, which has confused things. So he's shown this is a specific one of the decats that activates these atypical PKC molecules and that serene phosphorylates the insulin receptor. When you serene phosphorylate the molecules in that pathway, it inactivates them, okay? And so he's done these very nice elegance studies both in peripheral muscle and in the liver showing that this plays a very, very important role in the insulin resistance. This is part of the lipotoxicity.

1:15:56I don't believe that this is the genetic basis, the genetic ideology. You get fat and you start putting fat everywhere. This is very important, critically important. That was when he gave his banning lecture, and I might say, I'm delighted that I got to write his letter of nomination for the banning lecture. He was incredibly deserving. He's done phenomenal work in this area. But that was his banning lecture, and you're right. very, very, very important mechanism of insulin resistance. And so given that that's both a very important and very common pathway towards insulin resistance, bringing it back to P par gamma.

1:16:33P par gamma is part of the pathway. It's part of the IRS one P par gamma, P i 3 K, glute four, bring the glucose in the cell. In other words, if people don't want to get mired down in this, which is totally understandable. Insulin hits a receptor, that receptor kicks off a cascade that ultimately results in a little tube, like a little straw that goes into the cell surface that allows glucose to freely flow in its gradient. Remember that same pathway also activates nitrogoxide synthase, that's right, generates nitrogoxide. And that's why we see in patients with insulin resistance, even if glucose is controlled cardiovascular disease is still up.

1:17:15A very important Yeah, a very important point. So, back to actos. So, what does it do? It activates that signaling pathway, you generate nitric oxide. Now you vasodilate. That's why the blood pressure drops. When you vasodilate, so I'm an oprologist, I understand this very clearly. Anytime you end up refuse the kidney, you'll hold on a salt mortar. You become a demeritist. And so, people associate fluid retention in a demon with heart failure. So we did the definitive study it's published in diabetes care in 2017. People just don't read. So we took people who had diabetes and we treated them with paleolidazone.

1:17:56And then using NMR very, very sophisticated techniques, what we showed is paleolidazone markedly improved marcarid blood flow. Now these numbers are going to blow your mind away. Marcarid insulin sensitivity with PET and fluorideoxyglucose improved by 75%. Your heart, we showed this before, is severely insulin resistant. I came pretty damn close to normalize insulin size therapy in your heart. Now since we're doing the insulin clamp with tradiaglucos, you can track it. 74 % improvement in skeletal muscle insulin sense. The same. Exactly the same. If you look at ejection fraction, it went up by 5 to 10%.

1:18:35Not down, it went up. If you look at every measure of diastolic dysfunction, E over A, E over E prime, LV peak filling pressures, et cetera, cardiology people understand this. The point is whether you're looking at systolic function or diastolic function, it all got better. It's a victim of maybe not so nuanced thinking about the drug. Now the critic would push back and say, okay, Ralph, but don't we have better drugs like I mean, no drug that corrects insulin resistance. Metformin is not an insulin sensitizer and people keep going back to this. I brought Metformin to the US in 1995. I did all the mechanism of action studies.

1:19:16What we showed was the insulin clamp. The drug absolutely does not improve insulin sensitivity. So let's talk about Metformin. Everybody wants to know if Metformin is geoprotective, but let's just remind people, Metformin inhibits complex one of the electron transport chain. Is that a given? Yes, I'd say this is still controversial. In high doses for sure, yes. And the kind of doses you see with giving a metformin, I would say somewhat equivocal. Is the belief that metformin's efficacy in diabetes is through reducing hepatic glucose output? That is 100 % true. Okay, and what's the mechanism by which it reduces hepatic glucose output?

1:19:53Inhibiting the mitochondrial chain and inhibiting gluconeogenesis. Well, for short, inhibits gluconeogenesis. Metformin gets indiscills through the organic cat iron transporter. The organic cat iron transporter does it exist in muscle? It can't possibly be an insulin sensitizer in muscle. You're asking the drug to do something that's impossible. Does it get into muscle mitochondria? No, it doesn't get into muscle at all. Why does lactate go up when people are taking metformin? Level of the liver. It's interfering with a robot metabolism. There's a block. This is very important. I have erroneously always believed.

1:20:31So I'm really happy to be corrected. I love being proved wrong. I have always believed that the reason we saw an increase in fasting lactate, even in healthy people, if they took metformin was because of the inhibition of the ECT in skeletal muscle. No, no. And you're saying, Peter, it's all in that. That's not possible. It can't get into skeletal muscle. Absolutely not a single molecule in the world of metformin has ever gotten into any skeletal muscle anywhere. And tell me again, Why? What's the transporter? The organic cationine transporter. That's the transporter by which metformin enters cells It does not exist in skeletal muscle.

1:21:12It does not exist in cardiac muscle So metformin cannot get into these tissues. It's a huge major misconception It can if you have very very high doses that can occur when you have very low GFR car, because metformin is excreted via the kidney. If the metformin levels build up, you can get lact gas doses. That's a very, very rare complication. That's not a reason why you shouldn't be using the metformin. And I'm not saying that metformin is not a good drug. It is a good drug. I don't think it's as good as the other three drugs we talked about. But yes, it does at high doses increase the lactate level, all in effect on the liver.

1:21:52And the old drug that caused all the problem was fendformin, I buy guanine as well, but it had a powerful effect. Yeah, fendformin was much more powerful. And when you say high dose, I mean, is two grams a day of metformin? No, no, no. That's the normal dose. That's the normal dose. Okay, so metformin has the following going for it. It's free. Yes, it's basically free. Yes, free. And it does a pretty good job at reducing hepatic glucose output. And it has no myotoxicity, frankly any toxicity. G .I. Yeah, the G .I. But you can usually overcome that with a slow ramp up. See, this is the reason why some people thought it's an insulin sensitizer.

1:22:31Fifteen to twenty percent of people have significant GI side effects and they lose weight. And if you look at the studies, on average, there's about a three kilogram weight loss with midform. And when you lose weight, you can improve insulin sensitivity. So, I think this is what's confused some of the old literature to make people think that Metform was an insulin sensitizer. But when we developed Metformin and I did all of the work that went to the FDA, if you look at the New England Journal Medicine article 1995, there are only two names on the paper. Myself and a PhD oncology lady who was the person from Leap of Pharmaceuticals.

1:23:12We did insulin clamps. many of them. We never could show MFOMO and your proven insulin since David using the gold standard with radioisotopes. Do you think many people, I feel like I'm asking you this question a lot and it's getting a little old, but do you get the sense that most people are still thinking what I think? Yes. MFOMO and gets into the muscle. Yes. MFOMO and insulin sensitizer. Absolutely. And it's an insulin sensitizer by getting into the muscle and inhibiting complex one. Absolutely. People have done pet studies, so you can label MFOMO and you give it. And then where do you see?

1:23:43It's all accumulating in the liver in the first three, four, five, ten minutes. And then what happens, you start to see it accumulating in the kidney. Why? Because that's where it's excreted. And then wait another five or ten minutes, you see it in the bladder. And that's the only place where you see metformin. You never see it in the muscle. And that's even more graphic demonstration that metformin is not getting in the muscle. And it is definitely not an insulin sensitizer. Is there a downside to using metformin in combination with the other three drugs? No. The classic study which we'll talk about, which to me should change the entire approach to treating diabetes, it's called the edic study.

