The Division of Endocrinology, Diabetes and Bone Diseases presents a Grand Rounds discussion by Zachary Bloomgarden, MD, Clinical Professor of Medicine (Endocrinology, Diabetes and Bone Diseases), Editor, Journal of Diabetes. Dr. Bloomgarten looks back at the history of research on insulin resistance and its impact on cardiovascular disease. e think it was gonna get started? Um, in honor of trying to keep on schedule. All right, so we're gonna get going. Um, once again, thank everyone for coming. We It's always wonderful. Zach is kind. Thio provided always with very area diet lecture pretty much every year. Now I think is that looked through your cities announced, um, introduce that any time someone who really doesn't need much of an introduction, But does that look you're conceiving this time I find a fax, it will share with all of you that down. So, you know, that graduated from Princeton a mathematics nature with honors and then decided to go into medicine. So I felt that very interesting usually see some type of a bio, bio chemistry or some other type of nature, so that was very interesting. He his published training at Vanderbilt and off very rapidly, moved up the ranks on it has been a professor here in time for well over 10, I think almost 15 years of this point, it's over 500 well over 500 publications on, uh, for those of us who are that productive in that area, that is really quite impressive. Andi always has some really helpful. And inside the boat for measuring. I know for me and many other of the faculty within the division as well as our fellows. So we look forward today to another talk by Zach this time speaking on insulin resistance, diabetes and cardiovascular. Thank you. Thank you, Carol. So try to talk a normal loudness. But if I get, you know, start going down to my usual bumble Just elope growth. Exactly. And I will try to speak louder. Elliott, please, Please let you don't. So a sober and sad note. I do want to recognize that Andy Draxler, who was truly my best friend and was the head of the Mount Sinai diabetes, uh, institute, uh, 2002 and then moved to U C l. A. Where he was the head of the, uh, Institute for diabetes until 2016. Develop a a obscure form of what? Both sarcoma got better and then had rapid progression over the past six months. Passed away about a week and a half ago. So you will truly be missed. And I would have he was going to come back to New York and and spend more time than that. Sinai. And I certainly wish that had been a key. So Thistle is gonna be my talk through the world Congress into the resistance. Uh, about a week, Um, I was I wonder if I getting the the reason for contributions. And I said, What do I do? Um, I have a lot of patients with diabetes that I write commentaries, and I do a little research, but, um, that before it seems e looked around and I said, Well, what constitutes an expert? There's a cartoon find somebody, um, in rights cartoons for the New York Times. And here's all you do for your expertise, focus by patterns, go in some depth on some of that, get the intersection, and then you have expertise. So this was a lovely, uh, quote one of the early articles. Uh um, the secret of a learning, bythe wonderful thing about medicine is that we're able to really go over so much, Understand? So here's my favorite website in the entire universe of that, um, which links to the that side. I like really hilarious. You essentially, uh, everything. So it's sort of the time sense because If you type into the search bar, quote insulin resistance and quote and then brackets title so it will only look for or limited with title. Then you come up with still interesting numbers of articles. So two articles in the 1911 articles in the fifties, uh, from sixties, 29 articles, tiny numbers. But then So, um so here's the growth of articles on resistance, and it's quite remarkable. So I thought I would take a look. And my assignment from Beauty and Handelsman has spearheaded local resistance for a while these years, and it's interesting. Title. What are you gonna talk about? My research? I don't know by articles covered so many topics. It's the resistance looking back. So, um, so that's Bush back. So yours. One of the early articles, findings and resistance didn't mentioning that it's Linda. It could be characterized as almost glowing, which and, um, we can I have used that for a, uh, operational definition of instant music. This is 1940 and here's an article frog, right? Seven in the JC, I looking at characteristics of insulin resistance persons, but this waas not exactly what we think of what we're talking about insulin resistance today. Articles one from 1950 years old on um, like both dystrophy, essentially, the impure instant preparations was in local areas off hypo hypertrophy YouTube. Inject those areas as people still do today. Your resistance to that there is even I don't know how many of you do Henry Soldier things just going back to our history. A bad sign. I think it was the of the Nazi diabetes, uh, many years ago on. And when I first came to Sinai, this was part of the fascinating and wonderful ambience. Once a month, we would get together and have diabetes conference, but it was at someone's apartment over cold cuts, various things that I was a kid. Uh, way told your wisdom, lovely person whose ideas of diabetes management different quite a bit from this today, But who has a physician. You don't leave with so wonderful. Um, So, uh, here's the lily lecture. 