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It's /, subscribe. So without further delay, here's today's sneak peek of the ask me. Anything episode. Welcome to ask me anything episode number 43. I'm once again, joined by Nick Stenson, in today's episode, we answer a lot of follow-up questions. We've had on some recent podcast topic, specifically around insulin, hyperinsulinemia, apob LP little a and how they all relate to how a person should be thinking.
Out their risk of atherosclerosis cardiovascular disease, which is just as a reminder, the number one leading killer in the u.s. worldwide for men for women. So one of the things we try to do in this podcast is really get at the data around. How much residual risk is conferred for a SCV D, through metabolic dysfunction. Once you correct for apob and there are some things that I think we have data that we can speak to and we talk a lot about those things. So for example, we
It into the mechanism by which hyperinsulinemia increases the risk of a scpd. And of course, the question is once it will be, as corrected for does that risk still exists. Well, we attempt to tackle that we also talked about what mendelian randomization tells us about lifetime risk, reduction of ascd in the context of low a bo-beat. So these are just a couple examples of some of the topics that we get into at a pretty nuanced level in this podcast, if you're a subscriber and want to watch the full video,
Of this podcast. You can find it on the show notes page. And if you're not a subscriber, you can watch a sneak peek of the video on our YouTube page. So, without further delay, I hope you enjoy am a number 43
beer. Welcome to another am a, how you doing?
I'm doing well. Although looking at your T-shirt and realizing that you probably bought that at Kota, I'm a little less good because I'm realizing I somehow missed that shirt.
And didn't buy one myself.
That's a good-looking shirt and we didn't plan this, but we're both wearing the white black and red today, just a little different fonts on the front. You want to tell people about your
shirt. I have a Red Hot Chili Peppers shirt. You have Senna 1988 MP4 for McLaren shirt? Which I really like.
Well, next year, we'll make sure to track one down for. You have to find it. All right, perfect. So Peter for today's AMA what we did is we just gathered
Of questions of come from past podcast, content as relates to a scpd. We've talked about this so much with. Am a 34 recovered? What causes a scpd? We've had podcast, guess dive deeper into things that can mechanistically contribute to increased risks, with LP level away and Benoit, which is episode 2. 10 April be with Alan snyderman which was episode 185 and then insulin with Gerard Schulman, which was episode 140. And that was also one
we recently rebroadcast because we know we have a lot of new listeners who may not have heard that in the importance there. And so what we did is we combined a lot of these questions because there's a lot of people who are kind of wondering how they fit together, right? They know a bow be can increase risk, you know, LP little I can increase risk insulin, not good for a SCV D, but the question is kind of how can they collectively influence the risk of someone? You know, there's questions.
Around. If my a bobi is low, but my LP little a is high, you know, if my insulin is good but my LDL or a bobi is raised. How do I think about that? And so, we compiled those questions. And that's what we're hopefully going to cover here today. And so it's a little bit related to formula one but not quite fully there, but on the plus side much like Formula One, you do like talking about cardiovascular disease. So at least it's an interest there, but anything
You want to add before we get started?
No, but just for the record, I do prefer talking about Formula 1 over a poby, but I think a probie is more important. So I probably spend more time talking about it. Just to
clarify, is there an analogy that you can use that ties a bow be to cardiovascular disease as it relates to Formula? One,
not off the top of my head, but I accept the challenge.
All right, I feel like that's a good thing for you to work on because of, I'm
Is that you don't have one off the top of your head. Usually racecar analogies as it relates to health. You're pretty good at whippin those
out. Well actually I do now that I think about it so if you imagine this could really be applied to other things but I think with a SUV D there's a pretty good application right? So if you imagine your life span is the length of time, it takes you to drive a race car from point A to point B. Where point B is driving it off a cliff.