1:24:21And in the edic study, what we did is we used triple therapy right from the beginning. And my point of the banting lecture, the ominous octet, if you have eight problems, I'm sure are going to be more to be found that I can give you a few more if you want. But if you have eight problems, why in the world you think one drug is going to correct eight problems And it got to happen in our lifetime So the point was you need to use drugs in combination We said we're gonna use what we think are the best drugs at the time So we started with metformin with Xenotide An old time GLP one. It is not the kingpin.

1:24:58This is the pre -Liraglutide Yeah, exactly because that's what was available drug was useless wasn't it? No, it's a good drug Sure, it's not semagglutide. You're a semagglutide. But you have to start some way, right? Yeah, let's pay it its dues as being the Gen 1 OG version of that drug. Without which we might not have, we wouldn't have semagglutide or chisepatite. Yes, it's kind of an old timer. In Pioglisone, that was the triple therapy. And then we said, every diabetic patient, they're 315 people in the study. They're having insulin clamps, hyperglycemic clamps, muscle bibles, known in the world can do this study.

1:25:31315 people, follow it for six years. So we said this is what we believe is the appropriate therapy. Then we said we'll use the ADA approach. The ADA approach is you start a metformant and when you fail even not explicitly said the next drug that you use this cell phone you're is and then the third drug that's added is insulin and we said that the goal of therapy was an A1C of six and a half. Okay, and that if you're A1C rose above six and a half, either on our triple therapy or on the stepwise treat -to -fail approach that the ADA says, ADA says, start metform and you fail, you add self -alulary or you fail, you add insulin, you titrate the insulin basal insulin up to 60 units and we said 60 units is really will cap it.

1:26:21Yeah, you're already at 2x physiologic. Yep. Now you have to split the dose of insulin, you have to be adding rapid acting insulin. I think this is quite reasonable. Six years later, 29 % of the people with the ADA approach have failed their A1C's above 6 .5. Six years later, with our approach, 70 % of the people have an A1C, it's less than 6 .5. Why? Insulin Clamp. Huge improvement with our therapy. Okay, this is the EDIC study. The three -year data published, the six -year data were writing it up. How much improvement in insulin sensitivity with the ADA approach? Zero. Betisile function. You have almost a normal betisile.

1:27:01Ralph, why the disconnect between what you're seeing in the edict study and what the ADA is promoting? You have to ask the ADA. What's their answer? If I'm a patient or if I'm a physician who's treating these patients and I'm saying, guys, I'm confused. I'm looking at the literature. I'm seeing this. I'm looking at you. I'm, by the way, I see this with the AHA and Cardiovascular guidance. And so I'm not singling out you, but is this simply a question of the pace at which medicine moves is so glacial? That's part of it. Plus, remember, if to do 315 people follow them for 16 years and do all the stuff we did, it's unequivocal.

1:27:37And why has there not been political pressure? Because the cost of insulin is enormous. Your approach is going to be less expensive. They finally said in 2022, this is state. The ADA approach is not based on paleovisiology. I view myself as a scientist, as well as a clinician. As a good clinician, I take care of hundreds of thousands of patients and 850 publications. I do clinical research, I work in people. When I do an insulin clamp study and I see an improvement in insulin sensitivity, I do a hyperglycymic clamp and I see in 350 people your base self -function, I don't need 5 ,000 people. I can't do this study in 5 ,000 people.

1:28:16No one can do this study, but the tools that we're using are so powerful. Look if I normalize your insulin sensitivity and I give you a normal beta cell and your A1C is less than 6 .5, well it's half of the 315 people, why you not think that's the best therapy. And now on the other side I have this metform and SU insulin and 71 % of the people have failed, there's zero improvement in insulin sensitivity, zero improvement in beta cell function, why you think that's such a good regimen? Now, above and beyond all that, I didn't do this study. This is the great study, GRAD. It's sponsored by the National Institutes of Health.

1:28:56And what the great study said, and I have to say this is the third study they've shown what I'm going to tell you. Dr. Robert Turner's United Kingdom Prospective Diabetes Studies showed this in 1990. Stephen Karn showed this in the adopts study in year 2005. And now we have the great study, 2020. I called this the 15 year revelation. We saw what didn't work 1990. Oh, Stephen Khan did it again. Oh, it didn't work in 2005. And now 2020, and I aged it. You know what? I'll show the same thing. And this was a sequential approach. You had to have failed on metformin to get into this study. Okay, so you failed in metformin, then you enter the study, then we go single agent.

1:29:36They want to know what's the best next drug to add to metformin. I can add a cell phone in your rear. A. When C. Went down in year one, up straight. Tell folks how a cell phone area works. Cell phone areas are all time drugs. They bind to the cell phone area receptor on the beta cell and they kick out insulin. And they're very good drugs in the first year. And then they burn out the pancreas. Well, they stop working. Yeah, I mean, basically they kick the can down the road without addressing the pathophysiology. I like that way. Other drug, DPP for inhibitor. Tell people how those work. So a DPP -4 inhibitor increases your GLP1 and your GIP level.

1:30:14Indoginously, it makes your gastrointestinal cells, the K and the L cells, that secrete the GLP1 and GIP, makes them make more GLP1 and GIP. But it doesn't increase the GLP1 and GIP enough to really give you a knockout punch. I give you an injection, you all people out there, Montenegro or Semoglutide, that's the knockout punch. When I give you the DPP4 inhibitors, they do increase GLP1 and GIP a little bit, but not powerful enough to give you a long lasting effect. So first year, A1C comes down, shh, A1C goes up. Third drug, this was very surprising to me. This was Lyroglytide. This is one of the earlier GLP1 receptor agonists.

1:30:54I thought that was going to work the best. It failed. It worked in the first year and then failed. And then the fourth drug was insulin. And the docs just didn't type to ate the insulin enough, so A1C it out and then they failed. So five years later, all four of those regimens added to metformin failed. Triple therapy, Exanditide, an old time GLP1. Pial litusone, which people don't appreciate. The only true insulin set stiser and metformin, six years later, 70 % of the people have an A1C less than seven. And let's just go back. Metformin is free. The Gen 1. Exanotide, basically free. It's basically free now.

1:31:34Piolytazone is five dollars a month. Okay, so we have three free drugs that work better. Correct. Now it's interesting when you talk about today's triple therapy, which is way more efficacious. Different choice. Two of those three drugs are very expensive. Yes. Yes, Gila Tatooine inhibitors are very expensive. And the modern day Gen 3, Gen 4, and soon we'll have a Gen 5, GLP 1, they're very pricey. Thousand dollars a month. Now, are they great drugs? Of course. I guess the question is, do you need to be on those drugs if your old version of triple therapy? Our old version is incredibly effective.

1:32:08The problem is you can't get people to use pale glittersome. And the reason is patients are frustrated with the fact that they're retaining water? No, game weight. How much weight do they gain typically? How many kilos? Depends on the dose. I don't go to the 45 milligram dose. So at the end of the year, they may gain two or two and a half kilos at the 15 and 30 milligram dose, okay? But their A1C is controlled. If you give PO plus a modern day GLP1, don't you offset the weight gain? Oh, you lose all the weight you lose with the GLP1 receptor. So if a patient is willing to go down the path of a modern day GLP1, that's my treatment.