1957 was actually given than at the American College of Physicians. This was on its resistance, and this look in more detail what is really not all of our existence, but related having I oh, levels of insulin binding and So that's where the disease was that time. There's a patient. Please. Thank you. 50 units of page one today or whatever. Waas then went up to 500 units today. Something out? Its existence, South steroids, all sorts of things, Because that is it. Well, this is for without knowing what insulin is. Another famous part of not so nice history really is Gallo diversity. So it's offers and was generally the department, is it? Uh huh. Yeah. So what's that? Okay. They get all their research in the box, and they are This article Family was respected 58 times by the C I, uh, a yellow show for slides, rejection letters She kept t o e O s. So this was the very first in the USA. Here's the data. So your nation, your insulin levels uh, here is people with diabetes, huge variability of insulin. Us here is people with early diabetes really characterized eighties. So this is a fantastic So go and we take it for granted picture. It's when you all these things off my mental As a fellow with David Rabinowitz moved to Israel changes names David with with monologist Wonderful to get your wonderful person. Uh, this was one of his early articles Where, uh, they took our people and they had essays from diversity hook off normal levels of insulin at nine. Oh, beats with 30. And they found that there's a link in the chain of evidence off PC. Oh, surely onset diabetes. Now. Sorry to day. Oh, so here's skipping ahead a few years. 1970. Here's another Casey I article by Children. Uh, and they took a group of people with diabetes with normal people. Hi, so on. So they try to match for, uh oh, a police city. Obviously the normal ones head. Which one? Steroids. Oh, once with diabetes mild type and what it waas they confused. It's one major U two levels. They were able to get a steady stay classmates with a microphone, and, uh, and then they looked at how much? Because you needed to refuse. She what? Um, so this was beginning off what? You think the SPG steady state level, which is a perfectly nice way off looking at consistence on. They found it in a diabetic patients off. Actually here is done something differently, so they confuse the same amount of glucose had similar insulin's on the fact that but glucose levels with eso the steady state plasma glucose done here is a given level of hyper you have What's whatever it's higher take. Um, so then using the same approach, they said, Let's look at the s s speech. Individuals with O piece lose weight and both Uh huh, That's good. So what like background? Uh, but very nicely. That s Yeah. Eso then here is a non article technologies five. Looking at who cooks up taking total. And it's little stimulated yourself and they showed a marked difference. Uh, was it most insulin stimulating glucose disposal individuals with diabetes versus, uh, So this is It's the resistance thinking of that off So immediately. Lydia leaving gave, uh, yeah, about eight years on a what equal then Problem X town hall. Its existence in a galaxy. A lot of other terms, he said, Uh, here's a condition, uh, assistance. It stimulated because of a high insulin increased like this, right, decreasing HDL, high blood pressure and on and on. And so this is one of those things that I was actually at that MBA thinking, and everyone said, Well, sure I do that. But nobody actually said. And this is, uh, what you It's the resistance that happen in, uh, here's an article by Tracy McLaughlin. Oh, uh, is so it's Sanford doing? It's studies addiction are protesting Americans. Um, and they took large numbers of individuals. They looked at various parameters to see using this, uh, looking at sensitivity versus specificity. You? Yeah, state. What's a good partner off its resistance on? And sculptures have that trackless ride or the trackless right HDL ratio are basically as good as the plasma tickets in determining whether somebody has excuses. That's with this particular instance approach to characterizing resistance on it might not be so, general, but really trackless side level is readily available water resistance. And in this population, V online was considerably less useful than the um, in the level of looks like That's right. Characterizing people resistance, please, uh, really was the guiding spirit of the world Congress on Incident Systems For a while these years, uh, would constantly say, Forget about home. Home is just Fletcher times insulin level. Just look at the level that's really all you need and shorts is that its finances are not very well characterized. So it's one of 21 28 others that don't necessarily the same thing. So, trailer, it is probably better general way if you you have to look at it sensibly and say, Well, people who have a genetic forms of agriculture Yeah, don't billions but bind people with Travis, right? Levels off