And you have two feet and two pedals, right? So you have the accelerator and you have the brake and your feet are always on both pedals. So it's really just a question of. How hard are you pressing on each one? Now, in this analogy, there's never a point when the car is not moving towards the edge of the cliff, but you can do things that really speed up the drive, which means your
you're moving towards death more quickly. That would mean, you're pressing much more on the throttle than you are on the break, conversely. You could have minimal pressure on the throttle and much more pressure on the brake and really slow your forward progress. So, then the question becomes, what are the factors that you could be doing that accelerate the drive towards the cliff and what are the things that you can be doing that slow, that trajectory. So some of those things are kind of
Not under your control so apob I mean, pardon me, LP little a is not under your control. So LP little a is just a low level of Maintenance throttle. That is put on the pedal. So somebody who's born with a low LP little a has a very low throttle application. Someone who's born with a high LP. Little a would have a higher throttle application. So we would just call this sort of Baseline maintenance throttle. Now, you're a poby is also going to be a part of that. So the question is, do you
You do things that lower a poby obviously. There's dietary things that do so. But if we're really talking about reducing elbow, be to the levels that we call physiologic, that's really going to be the application of pharmacotherapy. So that would be kind of pressing much harder on the break. The more you're lowering apob the harder you're pushing on the brake person has, for example, type 2 diabetes, which we'll talk about in a second that is generally accompanied by hyperinsulinemia. Well, what is hyperinsulinemia doing in this equation? It is pressing
Harder on the throttle. It is accelerating through mechanisms like upregulation of a possi 3 expression which regulates apob in the wrong direction. So more a possi 3 means more apob impacts the LDL receptor, the LDL receptor related protein, it moves, all of these things in the wrong direction. So insulin is basically changing the amount of LDL particle that you have in circulation. I guess I could build that out a little
A bit more obviously smoking. What would that be? Smoking is hammering on the throttle, having high blood pressure and lowering high blood pressure. Those are really big thing. So what are the big three things that are driving a scpd, smoking hypertension, a poby and then of course you have other things like LP little a hyperinsulinemia. So I guess that would be my analogy right? Which is we have a car that we can't actually stop but we can really slow it down to a dull Roar and that's going to be through some combination.
Manipulating the break in the throttle.
I mean, the other piece of that, which to tie and other things. We've talked about is also, how much space do you have between where your car is now? And the cliff is going to be a result also of how old you are. And so when you look at risk and how you think about risk, you know, it's something you announce snyderman talked is do you only look at 10 year risk when it comes to a s CBD, which is kind of that medicine.
2.0 approach or do you look at 50 or risk when it comes to that, which is that medicine 3.0 approach? Because if you wait until the earlier, you work on the throttle and Brake the more time you have to make interjections in the longer you. Wait, the harder you're going to have to press on that break, but that still might not be enough with based on where you're
at. Yep, I think that's exactly right. And it's another thing I like about that analogy, the more I think about it is if you're 100
From the end of the cliff and you're traveling fast, you better get ready to lock up the brakes. And if you have a mile between you and the cliff, you can be a lot more judicious in your use of the brake pedal, another
way to say it and we don't have to get into it because we covered a lot in. Am a 34? If anyone hasn't lessened the beginning of that is basically no matter what age you are, don't tune out on this conversation because you need to care about these things. Even if you're 30
A 35 40, you may feel you're in good health, your insulin may be low but what is your a poby? What is your LP little a showing, which we'll get into here shortly. So ha, look at us, we're able to bring in a race car, analogy early on, which is always a positive.
So, the first
question, I don't think we need to go into this level of detail. You've may be covered in other podcasts, but just kind of summarizing for the rest of the conversation to set.
Stage a little bit, are their relationships between insulin levels and other lipid ascd, parameters, such as a Bubbie ldl-c. Before we say that it might be important, we might enter change throughout these questions a poby & ldl-c. You know, sometimes we get a bow, be specific question, sometimes people don't know their apob and so they only know their ldl-c. So do you maybe just want to give that 30-second version of
In times they are in concordance. Sometimes they're in diskin coordinates, you always prefer to know apob. But if someone doesn't know a bow B and they only have their LDL see, that can be a predictor as well. Is there anything maybe you want to say on that just to flush out for? I
think it's important for people to understand what they are. So ldl-c is a laboratory measurement that measures the concentration of cholesterol contained, within the LDL particles LDL by itself.