1:32:46That's my treatment. Completely eliminate. Absolutely. And he also gives me the edema. And believe me, their A1Cs are down in the normal range. Let me tell you this first thing about PEOGlytazone and the Proactive. I'll come back. So in the proactive study, this was done long time ago. You have to show cardiovascular safety. 5 ,238 people to get into the study. You had to have an MI stroke or something bad. Have people on PEOGlytazone have to people on placebo, okay? And the Mace Endpoint, major adverse cardiovascular events, which is non -fatal MI, non -fatal stroke cardiovascular mortality, you have to show the benefit to get approval by the FDA.

1:33:22The Mace Endpoint was positive. And so when I talk to cardiologists, I like to say, what was the one thing in the P .O. glider zone that predicted that you would not die? They don't know. You know what the one thing that predicted that you wouldn't die? Way game. So I jokingly say, look, you can either be a little fat and alive or you can be lean and dead, which one you're gonna pick. I think I go for being a little bit chubby. But now that's not even a necessary comparison. and you don't even need to make that trade off with a modern day GLP1 agonist. And we've done this, and we've published this.

1:33:58If you tied my hands behind my back and said, Ralph, you can only pick one drug. I would pick one of the newer GLP ones. They're incredible drugs, but that's not what I'm gonna do. Even for a lean diabetic? They're a little bit different story, but the answer is basically yes. Let me narrow that down a little bit. If I had to pick two drugs, I would pick Peele Glitter Zone with one of the newer drugs. And for sure, if you had any kind of renal cardiac disease, I'm going to pick an SGLT2 inhibitor. But I would say, although this study will never be done, if you're a newly diagnosed diabetic, and you don't have any cardiac symptoms, why do you think that the SGLT2 inhibitor is not doing all of the beneficial things in that newly diagnosed diabetic that it's doing and the people who get into these studies already have cardiac disease?

1:34:48So if you have a cardiac problem, I put you on the STLT2 inhibitor, you're less likely have MI stroke, etc. It's doing good things. It's doing, in my opinion, the exact same good thing, and someone who I'm just diagnosing for the first time when I put them on the STLT2 inhibitor, but no one is ever going to do a study. It's impossible. I'm going to take 1 ,000 people, and probably have to take 20 ,000 people, newly diagnosed, and then 10 ,000 going STLT2 and 10 ,000 on placebo. I'm going to follow them for 20 years to see who's going to have their heart attack. No one's going to do that study because they're going to get all kinds of drugs.

1:35:24Yeah, that's never going to happen. But I also don't think it needs to happen in the same way that... I agree with you. In the same way that we saw, for example, PCSK9 inhibitors reduced mace in people with secondary prevention. Yeah. Take people who had already suffered mace, put them on a PCSK9 inhibitor, you secondary prevention, reduce, subsequent. Well, of course, everybody's using these for primary prevention. Now, that's effectively what you're saying. Sure. We already know the SGLT -2 works for secondary prevention. That may never get approval for primary prevention, but it probably justifies its use.

1:36:00I agree with you 100%. So just to make sure I'm synthesizing what you're saying, Ralph, if you only get one drug and your price agnostic, G -O -P -1 agonist, if you get to add a second drug, you're gonna add PO. If you get a third drug, especially if you care about your heart, SGLT2. Yeah, SGLT2. And what's amazing is Metformin didn't even make the top three in your list. But it's never for it. So here's my question. Given that Metformin is free, should we just be adding it the second we put on the GLP1? I don't have any problem with that. Yeah. And also we have to be cogniz of the fact these newer GLP1s.

1:36:37So potent. But they're $1 ,000 a month. Yeah. I want to ask you about that. So just again for the listeners, right? Semiglutides Gen 3, Terzepatite is Gen 4. Redid True Tide is coming out, assuming the Phase 3 goes according to plan. Hey, Kargisama is the new Nova 1. Yeah, let's go back to Redid True Tide. GLP 1, GIP, and Glucogon. Glucogon, can you explain that in the context of the octet where Glucogon is going up? Yeah, I can, I think. It's not proven. So, remember I told you that insulin knocks down Glucogon. So if I give you a GLP1 receptor agonist, and I kick out insulin, and I get you well insulinized, any negative effect that might be related to Gugugan is going to be obviated.

1:37:23So that Gugugan effect to drive a paddock glucose production will be totally blunted by the insulin secretory effect. This is the other thing that bothers me about these GLP1s. These are the best drugs in the world for losing weight. These are the best drugs in the world for saving your beta cell. I told you that when you eat a meal, 70 % of the insulin that's secreted is coming from the GLP1 and the GIP. People have stopped talking about this effect on the beta cell. I told you, if you want to look at type 2 diabetes, big problems beta cell failure, insulin resistance. These GLP1's, they're saving your beta cell.

1:37:58We've forgotten about, we've come so enamored with the weight loss. I don't want to downplay that at all because the weight loss and the lipotoxicity, a huge problem is causing insulin resistance. But people are forgotten how powerfully drugs are on the beta cell. So when I give you this drug and they work on the beta cell and they kick out insulin, any negative thing that glue guns doing will be totally negated. Now you may see some good things that glue gun are doing that we couldn't appreciate before. So what are the good things? Some people have suggested the increases thermogentic energy expenditure.

1:38:32I don't believe that. There are animal data. I don't believe this in humans. I believe that it's exerting an anorectic effect in the central nervous system. That is, I think, yet to be established. Pretty sure there are studies going on now at the Pennington Institute and maybe also in Orlando where they have these chambers where you can. TRI. Yeah. Yeah. So I think we'll get an answer about energy expenditure. Yeah, I would be surprised if they're going to see a clinically meaningful increase in involuntary energy expenditure. I'm with you. I think it's all appetite. Here's another issue. It is very interesting.

1:39:08If you look at all these big GLP1 studies, Cardiovascular, what's the reduction in Cardiovascular events? Almost uniformly 20%. Old dudes, Exanotide, etc., Lyroglytide, new dudes, 20%. Even though the weight loss with the newer ones is much greater. much greater. I suspect in terms of cardiovascular benefit there is a cap that once you've lost a certain amount of weight and you got in a certain amount of lipotoxicity and all the good things that these drugs are doing, you don't go beyond that. Even though you're losing more weight and also if you look at the A1C, yes, Mangaro does drop the A1C a little bit more than Semaglutide, but they're both pretty powerful.

1:39:54returitide does a little bit more and does cargisama do a little bit more, but they don't do a lot more. So I also think there's also going to be somewhat of a cap on how much you drop the A1c. You get two and a half percent drop, do you need to drop a three? So you're saying if a person shows up with an amy -glub and A1c of nine and a half percent, this is a person who hasn't come to medical attention soon enough. And I'm going to give you the answer definitively, but I'm going to let you ask the question. You were happy if they only go from 9 .5 % to 7 % if they only had a 2 .5 % drop You wouldn't try to get them down to 6 % I wouldn't we've done the study Old time guys, right?

1:40:34So this called the Qatar study So there's this concept that's out there and again what drives me as science if you understand pathophysiology And as an abnormality and you correct the abnormality things get better So in the Qatar study and there are 220 people are so in the study To get into the guitars that you had to be poorly controlled and met for them in cell phone area. So you had to have failed on this. And the average A1C was about 10. And about a third of these people were symptomatic, meaning they had polyurea, polydipsia, they were losing weight. And so the current concept is, in those people, you would put them on a mixed split insulin regimen.