organs and systems. So this is very bubbly. So what tracks with resistance? Uh, there's a, uh, a long time look at people with insulin moments. So here's a you black Stephen clan, uh, people with looking at because disappearance rate, normal controls and people with tuber related Amelia And you can see that using, uh, tracers the date of who puts disappearances. Farlow, what is simply in this panel on the right, if you look at the amount of because required, refuse But Stephen, it's much better. So what brings the union itself gets its resistance. This is our former facing resistance. What? Under license with resistance. Well, obviously, major factory. So looking at this time machine, Uh, okay. There's a beautiful article, uh, frame looking at affluence. Public obesity 15, 70 seventies, eighties nineties. Two thousands on looking went up from 10%. 13, 2025 32. Resistance is completely gone. The same basic pattern. Uh huh. Here is anything, uh, which is a wonderful epidemiologic data set that gives that's now in its it's the eighth iteration giving population data on all sorts of characteristics of the United States. Eso looking prevalence of migrating 30. Cohen ist straight up from the 1972 thousands. Um, and being migrated 40 much lower with same correct, but it's quiet. Oh, on. So I think this is kind of another study of historical interest. So here's, uh tomorrow rise. Jessie Roth, uh, looking at this was published first invited east hair than in a slightly different quiet article. Oh, diabetes, Capitalism research refused. If you look at individuals in the fifth quarter mile of fast Indian slip of age 49 fourth quarter mile, third quarter, 2nd 1st. So as, uh, instrumental baseline level goes, uh, the likelihood of this studio utilizing changes exactly as okay, um, over 20 year period. So this really is the underlying condition off diabetes On the predictors are obesity fancy because it's played, uh, factors in Israeli population? A little different? Yes, like thank you, very unique. I'm wonderful stuff with find help showing that essential pretension in taking diabetes are approximately equal reference off. It's the resistance like this red levels, Wood nails. I'm so now let's move forward in order to look forward said, Well, let me just look at the most recent 1000 articles are, uh, assistance. E didn't actually a articles, but for about two. And, uh, I think there's all kinds of injuries. So this is just a matter of a what's going on. Insulin resistance today. Um, and of course, the 1st 1000 articles heard over for a five year period or more, and the last dozen wrinkles of this surge were done in 2019. Uh, so huge problem. Phil are so, uh, linkage with coronary disease. So this is a It's like a Korean population of individuals did not have those coronary disease. Yeah, referred for all right, NPR graffiti depart. And so it's a dishwashing. Who knows what characteristics you are but very interesting. If you look through my idol are, or if you look a trend, that's right, because Xcor Thailand others similar measures trades or trackless, great she ratio. Um if you look at people don't have time. Yes, um, as you go lowest to the highest court tiles off resistance. With all these measures, you see that the prevalence off primary artery disease goes on. Bye. That certain Try this rack. YouTube measures, sort of, uh, if you look at people have toe increases quite similar. Except instead of going from 32% 45% goes up from 58%. 70% showing what we know is the wait objective and of itself in reasonable. Right. Um, here's another interesting looking at essentially the same. So here's an article. Indiana. That happens. Uh huh. Which evening? So the question is, what a back there surgery use building the Onley objectively, hopefully uses. Oh, please, um and should be doing wars, not do it. But what exactly story? Well, if you look at population of more than 2000 individuals, uh, very accurate surgery. And what if we comparable control show? Okay. Likely of developing cardio vascular injuries went down by about half to those people. Very sorry. So this is essentially its existence. Uh, here's a lovely art which again is close this year off of it took a look at more than two individuals. What? What do you think? Uh, had more movement. Puts colorants here. Inputs, tolerance for diving. And they said, What are the associations of Homa are so Puma Are is what those times servants Bible 22. Um, actually, another version population. Okay, It was done by yes, 18 years ago. And so they could similarly have just looked at relationships. Insulin to these, they have three different adjustments. The third adjustment includes by the next events as one of the fact. So she went that, um, so first, very interesting. A relatively book bus, a measure of general health. And as you go from, uh, greatest degree of insulin sensitivity to the elites degree of insulin sensitivity court, I'll see a reduction. In general. You see all of the things that we think of as thes lipid measure. So try this, right, levels go out and not much of a for if you do the full model where you just for being a HDL goes down. Maybe that's a little bit more attenuated by Justin from my privates writing still ratio. Same