Elf is not a laboratory measurement, so not to be sort of too much of a stickler. But if somebody says, what's your LDL? There's no answer to that question. Meaning LDL low. Density lipoprotein is not a laboratory measurement, so it's either ldl-c the cholesterol concentration within. Or LDL P the number of LDL particles. I prefer apob which is the concentration of all particles that carry
The apob lipoprotein which includes LDL and that's the Lion's Share of them but also vldl and LP little a which is a subset of the LDL. So in summary, then your LDL cholesterol concentration is a predictor of risk. A higher. It is the more likely your risk, but the apob is a better predictor of risk. Because it captures, not only the concentration of
DL. And we know that it's the number of particles more than the cholesterol concentration of the particles that drives risk but also because it includes the other atherogenic particles namely the vldl because the lp little a is generally captured inside of the LDL that we like to know that separately because in people for whom, it's very high and we'll probably get to this later today. Our best strategy at the moment to reduce residual risk. Of course, is to obliterate.
Hippo be concentration. So, we measure all of these in our patients, but at the end of the day, we look heavily at a poby concentration As the metric. We are using as our goal post,
perfect, and again for anyone who wants to dive deeper into that am a 34 and also episode number 185 with Alan snyderman really gets into a lot more in the weeds there if that's of interest in people haven't gone back and listen to those but
But that being said, let's kind of get back to the question which is, you know, are their relationships between insulin levels and other lipid, a scpd parameters, like a bow? Be
yeah, I mean to me, the two most obvious ways in which well let me take a step back. So let's explain the observation. The observation that is unequivocal is hyperinsulinemia, is associated with worse outcomes, in a s cvd. The most obvious example of that is type 2 diabetes, which is just a very extreme manifestation of hyper and
Anemia, of course. Type 2 diabetes is defined by glucose level. But, again, as we talked about, with Jerry Shulman, we've talked about this in many podcast, what is the precursor to that, right? What's the canary in the coal mine years? Before a person shows up at their doctor? And the doctor says, hey, you've got type 2 diabetes. If you knew where to look, you would see hyperinsulinemia. Now sometimes that doesn't occur at fasting. Sometimes that's enough postprandial State and that for us is typically the true Canary in the coal. Mine is, it's a post-production.
Randall, challenged glucose response, where glucose is normal but insulin is distorted. Insulin is elevated. So when we see that 3060 minutes after you've been challenged with glucose you have elevated insulin, we know that you're on the path towards insulin resistance. Okay, so we have this observation which is people with type 2 diabetes or about twice as likely, maybe 50% a 2X likely of developing a SCV D and in fact, all-cause mortality. So now the question is, why what's the mechanism?
Explanation for this. I think the two that are most important are the impact that insulin and insulin resistance has on the expression of a possi 3. So a plus c 3 is another lipoprotein. So April lipoprotein C3, it's very interesting when it's probably come up on a previous podcast, it might have been on the one with nir barzilai. I know I write about it in the book but it is one of the genes. So the ape oc3 Gene is one of the sort of centenarians
jeans. So centenarians are more likely to have a version of that Gene that results in lower expression. So in other words, you can think of it. That's a good thing. So the bad version of that is, you know what, we see the expression pattern in people with hyperinsulinemia, insulin resistance, is that we kind of up regulate that. And if we do that, if we increase the expression of that it blocks the activation of something called lipoprotein lipase or LPL and LPL is an
Enzyme that sits on cells, that basically performs a function of controlling lipolysis. So one of those side effects, we see of blocked. LPL activity is less utilization of triglyceride. So if you're using them less, what's happening, you're increasing the amount of triglyceride you have. So now let's think back to what does that mean? So if you increase the concentration of triglyceride and again clinically that's very obvious, you measure that in a standard.