1:41:16You would get rid of the glucotoxicity, you would get rid of the lipotoxicity, and you get their A1C down to six and a half and then now you could put them back on the oral medications or whatever and now they respond because you got rid of the glucose toxicity and lipotoxicity. We said, well, that may or may not be true. So we said, well, half of these people are starting with an A1C above 10. We'll go on a mixed split insulin regimen with a large gene and a rapid acting insulin. And the other half, I'm going to go on that old dude exeditide and piodlytosome, one years later, the A1C in the group with the mixed -plid insulin regimen is 7 .1%.

1:41:58And we're very good at insulin. Why couldn't we go lower? Because we got into trouble with hypoglycemia. The A1C in the group treated with exanityed and pyl -litazone is 6 .1. Then we said, okay, look, we'll do a subgroup analysis. So about one -third of the people will just look at the people who are symptomatic. The starting A1C is 12 .2. Three years later, their A1C is 6 .1. From 12? 12 .2 symptomatic. On which combination? Exanotide and Pio -Glitazone. Without even metformin. They had failed a metformin in SU to get into the study. So what we were saying, look, if you have drugs that correct the insulin resistance, that's Pio -Glitazone.

1:42:41This is almost impossible for me to imagine. I can send you all the papers. It's all published. I hope every single family medicine, internist, everyone who ever takes care of somebody with diabetes is listening. I also do. Because you're basically saying we can take these two old, cheap drugs and take someone from the most brittle type two diabetes. I mean, he may go up in a one -see of 12. Pretty bad. You're knocking on death's door. Correct. You're going to go blind, you're going to have your toes amputated, you're not ever going to have an erection again, and you're going to die of cardiovascular disease or kidney disease or Alzheimer's disease quickly.

1:43:26These numbers I'm telling you, they're right from the paper and it's a large, over 200 people. And in a couple of years on two old, cheap drugs, you're normal. Yep. What makes these studies so solid is we have very sophisticated pathophysiologic measurements. No one can do what we do. So the only pushback is those patients are going to have to gain a couple of kilograms. But of course, if you're willing to now spend a bit more money and switch them from Gen 1 to Gen 3 or Gen 4, GLP, 1 Agonist and GIP, then all of a sudden you ameliorate that and you get all the benefits. This becomes a non -issue.

1:44:01Put cost aside. I would wonder if you admet Foreman, you almost cancel out the weight gain a little bit because you might get a little bit of the GI improvement and you get the 2 to 3 kilos of weight loss there. These drugs are so powerful when you put them with pale glitters on. I mean, you lose almost the same amount of weight. They're huge in terms of getting you to lose weight. Which was that study? This is called the Qatar. It was done in Qatar. Qatar the country. The country. And I need to give credit to Dr. Bahamut Abdugani who's been sort of my coworker in all of these studies. And my amids on the faculty at UT in our diabetes division.

1:44:38Can we at least assume that the Gulf states are paying attention to this? A, the study was done in Qatar. B, the Gulf states are disproportionately ravaged by type 2 diabetes. Yep. Is it at least being heated there? They are. And I can tell you, we have a big program that's going on there as well as in Kuwait. And we actually have a formal cooperative agreement with the Kuwaiti people. So at the Dasmian Diabetes Institute, we have trained them. My people have been there trained them how to do these insulin clamps and sophisticated metabolic studies And they take care of the patients. So here's another thing that's pretty exciting that we're doing and again It's looking for genes that cause diabetes.

1:45:21So you eat a meal. Okay, you eat a meal your glucose goes up That's the Crete Sinslam. There's amino acids in the meal that secretes insulin and GLP1 goes up and that's secretes insulin So now when you eat a meal, they're already three stimuli. And now you're looking for a gene or a set of genes that might be associated with Betacel failure when you have three stimuli. Now that's going to be pretty confusing. So what we said, maybe what we should do is that we should do a three step hyperglycemia clamp. So we give you three steps of glucose and we can get Betacel sensitivity to glucose. from the slope, I give you a little rise in glucose, another rise in glucose, another rise in glucose.

1:46:03I see how much CPAPTide comes up. The slope of that curve is that's beta cell sensitivity to glucose. And then the M value is where it hits the axis. Then I can get glucose. But this is just now I'm going to focus on the beta cell because the hyperglycemic clamp is just for beta cell function. And then after that, now I'm going to give you GLP1 infusion. And I'm going to see how much insulin comes out. And then after that, I'm going to give you a balanced amino acid infusion. I'm gonna see how much insulin comes up. So you can sequentially measure the different? Three different stimuli. And now what we see is different low -sci.

1:46:35Some are associated with the defect in glucose. Some are associated with the defect in amino acid. So again, the more you can refine the phenotype, the more likely you are to identify defects that are there at the level of the beta cell. Let's go back to the guitar study for a second. How many people were in that study? About 2020. Big study, when you're doing all these Hitzel clamps studies and these kind of measurements are not easy to do. That was published when? Let's see, I would say the one and a half year data would probably about 2018 and the three year data I would say 2021 -22, something like that.

1:47:13I can send you all the references. Yeah, we'll link to all of these in our show notes for folks, just simply phenomenal. Let me ask you a question. If you take an individual with type 2 diabetes or insulin resistance and you presumably collecting urinary CPEPPTide for 24 hours is the best surrogate for total insulin secretion? No, it's an index. If you could quantify total area under the curve of insulin for a person and then you gave them a GLP1 agonist, is total insulin going up or down? Depends. because you have competing factors going on here. And I'm not trying to be elusive because I'm telling you, it's actually real.

1:47:52It's what happens. The drug is going to kick out insulin, and CPEPTide's going to go up, and now the glucose is going to come down. And then you need less insulin. And then you need less. So depending upon the relationship, when you look in absolute terms, the CPEPTide insulin levels actually may be lower. But now, when you express how much CPAPTide comes up for the rise in glucose, huge increase. So you always have to have something that you compare to, and that's the increment in glucose. And anytime you look at how much insulin comes out, or CPAPTide, which is another confusing factor, which I'll mention in a second, you'll always have to relate it to the glucose area.

1:48:32When you do that, huge increase in beta cell function. The other thing you have to be very careful about is you need to be measuring CPAPTide not insulin. What we've shown in this is a compensatory mechanism. Maybe just tell folks, I threw out CPAPTIDE as though everybody knew what it is. That's a mistake. Tell people what CPAPTIDE is and what its relationship is to insulin. Yeah. So when you ingest a meal, there's a precursor that contains both CPAPTIDE and Pro insulin. And so you split off CPAPTIDE and you split off insulin. And they both come out in one to one molar ratio. The problem is half of the insulin that comes out is taken up by the liver.

1:49:08So you never see it in the circulating bloodstream. The CPAPTIT is not taken up by the liver. So everything that comes out you see in the circulation. So when we want to know how much insulin was secreted, we actually don't measure the insulin. We measure the CPAPTIT. And that's the true measure. Now the other confounding feature here is, and we shown this, and this is now been reproduced by many other people, is that when you become insulin resistant in diabetic, your beta cells don't secrete enough insulin. That's one of the big defects. How do you compensate? You don't destroy the insulin that secrete it.

1:49:44So the degradation of insulin becomes markedly impaired. So you can have a high insulin level either because you secrete too much insulin or because you don't destroy the insulin. So measuring the insulin level is not a good measure of beta cell function. If you want to know about insulin secretion, measure the CPAPTide and express it per rise in glucose. It gets a little bit more clouded because your beta cell also can recognize how insulin resistant you are. And so it knows look, if you're this insulin resistant, I need to speak more insulin. If you're a very insulin sensitive like you're a lean person with normal glucose tolerance, you don't want to speak much insulin, but you get hypoglycemic.