thing. If you look at LDL cholesterol, it definitely goes. Uh, if you don't take out b m I but that's really the association, you know, while for sure no relation. So l d l is not particularly related. It's these deserves are different industries, so g and you know he not complicated sp um, it's none of this is striking, but it's fascinating that here's this very orange analysis that was published. Forget what journal, but relatively. Or I don't know that I have never seen a beautiful announced our reason allow the parameters of the CBC tracked with Yes, the resistance White. Yeah, everyone knows that. Obviously. Please. Oh, psychosis, uh, you psychosis and elevated neutrophils elevated Play this and elevated equal book. And these air pretty repressed associations, Uh, and vitamin E t. So you know that vitamin it goes down its existence? Probably much of that is related to the state, but you He's not being that folic acid B six and vitamin C also trapped with. So, uh, what could either say well or being Or baby Vitamin C is coming back. Had a conversation with what? Actually, uh, it started off as a biochemist. Got an award during his, uh, graduate period. from what it's calling a marries, brought together vitamin C, cleansing similar California. Uh huh. So more seriously, here is written off. Mark is written up covert with outside. So if you look at that exactly essentially no significant association with eliminated state. But there's a highlights. It says culture. It's You are. So it is a one of these lovely things That would be fine. You know what lovely and frightening and important for us to know that. So then I said, Well, I should really try toe look through these articles, See if I understand science. So I knew that Christmas. Yes. If I get through with Oh, okay. Uh, so here is a very ultra simply, uh, thes a role. Images from, uh, a very nice article luxury show. Are they journal? Let's hear another interest article Frontiers Intertechnology, which are e the sources. Editors of French. I regret it because I can't about 14, princess. Uh, they Curtis huge levels of editing, you know, really good conferring and not just assigning a few years. So I'm not very good, but I to read their articles. This with, uh so here is considered on the top finding the insulin receptor, which they order fast four lanes. Uh, after the incident, Senator, this leads to, uh, three place. Uh, and you know, I think of these letters, sort. But the reality of these very complicated molecules is obviously far, far were. But understand that my very simplified backs black box approach Uh huh. This in turn activates vacating. Please. It goes on. Instead of a series of defectors elevated itself Concordes, insulin, resistance, a Z we saw from that study. Um then a group of circulating factors are associating with resistance. Product of cannibalism rituals. Serra mites. Certainly a try thio. Interesting relationship with what? What is some of the new cremation? Autumn insulin resistance. Um, here's a oh, here's Here's a study that looked at macro finished bob in a rodent models with resistance. So, first of all years, uh, Katie, fast relation control animals with insulin from nicely attenuated in the model. So this is a high fat diet. Um, protocol very well would have. I mean, you look at a marker of part of resistance from sections of you is a off peritonitis response where legions made God. Oh, it's very relaxing. So cavity and Oh, atheism. Resisting the animals. How the occurred? Much more quickly. Although it looks like he even that study godless of waiting for a high fat diet or not. What's it so good? It all, uh, we're actually especially suck. Just go back. Prisons doesn't show that died Which kind of blues I've done. So they have increased survival. Oh, which is actually moved. Uh, right. So that is actually consistent with Texas talk, like two months ago. Were surprisingly, obesity is actually protective. E, this is This is why I wanted thio e give it in Los Angeles e s o e. So the bacterial load was greater with classic diet. Hi. So? So it's not that it's protected against a faggot faggot city from Max, so we'll just take off survival part. Not so important they lost to come. Oh, so now you look carefully. I did this help. Uh, so fascinating. Um, if you look at the same sort of model against resistance s, here's a high fat diet. Um, you can demonstrate both the skeletal muscle and in stand, um, that there is a decrease for relations with the tea. Um, with its, uh and so there is skin. It is the resistance. Um, so what did they find? Uh, put away the data slides. Fortunately, Chris was taking them apart. Uh, but barrier function. So transit, quarter loss, certain levels. Skin here. Uh huh. Subcutaneous issue. Uh huh. In our increased infiltration Hi. Macrophages in something in space. So its resistance expresses itself in skin. This presumably is related to the association. Insulin resistance with variety, German watching problems, for example. Scratches, relationship, Kansas system. So on, Um, there is a very interesting associations with with for, uh, there's a study of aural sora and the long even attempt to, uh, keeping explanation off. One of these factors are what leads, but they're