Or lipid panel, we know that risk goes up but the question is through what mechanism? Well it goes up through a poby. Why? Because triglycerides like cholesterol are not water soluble their fat soluble which means they can't be trafficked on their own. They can't just freely float through plasma. They need a chaperone and the most common chaperone we use to move. Cholesterol are apob bearing particles, namely the vldl particle, which is itself.
Very ask for genic. In fact, if it sticks around a long time and becomes a Remnant, it is especially atherogenic. So if we are increasing expression of a possi 3 and blocking the action of lipoprotein lipase, we're going to see a net increase in triglyceride and furthermore, we're going to see a specific increase in a type of LDL, which is triglyceride Rich. So we really don't want to see these triglyceride Rich ldls. We want the triglycerides to be utilized.
Because if you have now triglyceride rich ldls and their purpose, there is a really carry cholesterol. What is the body do? It has to make more ldls and that means the concentration of apob is going up. I would say that's probably the most common I would say. That's the most important mechanism and the way we basically see that is, you know, we were going to see high plasma levels of triglycerides and we're going to see other things as well. I didn't get to this, but you're also going to see a
L cholesterol, concentration, go down and that's probably due to the change in activity of a protein called cholesterol. Ester, transfer protein C tap which I don't think we'll get into now because I think we'll save that for an upcoming podcast where we will go. We have a dedicated podcast coming up, that's going to go into all things HDL. So I say we leave it at that and say that hyperinsulinemia is a risk factor. That also increases both directly and indirectly the risk of a scpd.
Peter that makes sense. And I know in your answer you mentioned. There was two things that really affect it and you covered one of them. Do you want to also cover the
second? Yep. Thanks. Sorry. I got a little carried away on a Bose III. I think the other thing we're insulin especially hyperinsulinemia is playing a role is with endothelial dysfunction. So, again, if you take a step back and ask the question, what is the Cascade of events that leads to a s? Cvd endothelial dysfunction, is an important risk.
Actor. Why? Because if the endothelium is not working, the apob particles, have an easier time getting through the gaps and into the sub endothelial space. And furthermore, we know that that's what sort of propagates the risk. So as the apob particles, get retained and oxidized and the immune cells, namely macrophages, monocytes that become macrophages undergo the phagocytosis of
Of the oxidized LDL particles and become foam cells. That creates sort of an inflammatory milieu in the sub endothelial space. That increases more endothelial that you know sort of drives endothelial dysfunction and leads to a greater and greater Cascade of more apob particles being retained oxidized, Etc. Well, insulin itself seems to drive this endothelial dysfunction. Now, this is a much harder thing to demonstrate because we don't
You lie have great, clinical commercial assays for endothelial function. We have a bunch of indirect things, but if you do, look at cultured endothelial cells and you alter insulin concentration, you're going to see signaling Pathways in the endothelium that suggests that they are becoming less functional. So I guess I would say that this is probably not as well studied and easy to demonstrate as the other mechanism I mentioned but I think there's reasonable evidence.
It's that endothelial dysfunction is also a manner through which hyperinsulinemia impacts the risk of scpd,
and for people who might be kind of listing this and thinking themselves, okay? You know, how are my insulin levels, there's a very clear definition of type 2 diabetes, which is you get your blood checked, your A1C is like above x amount, but for people, you kind of mentioned earlier in the conversation. You also look at a different test, which is
OG T Test which is something that someone can do which maybe is that Canary in the coal mine and you just want to let people maybe know a little bit about that ogt in case, anyone's wondering to themselves like look based on my blood work. I know I don't have type 2 diabetes but now I'm kind of curious what my insulin level is and if this is something I should be worried about, how do I find out more to learn my current state.
Thank you for listening to today's sneak peek AMA episode of the drive. If you're interested.
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