1:50:26How does your beta cell recognize that? Well, that's some of controversial that can give you might thoughts about it, but in either case, measuring beta self function is not just simply measuring insulin. That's probably bad. Measuring CPAPTI is better. Measuring CPAPTI peris and glucose is better. And then for somewhere or another, if you can express this all, per insulin resistance, this is called the disposition index, something that Dr. Stephen Khan developed with Daniel Port many, many years ago. So simply looking, as I said, as insulin or trying to do an OGTT and come up and say you know how the beta cell is working, that's not so good.

1:51:04And that's why I say in the Qatar study, in the Eidic study, we're doing such sophisticated measures of insulin sensitivity and beta cell function. You do 350 people. That's like doing one of these big cardiovascular studies with 5 ,000 people in it. The pathophysiology will always tell you the truth in my opinion. If you know what the problem is and you correct the problem, the A1C is going to get better. ADA does not emphasize pathophysiology. You had Jerry Schulman on it. I'm sure Jerry will tell you, he and I think very similarly, you understand what causes a disease and then you come with a treatment that will make it work.

1:51:43Do you have any concerns with long -term safety or anything other than simply the economics of the GLP ones in this current generation? Again, huge, huge leap forward between Lyra Glutide and Semaglutide. And I've discussed briefly elsewhere on the podcast what the roadmap looks like for how many of these drugs are in the pipeline. Oh, yeah. There seems to be no end in sight. And we're going to look back at Semaglutide and say, God, that thing was pedestrian. That's what's going to happen. Give us the bear case. What should we be concerned with? What should be at least looking out for? I would say overall at the present time, I would consider these drugs to be quite safe.

1:52:25The major issue is you have to go slow because of the GI toxicity. Where is the controversy involved? And it's something that I'm involved with myself. When you lose 20 or 30 % of your body weight, you lose muscle mass. Now I just gave a talk on this to one of the pharmaceutical companies that are involved in this area. I'm not going to name the name of the pharmaceutical company, but I started off by saying, look, here is now a study with real data. This is a gastric bypass surgery study, room -wide bypass, and the people lost, I think, was 33 % of their body weight. And their lean body mass came down quite significantly.

1:53:04One of the problems is people measure lean body mass, and that's not a real measure of muscle mass. In fact, it can be a very bad measure. You should measure muscle mass. But let's assume that the lean body mass largely reflects through reasonable assumption, muscle mass. So muscle mass came down. Why is that so bad? How much did it come down? Because if total body mass came down by 33 % But three quarters of that mass was fat and only one quarter of that was lean We would consider that acceptable and this is where the controversy is because no one is really measured muscle mass We're doing it.

1:53:43We will have a definitive answer and you're doing that with MR. Memorai. It's gold standard But now I said look in this study they measured absolute strength you can do grip strength or leg strength and absolute strength went down a Little bit maybe 25 % where these patients Exercising during the period no no no no no no no no no no no then they said let's express Strength per weight loss. Yeah, who up by 50 % per appindicular it goes up by 50 % and then they said how far can they walk? They went from walking 200 yards to two miles and then say one of the things is how many times can you get up out of a chair in a certain period of time?

1:54:25They didn't increase like three or fourfold. They measured your VO2 max. Yeah, of course, which is heavily dependent on weight as well. Yeah, it all got better. But in absolute terms, did VO2 max get better? Not necessarily. Yeah. The total VO2, not normalized per kilogram. No, everything got better. Okay, that's counterintuitive by the way. Normally when you lose weight, VO2 max in liters per minute does not improve because you have less metabolic tissue. But here, for whatever the reasons are, maybe all of the fat that's pushing on your lungs so you can't alternate the epicardial fat that's not allowing your heart to contract, the fat that's in the heart that's causing myocardial lipotoxicity, which I believe is real.

1:55:04These things are all changing in a positive way. So again, it's a balance. Of course, they don't like this. Why weren't they happy with these results? Well, because now the companies are all looking at developing drugs that will preserve the muscle mass or increase the muscle mass. But basically what I'm saying is that, look, it's lean body mass. We have to say it's reflecting muscle mass. Everything gets better. The patient feels better. They can walk better. They feel stronger, et cetera, et cetera. Why are you so worried about muscle mass? I look all these gloomy faces because they're all developing my statin inhibitors or eventin.

1:55:37And then the next slide comes up and says, retort. Here's a good thing. So now, if you lose all of this body weight and you improve insulin sensitivity and muscle and you improve it in the heart and there are cardiovascular benefits and you correct the improvement in all of the cardiovascular risk factors. Now even though you lost muscle mass, if you've improved insulin sensitivity, there may be an enormous benefit of seeing the improvement in the muscle insulin sensitivity, even though you've lost muscle mass. And they do have some concerns about these drugs, these myosetinibitors that actually may have some negative effects on the heart.

1:56:20My suggestion is actually you may find a big improvement in myocardial function. Where are myostatin inhibitors in their development? Phase two. Of course, I think we've talked about myostatin before on the podcast. When you inhibit myostatin, you increase the expression of striated muscle, of which cardiac is striated. It works through the eventin to a and to b system. Do you think that's a more promising pathway than the fallestatin pathway where fallestatin? Yes, I do. Increasing fallestatin inhibits myostatin, but this is a more direct way to go. It's a more direct way to go. So you can either have their antibodies by Magrubab to myostatin, or you can interfere with the signaling receptor itself.

1:57:00And we think that this can still be effective in a fully developed and mature adult. I mean, clearly this would be effective during development. And we see that in the animal world. How effective is it? A lot of the animal work as sort of a caricature stuff. It's knockouts, right? They take myostatin knockouts and they look like bodybuilders. But if you take a mature chicken or a mouse that's two years old and you give it a myostatin antibody, how robust is the response? Even more so, what about any human? We don't know the answer to that. So what the phase two studies obviously the toxicity passed in fast in phase one.

1:57:33Yes, that doesn't seem to be any adverse effect of these drugs. Or they wouldn't get through phase two. And there actually some fairly large phase two studies. What's the indication? Is it sarcopenia? I don't know. The FDA, if you have a sarcopenic disease, there are criteria that the FDA has established if you want to develop a drug that you have to meet certain criteria. I'm not an expert in this, I can't tell you exactly what these criteria are, but they are pretty well established. Now, for these kind of people, and I'm going to come back, you ask me about lean people, come back to that in a second, because this is really an issue.

1:58:10Let's say I put you on a GLP -1 receptor agonist, and you lost 25 % of your body weight, and I put you on a myastatin inhibitor, and that prevented the muscle loss, didn't increase it, but just prevented it. But that would be ridiculous. I mean, if you took a 200 pound individual whose 30 % body fat, they've got 60 pounds of adipose tissue on them. If you took 25 % of their body weight off, you take them down to 150 pounds, but you're telling me, potentially, we prevent any deterioration of lean mass. That means they're down to 10 pounds of fat mass on 150 pound on frame. I'm making an assumption.