clearly very different populations. You're looking at Lucas. Change over his findings. Sort of a We're major resistance versus, uh, really? For it. Our differences in population level. So there's a lot of this whole phenomenon A, um it's certainly soon. Um, he wants, um, here waas a a resistance model, um, which can be looked at our its resistance in the heart. So here are there's a cardiac because there is a week and, uh, stimulating. Um mhm. It's fun. Tom some who they voted for education model. They were able to demonstrate that Korean Lucas, uh, was reduced. So here, from 70 74 stimulated put 61 Numbers are irrelevant but decreased. Stimulated. Presented are with the order of education as a presumably a model of hyper trophy, part of my, um, so they were able to show that there is an association with a abnormal like country of function and, um, uh, cardiac patriots, force of valuables and so on. Now, is this a direct causal effect? It's the back of instant action or other mediators not clear out. But certainly it's an interesting suggestion. Uh huh. And on top of that, with his neighbor, hold some sort of Sunday wonder who really struck even associate based on it's is this whole idea that Alzheimer's disease is Type three diabetes? Um, consoled. Here's another of these population studies have done anything with relatively small group of about 30 individuals with characterizing, having moments insensitivity 55 for Houston's insects, and then they looked at age 70. At psychological testing, they found that there was a reduction in executive function and in process of up in individuals who were instant resistant 15 years ago. So this is very complicated. There are a lot of potential factors. Maybe that our socioeconomic differences between resistance insulin sensitive individuals that this is not a mystery introduction at all. Why, there is this very interesting metabolic processes off late onset outsiders is we're central, uh, services, uh, associating information in bringing by the kind of dysfunction. So oxidation stress, decreased energy availability, production, increased levels of black as in the in pick this whole these abnormalities in sequence because the watch book instructional change is about allergens. How important these countries? One of the fascinating association. There's a uh huh, interesting, uh, on this topic. And it looks as though hippocampus is major site off sitting down memories. Insulin action plays a role in memory. Its existence decreases that, and there are a number of fascinating studies. You get into the brain, hurry by. The ministry introduced, um, so it may be Can you do that? It goes in what we nine seats in a public session into the right protects Maybe this are really could be affected. Oh, boy does it easily, easily. He's related in some fashion. Sure, it's the that. So let's move a step away. Go to one of the older wanders off. It's the national. So here's her gamma in years she sleep one offer our gamma co activator once an Alfa, Um, he has, um I decreased expression. But even with diabetes work with family history of diabetes, uh, if you look for example, off are what did the genes related to oxidative capitalism. So here is off part of a hydrogen ease off related here's decrease off individuals in existence off. Okay, what's important here? Well, here's a study in tasty and have of most years ago which looked at the animal. But, you know, it was This is this is in man looking at, uh, skeletal muscle. Uh, GC one expression on individuals with over inflated persist. Normal worth. Um, so if fears that individuals with low birth way felt peripheral insulin resistance in response to a high fat diet and skeletal muscle biopsy shows a DNA methylation off, you see? Did you see one offer? Um, so may be part of this is actually infected. Exactly. Um, that sleep in some way with a developmental exposure to right insulin resistance causing stress. So Why am I bringing itself in the context of outsiders disease? Well, it's an article that just came out. Uh, October 2009, Hm. Internal insulin resistance. And then a synaptic. That's just the memory eaten subsequent generations. Um, so without trying to go through the actual data, you, sir Christian. Um, So, um okay, it appears that all right, long term appreciation of members it's abnormal through the third generation. After resource to insulin resistance, closing environment. Oh. Oh, it's true. So So how exactly is this get out are not clear. But this is interesting way of, perhaps Weiqing a You're cockeyed and every maladies. Um, there it is really resistance mechanisms, Uh, something that actually characterize And then perhaps something that way. I've seen that way. Um, so a couple of other things interesting came up periods of that state's group looking conscription will collapse Decatur, right? Yes. Which is an indigenous, uh, wow. Years, Um, a factory in It's the resistance. Okay, if you knock out THC, uh, compare incentive, Not after the effect of the ministry with his own. Besides holding diet, you see interesting differences. So both of them increase people. Yeah. Uh, we increase in sensitivity decrease for the accident. But psychology Diana's known associates wait in particular increase