1:58:50Okay. This is remarkable. Right. So let's say that happened. What would be the FDA's criteria? I'm going to give you approval for this drug. I think the FDA would ask that you've also improved function in some way. And the function would have to be determined through absolute strength, not relative strength would be my guess. I don't know the answer to this question. Because the way I think about these drugs is less about that situation. It's more in the sarcopenic adult. This is the lead, particularly the older person. That's right. That's right. This is the elderly individual who's sarcopenic and whose fall risk is enormous.

1:59:31And their risk of fall and morbidity and mortality is very high. And in that individual, I don't think the FDA will be satisfied with simply an increase in lean body mass unless it is accompanied by strength. Now, I think that some of the tests that are used here are silly. I think the six minute walk test should be folded up, discarded, put in the waste basket, and never discussed again. It is such a stupid test. They do it all the time. I know they do, and it just makes me want to scream. We need much more rigorous tests than a six minute walk test. We need a test that is actually more of a sub -maximal test.

2:00:08So if we're testing cardiac respiratory fitness or some sort of peak aerobic fitness, we have to do more than walking. And if we're testing strength, I much prefer grip strength, leg extension, bench press. Again, these can be done with machines. They can be done very safely. But we really need to test strength. You see, you're raising very important and critical issues because there are many, many companies that are going ahead with these drugs that increase muscle mass. But to me, okay, increasing muscle mass, what does that mean? There needs to be some functional translation of that. There could be other functional benefits that exceed strength.

2:00:45For example, glucose disposal could be a functional benefit. Insulin sensitivity, that's the one I put at the top of the list for them. Get rid of the insulin resistance. They have to, I won't give them credit for that, I don't think. Yeah, but I think that, again, it's harder to tease out because there's more moving pieces and they might argue there are easier ways to increase insulin sensitivity in glucose disposal. But one way to think about this is to go back to what if you did it the old fashioned way? What if you got in the gym and lifted a bunch of weights? That's been done. Yeah, and it increases insulin sensitivity and functional strength.

2:01:13And so the question is, can we replicate that pharmacologically? And that is actually exactly the way I ended my discussion to these people. I show them what resistance training did. And if you could show what resistance training did with your muscle mass increase, then you'd have something. But you need to design the studies appropriately. And as I said, and as you said, I don't know what the criteria are going to be that the FDA uses to judge these things. They do have a sarcopenia set of criteria, but that's a very different group of people that we're talking about. But this comes and hits home to one of the things you asked me earlier.

2:01:50What about the lean person who's 80 years of age? Is this the right drug for that person? I don't know. Maybe not. But now let's say you have a healthy 80 year old person and Everybody in the family lives to be 105 and they have diabetes well. They're at risk to the toxic effects of hyperglycemia Would it be reasonable to treat that person? We know this powerful effects on the beta cell. I would say it would be quite reasonable But I think you need to monitor what's happening to their weight and other Features here's a bigger issue childhood obesity You are obese when you're four years of age, you're going to be obese when you're adult.

2:02:29And your life expectancy will be significantly shorter. And your quality of life will be significantly reduced. Now I'm going to make it even better. At a lessons, these young kids with diabetes, they don't respond to any of the drugs. What is the prevalence of type two diabetes in under 18? It's increasing, but I would say maybe around four or five percent something like that. One in 20. teenagers has type two diabetes. I'm biased by San Antonio because we have more people with type two diabetes in our clinic. You could say potentially in San Antonio, one out of 20 teenagers. It's going to be very high.

2:03:05Gosh, that is. In four adrival. In four adrival. And I'll tell you about the pre -diabetes study that we did. And we know these studies are out there. These kids and this big NIH sponsored study, they don't respond to metform and cell phone you're ears, they don't respond to any drugs very well. Even the GLP1 agonist? The first study has just come out that respond better. It's a Lyroglytide study. They don't have any of the two. Just clinically if you're in the clinic and you're using the best drugs you have available. You're in trouble. Why? Because you can't get them controlled. Why? They're so insulin resistant, much more so than adults.

2:03:41These are well published studies. Is this really a selection bias where for someone to develop type two diabetes as a 16 -year -old, the underlying genetics and pathology are so severe that the current crop of drugs are the problem, as opposed to when you take the current crop of drugs and you apply them to people who are young, they don't work. All three, because I'm going to have one more. Genetic predisposition, so Hispanic population, huge problem. obesity. All of these kids are huge. So you don't have the lean diabetic phenotype in the sage. No, not in these people. And then the drugs don't work very well.

2:04:19So all three of these things. And what now is come, it's called a rise study. And as these kids have been followed up, they're starting to develop kidney disease. They're even told a couple of people have had MIs in their 20s. They're incredibly difficult to control. What do you think? I mean, Yes, we're going to argue that these kids are this is due to what they're eating, but what is it in The environment that is so abyssogenic to these kids. I'll come back to this in a second But I want to raise the issue now Let's say you're 16 and you don't met for myself. You're a one -seas nine You can put someone on my jargon and they're gonna have to take this for the rest of their life Because as soon as you stop the drug so this is what I treat the person the chorus I can't let the A and C in nine.

2:05:03If you take that 16 -year -old with a hemoglobin in two of nine and you give them a manjarro, where are they in a year? I think that if they can afford the drug and they stay on the drug, the three big ifs, if the doctor knows what to do, I know what to do. If the patient will cooperate with you, if you don't, they'll lose every time and if they can afford. If you can satisfy those three ifs, that person we know from the studies be pretty well controlled. What fraction of insured patients will have coverage on Mangero if they're A1C is 9? I can't answer that. Does CMS cover it? Does Medicaid cover that?

2:05:39Yes, if you have diabetes. The Mangero coverage I think is pretty good if you have diabetes. If you have obesity without, that's a whole different issue. Should you be treating these young kids obesity as a disease? They can all kind of have problems. Should you put these young kids on these newer drugs? And knowing that all I did is change you from food addiction to drug addiction. I didn't do anything else. It's almost like alcohol addiction. There are drugs that things I can give you that can help you, but they tend to relapse. Food addiction, I put you on the drug, you lose weight. You stop the drug, you regain the weight.

2:06:13This is a huge public health concern. It is almost way beyond my capacity because finances are involved here. Can we afford to treat 42 % of the people in the US or obese, or is there some way amongst the 42 % we can define who are the people who are insulin resistant, who are the people have the metabolic syndrome that we know they're at risk that we can treat them. My guess is that the great majority of that 42 % of the people can we treat all of those people and moreover they're going to stay on the drug. We know on average what the data is saying I put you on the drug we don't know all the reasons why but within a year half of the people stopped the drug.

2:06:51Yeah, and it's probably a combination of cost and side effects. Yep. And my patients very commonly tell me, I enjoy eating and I can't eat anymore. Some people just tell me they just want to eat. So I'm going to get fat again. So I'm going to eat some GI side effects and some is cost $1 ,000 a month. There's a lot of money for it people. Yeah, of course, this begs the question, will the next generation of weight loss drugs be true on coupling agents where you can basically eat as much as you want and they're going to create so much mitochondrial uncoupling and thermogenesis that you're truly going to see this increase in non -voluntary energy expenditure and of course not have the GI side effects.

2:07:33But before we go on to the next thing I want to chat about, I just kind of bring it back to this question which everybody wants to understand this, which is what has changed so much in the last 30 years that has created this epidemic. And everybody has their favorite pet theory for what it is. It's the sugar, it's the carbs, it's the plastics, it's the video games, it's the internet, it's the whatever. Perhaps suggesting that it's many, many things. What is your best explanation for what's going on? I would say all of the above, processed foods, clerically dense foods, lack of exercise or critical.

2:08:11But these are, I would say, the stimuli that has done something, That's changed the neurosurker tree in the brain. So yes, there's a stimulus and because now you've been oversubscribed to the stimuli, that's now initiated a process in the brain which is going to be a self -fulfilling process. This is something that I'm very interested in, Dr. Peter Fox and I at the Health Science Center. But if you go through the literature and we've published on this as well, in the areas of the brain that control food intake and I'm not talking about the hypothalamus, that That kind of regulates your basal energy intake.

2:08:49What you need to keep your BMI of 25 do what you do during the day. But what is it that makes you a BMI go to 35? That's all related to the hedonic areas in the brain, the putamen, the amygdala, the prefrontal cortex, etc. And then when you do structural MRI, what you can show is that those areas in the brain, the gray matter is shrunk down. And if you now map the neurosurker tree, which Peter Fox has been involved with, you can see that there's clear disruption using functional MRI of the neurosurker tree in the brain. We have a particular interest in defining where this function occurs and we have some ideas which I'm not going to go into, but how we might be able to sort of reprogram the brain.

2:09:36And in concert with this, these are not I'm data, but these are data that are published in literature. And I think I mentioned this earlier, if you do an insulin clamp, okay, I told you that in URI, your brain doesn't respond by taking up glucose. But in people who are obese, actually almost impoportioned to how obese you are. In these areas in the brain, in the hedonic areas, there's a marked increase in, it's called fluorodeoxy glucose, which is the pet rayoacetopterase we use in these areas. And that correlates inversely with the muscle insulin resistance. The more insulin resistant they are in the muscle, the more FDG glucose uptake there is in the brain.

2:10:16Now this is very interesting because what it's saying, there's a connection that somehow or another, we believe that the brain is talking to the muscle or the muscle is talking to the brain and that somehow or other, the brain is playing a very important role in the development of the insulin resistance and that in large part this deranged neurosurgery which is related to food intake is now making you overeat. And as you overeat, then all of the things that we know that we've studied that other people have studied that go with lipotoxicity, you put fat in the muscle, you're insulin resistant, you put fat to live, you got gnash and naffle.

2:10:55What people have totally overlooked, you put fat in the kidney, you get kidney Yeah, yeah, so you've been in San Antonio since the late 80s. When did you really start to notice this was a problem at least in your community? Almost instantaneously. Even in kids? Even in kids. We can't blame video games, we can't blame social media because that wasn't going on in the late 80s. I never saw fat kids at Yale. I was on the faculty from 75 to 88. And I kind of thought back. Now, I would say New Haven's not a large Hispanic, but it's more African American. But I don't remember seeing 12 -year -old kids with type two diabetes.

2:11:35And when I came here and I remember this very distinctly, they're saying, oh, you're crazy. You don't see kids with type two diabetes. Believe me, I see them. What did your colleagues at San Antonio tell you as far as when they started to notice that in the Hispanic kids? I don't know that I can give you a specific time that they told me, except they knew it. So, okay, what about in non -Hispanic kids? Because if the Hispanic kids are genetically predisposed to this, then the question becomes when did you begin to see this in African -American kids and Caucasian kids? Yes, so we don't have a large African -American population here.

2:12:13But like in Philadelphia, there's a lady, so are Slavian. She sees the same thing. And she sees, I think it's a significant African -American population. So I think that in certain ethnic minorities where the genes for diabetes are enriched, those are the populations that are predisposed. And do you think this is mostly an energy balance issue and therefore it's mostly a food environment issue? No, I think it's both. So I told you I'd come back to the genetics study that we did. And the Italian fellow was with me, Giovanni Gulli, a long, long time ago here in San Antonio. So we wanted to know what is the earliest defect that you can see in people who are going to develop type 2 diabetes.

2:12:56So we said, okay, in the Hispanic community it's very common to see mom and dad with diabetes. And it's very common to see a lot of children in these families. So we said, why don't we go look at the children? And let's see if we can define, because they're at high risk. And if you have mom and dad with diabetes, you probably have a 70 -80 % chance if you're Hispanic, if you're born in that family, developing diabetes. It was very easy to find the children. The problem was we couldn't find lean children. So it took us a while because if you're obese, then you got the lipotoxicity. So we finally found them.

2:13:29This is a JCI paper, I believe. And so we did an insulin clamp. Here is resistant is their parents. They have normal glucose tolerance. Why? Because the insulin levels are astronomical. And then we do a muscle bives. How high does for understanding? Oh, they're like two times normal. even higher sometimes. We do a muscle biopsy. The same defect in the insulin signaling pathway. How many of the tyrosine kinase defects do they have? It starts at IRS one. Insulin binds you to receptors okay just like their parents. The ability to activate these insulin signaling pathway, the level of IRS one, it's already well established.

2:14:08Which enzyme in particular? It starts at the level of IRS one. It starts at the first one. Yeah. Oh, so it's not just one enzyme though? Well, you know, it's iris one. You can't tyrosine phosphorylated. You cannot activate P .I .T .P. Oh, I see. Okay. So it starts at iris one. And then the other thing, Jerry and I have both done this in somewhat different ways. I'm talked about Jerry Schoenman. He uses anMR by looking at phosphate derivatives. Even though I believe the primary defect is in the signaling pathway, there's clearly severe impairments and glucose transport in phosphorylation. His work would suggest that the primary defect is at the level of glucose transport.

2:14:46We developed a novel triple tracer technique using three isotopes infused into the brachial artery. We believe that the primary defect is at the level of hexokinase and phosphorylating glucose. We kind of agreed to disagree because we can't do the study. We'd have to do the MRI study at the same time we're doing the triple tracer technique. In addition to the insulin signaling defect, there's a severe defect in glucose transport in phosphorylation. Let's just make sure people understand this. We're kind of getting into some biochemistry here. When glucose enters the cell passively through the Glute -4 transporter, it gets free glucose in the cell.

2:15:22Yes. Then to metabolize it. Yeah, the first step to that is hexokinase, which takes a phosphate off ATP and puts it on the sixth position if I'm not mistaken. And it's a specific type of hexokinase, so it's hexokinase, too. Because there's a different one in the muscle in the liver, correct? That is correct. So, Jerry would say the primary defect is in glued for the transporter. I would say yes, that is really impaired. Remind me what Jerry believes is wrong with the glued for transporter? That it doesn't work normally. I thought it worked fine, it's just not getting this signal to work because of IRS one.

2:15:56That's where the controversy is. We were the first to show this defect in muscle. If I were the only people I think they'd shown this in human muscle, it's been shown in rats, etc. to me, metabolism and rats and mice are so different. This is all people data. So you're saying it's possible that just having the IRS one problem is enough. It's also possible that even if IRS one is functioning reasonably if Glute4 is not getting up, that's the problem. And there is evidence to support that. And then it's also possible that even if all those things work, if you don't get hexakinase to phosphorylate glucose, you back up the whole system.

2:16:32And I can show you that it's a primary defect and aggravate dehydrogenase in glygogen synthase. This comes back, I have an ominous octet for the insulin resistance. This why people don't understand. Look, there are eight organ sort of things that are a problem. There are eight problems I can show you within the muscle. Why do you think one drug is going to correct all these problems? We need drugs to work on the beta cell. We need insulin sensitizes. We probably need different types of insulin sensitizing drugs. drugs, we need drugs that reverse the lipotoxicity. And will we ever have a single magic bullet that corrects all of these?