wear is, uh, not a model. So we keep victories adverts. There's decreased number of small, metabolically healthy appetites. So maybe this will prove to be places on logic. Got back. Recycle. Smile. Um, here is a very interesting studying and just came out this year. So sharers group off instead of the original idea was left waas Okay, that is going to be key treatment for me. Simply administer elected will be able to take advantage of that. Um, who thinks that was weight Minutes. So good that that that's not so easy. Onley works in individuals General elected deficiency, which is an extraordinarily rare situation. Oh, for sure Study with important. So metabolism. So that was is a fixed in your being to look at because it has so much aphorism diving fight. You're the articles that I can't possibly understand that you, uh, there's there's still a lot of interesting. So Scherer has this model off top Nick looking partial left in production. So obesity is associated with elevated. You don't know why that wave our hands care what it is that resistance? Uh, so this animal model, our using that wasn't anybody. Abel's, um, I've improved that sense on in heightened elements, so whether that will again be interesting. Um, wait, States, Let's turn with It's, um So, actually, you are the new acid there, princess, about science following. Yeah, uh, their produce synthesis. They're using heroism. Um, so here's a he said of pathways. Okay. Uh, nitrogen released from rich US capitalism. Centuries. Different A. Yeah. Um, yeah. There is a cycle with some hands. Times branch chain, trance phrase, French. It's good. Still imagine it's off. Bleeding's who are are actually into the tch cycle. Important energy levels. Um, so, uh, AWS is playing a role energy metabolism on deliver, solving problems. And this is a because from these spaces, did you regulations. So there's a very straightforward associations of branch euphemisms, um, with our diseases with obesity excuses. So another very important said so feeling is, um, was really a key investigator. All aspect of my fellow said kind of a another story, right? Utterly brilliant. Uh, here's one of these early studies, uh, and association off of failing a solution producing with eso proposed Thetis interesting, uh, linkage with students existence. Hyper immuno academia with 1969 you're high number of particles of their area. Years on Lee showing this historical interest. This is my fellowship cited based on a is complicated, um, really vain catheterizations that I baby did. But really, the Phil Williams was, uh, the lab techniques did all the work. I'm Alan. Check this up. Alex is going on to oh, here, Siris of important investigations using this kind of model. Um, so we found that if you look at French classes, actually, after a guest beef, uh, you find that, uh, yeah appears in circulation without any YouTube gives you administer with World War I equals Post Show that there's a hey, issues. Oh, century of amino acids from God. Here's from paper. And exactly what mechanism. That is clear. It really has little to do with this talking. That was close. Yeah. What's it? Oscar programs, please. But it was actually really bad. Morning. I told Phil that I will pick up e have investigators. We're gonna do a site visit. Film can, study, started. Uh, these were incredibly complicated studies. Anyway, I got lost. E Oscar was parents got it. Um, so this is a viable from a priest? Dugard who came here and talked about this. Interesting. Oh, uh, looking at, um uh, question USC, which was less association. Wait, what similarly associating with, um And so if you look at eventually, you know, West Agent studies that track with its resistance. But here's the address with this study, um, on direction amino acids were associated with increased in response. Um, non Hispanic whites, Hispanics, but interesting. Not at all in America. So they're probably a lot of variation. There is a queue on range, you know, essence presidential resistance on same again e fatally after the streets mentioned request here is not studying enough professional follow up study showing, uh, you go to increasing court titles. Lucy, Lucy failing, you find, um, its existence diet, preparation classes, association meetings and resistance, perhaps particularly with value. Um, so there are to kind of existing prophecies. One is that resistance itself decreases university level so that the, uh, skeletal muscle doesn't respond with anabolic effects. Excellent. There's decreased. Pretty Allah assists off. Wrenching us to release or alternatively, a French interesting themselves causes existence. Maybe with dissect great present. Rajan, ease eating this whole um so that is my, um really out Very high up. A few of certain diversity aspect resistance Historically going back to the fighting bodies off economy, but interesting, uh, discovery of insolent, uh, which really, it wasn't discovered. 20 again. That's discovery in 1960 by person. Because that measuring we're talking about, what is it? And then, um, forward. It's the resistance is not just now. It involves aren't playing. Didn't talk about cancer association tremendously. It's a perfect community. Uh, what a terrible. So, uh, so that's my story.