2:17:07Probably not. Until we discovered the genetic basis, and remember I said the diabetes is a heterogeneous disease. In diabetes metabolism reviews, I would say 30 years ago, I wrote a review article that said, I can put a defect in the muscle and reproduce diabetes. I can put a defect in the liver and reproduce diabetes. I can put a defect in the fat cell and reproduce diabetes. I can put a defect in the beta cell and reproduce diabetes. I went back and read that and I said, I can put a defect that starts in the brain and reproduce diabetes. So we see someone with an A or C of 8 or 9. All these defects we've been talking about, they're already there.

2:17:50So you put that defect in the fat cell, they can look lean. There's a syndrome called Alstrom syndrome. There's a specific defect. This is white atopocyte. There's this Phil Scher will love me for saying this. He's the top guru in atopocyte metabolism up in Dallas and it's Alstrom syndrome. There's a specific defect in the glucose transporter in white atopost tissue. You know what happens? You become diabetic. You know what happens? You game weight. You know what happens? You get Nash. So here's a defect fact that I said 30 years ago, I just postulated and said, here's a syndrome. And not only that, now that they define this in people in this paper, they then went to the animal model and they knocked out the gene that's causing the defect and they reproduced diabetes in the normal mouse model.

2:18:39Well, if I want to close by bringing it back to something that people can do to help understand if they're at risk, either lean or otherwise. We talked about it at the outset, but didn't go into it in detail, which is the OGTT. the oral glucose tolerance test. Now again, none of us have the privilege of being able to use a uglicemic clamp both clinically as physicians or as experienced as patients. So we're gonna have to kind of rely on other things. We're gonna have to rely on body fat. We're gonna have to rely on triglycerides. We're gonna have to rely on hemoglobin A1C, although I find that to be a particularly useless metric.

2:19:14Not that useless. At the individual level, I find it very unhelpful. I think at the population level, it's great. and in Delta's it's great, but boy, the correlation between the hemoglobin A1C and realized glucose levels is pretty weak. But let's talk about the OGTT because this is not a test that is done frequently. I believe it should be. And I'd love to have you walk us through the interpretation of the following. I'm going to give you a couple scenarios. So case one, I'm making this up as we go. You got a person who starts out, all these people are going to start out normal. They're going to start out with a glucose of 90 and an insulin of six.

2:19:46At 30 minutes, this is after 75 grams of oral glucose. The insulin rises to 90. I'm nervous. Yep. The glucose rises to 130. At 60 minutes, the glucose is down to 100. The insulin is down to 60. And we'll just do one more check at two hours. the glucose at this point is 60 and the insulin is 20. Is a prediabetic state? This is a very insulin resistant person and two hour later hypoglycemia is a reflection of the beta cells early insulin separation. This is kind of a prediabetic state. Yeah, agree with you completely and we see this all the time. This is a person by the way with a perfectly normal hemoglobin A1C and this is a person who gets passed all the time as totally normal.

2:20:43They're severely insulin resistant. They bet it's all doing a good job. You hear me glove, anyone see his normal and your insulin is six, even if the doctor is checking insulin. But as you point out, the thing that trips you off is not their glucose. 90 to 130 to 100 is amazing. It's 90 was how high the insulin was at 30 seconds. And of course, they overshot, which is why they become hypoglycemic. Yes. Well known. Yep, go another one. This person also starts at 90 and six. At 30 minutes, they go to 180. Insulin goes to 30. At 60 minutes, they go to 200. Insulin is 40. They diabetic. But just be clear, these are almost real cases.

2:21:24By the way, this is a person who's hemoglobin A1C is 5 .6. Got it. We already published this. The best predictor who's gonna get diabetes is a one hour glucose greater than 155. And this is from prospective data from the San Antonio Hard Study, also from the botanyist study where these people have been followed up. We were the first people to publish this, oh I'd say 7, 8, 9, 10 years ago. There been, I'd say at least 15 to 20 studies that have reproduced what we showed 10 years ago, can send you all the references. So if one hour glucose is more than 155. Yeah, I'm in trouble. And that's a great predictor of type 2 diabetes regardless of all the other metrics.

2:22:01Yes. And if you also happen to be hyperlensal leemic, that adds more to the predictive value. But just pick 155 without knowing the insulin, that's a huge predictor of whether you're going to develop diabetes or not. That's from the San Antonio Heart Study and that's also from the botanist study and also from our Vegas study. Okay. Next case, I'm not even going to give you the numbers, I'll just describe it. This is a person who has a delayed onset of insulin. So in other words, they start out normal at 90s. 30 -minute insulin is deficient. That's a predictor as well. Yes. So what's going on in this person where 30 minute insulin does nothing glucose rises.

2:22:36Yeah. And then at an hour and 90 minutes, the pancreas kicks on and starts the dispose of glucose. What's happening in that person? That's a primary beta cell defect. And one of the earliest things you can detect in people who are predisposed to develop diabetes is loss of first phase insulin secretion. Now first phase insulin secretion strictly speaking can only be measured with the hyperglycemic clamp that we develop. So when I acutely raise the glucose from say 90 and I raise it to 200, in the first 10 minutes there's a big spike of insulin that comes out. That is typically lost in people who are going to develop type 2 diabetes.

2:23:14In its counterpart during the OGTT is the insulin level at 30 minutes. So when you ingest the glucose, of course the rise in glucose is more gentle. When I acutely raise your glucose from 9 to 200, that big spike of glucose gives the first phase. But a low insulin response in the first 30 minutes is another predictor of who's going to get into trouble. We use the following numbers in our practice as what we consider what we want to see. Do you think we're being too aggressive? At time zero, we want to see you less than 90 and less than six. At time 30 minutes, we want to see you less than 140 and less than 40.

2:23:53At time 60 minutes, we want to see you less than 130, 90 minutes, we want to see you less than 110 and less than 20. Do you think we're being too hard? Yeah, you might be being overly aggressive. But for sure, if they meet those numbers, you're probably safe. Okay. Ralph, I don't know where the time went today, but it went. And this was a fascinating discussion. I could talk about this stuff all day long. It's interesting because someone listening to this podcast who heard the podcast with Jerry Schulman from probably three years ago will be pleased because the overlap is virtually zero. I mean, that's what's amazing about a topic as rich as this, as you can talk to two of the world's experts and have two completely different conversations.

2:24:40Conversation with Jerry focused so much on the pathophysiology of insulin resistance. Here we focused much more on the actual organ specific aspect of type 2 diabetes. We got a master class in the pharmacology of it and then I think kind of brought it back to ways to diagnose it. If you're slumming it with those of us in the clinic who don't have clamps. So maybe we should do it in the future. We do them with both Jerry and I. I will 100 % agree that in a few years we come back and we do a double version of this and we have been fantastic. I sign up. All right. Well, thank you so much. Not just obviously for this, but for your contribution to this field.

2:25:19Okay, appreciate it. This is wonderful. Thank you for listening to this week's episode of the drive. Head over to PeterAtiaMD .com forward slash show notes. If you want to dig deeper into this episode, you can also find me on YouTube, Instagram, and Twitter. all with the handle Peter Atia MD. You can also leave us, review on Apple podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional healthcare services, including the giving of medical advice. No doctor -patient relationship is formed.

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