#149 - AMA #20: Simplifying the complexities of insulin resistance: how it's measured, how it manifests in the muscle and liver, and what we can do about it

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Hey everyone. Welcome to ask me anything AMA episode number 20. As always, I'm joined by Bob Kaplan. And for this ama, we do something a little bit different. We actually devote the entire episode, which is a little bit longer than usual, to to sort of the deconstruction reconstruction of a podcast that many of you have said was simultaneously one of the most interesting and yet difficult to comprehend. Specifically the podcast with Gerald Shulman, which is the masterclass on insulin resistance. We felt, because this content is just so important, meaning understanding insulin resistance is just paramount to being healthy. As I hopefully make the case in this podcast, you simply can't be healthy if you're insulin resistant. And tragically, about 88% of people harbor some amount of insulin resistance or metabolic dysregulation. Maybe more broadly, this is something everybody really needs to understand. So we go really deep on trying to explain a lot of the stuff that was discussed in this podcast and hopefully doing so in maybe a slightly less technical manner and also spending a little bit more time on on things that we in the podcast probably glossed over a little bit quickly. So if folks enjoy this format, this might be something worth doing a little bit more of, where we take some of the more complicated and important subjects covered on the podcast and revisit them in this way. So without further delay, please enjoy AMA number 20.

Peter, ready for another exciting ama?

I am, Bob. This is a different one. This is the first time I think we've embarked on what we're about to do, and if folks like it, maybe it's an interesting thing to do every once in a while. But why don't you give folks a sense of what we're about to do today and why we're going to do it?

Sure. So you did a podcast with Gerald Shulman, which I thought was amazing.

Stop. Just stop.

You might have said it best in the intro for that, where you said this was fascinating and you didn't say this, but you said it before. It was probably like drinking through a fire hose, that there is a lot of information, a lot of mechanisms, a lot of stuff coming in and that you would have to go back and listen to it probably a few times to gain the insight from it. And a bunch of listeners, I think, expressed those thoughts, more or less. People would say, that was amazing. I wish I could understand it. Which means, like, they probably understood it to a certain percentage, but there was probably a lot there that they thought if this could be a little bit simpler to understand and synthesized, that would be awesome. And that is, I think, one of your superpowers. So not to put you on the spot, but actually to put you on the spot or us on the spot. I think the goal today is to try to synthesize this information and make it a little more digestible. And. And what are the insights? What's the. So what from all of this?

Yeah, I think you're absolutely right. I think people probably deserve more credit than they're giving themselves. And the comments on social media and such were, oh, my God, this is such an amazing discussion that Shulman was able to give all of these insights. But I'm going to have to listen to this three times, and I'm not sure I'll ever fully understand it, which probably says, look, I understand enough of this to know how important it is, but it would be great to revisit this maybe with a slightly different lens. So I think that's what we're going to try to do today. I think we're going to basically go through the important points of that podcast, slow it down a little bit, and sort of unlock a little bit of that stuff. So if folks like this, I think every once in a while, maybe, I don't know, every 10th podcast, I think, is a Shulman like podcast where the subject matter is so important to health that it's worth investing in it. And if we can do anything to facilitate that beyond the interview itself, then I think we need to think about it. So I guess the other thing to explain is how you and I thought about preparing for this, which is putting together a bunch of notes. Right. We kind of went through the podcast and pulled out various ideas that Jerry discussed, coupled them at points with slides, either figures that we found separately or more often, figures that he had used in his Banting lecture, which often spoke to the same points. And so when appropriate, I guess when we talk about that, we can reference slides so that people could actually go back and look at various figures.

Yeah, yeah. And I think this will probably be like, as a standalone, probably good. And it makes sense too, probably to go back and listen to the Shulman podcast. And that said too, when I say it's like really people said it was really complicated or difficult to comprehend, I will say that it is. Although I'll also give Dr. Shulman credit that I think that he put together a really compelling episode. And also he gave a lecture we'll probably link to that, his banting memorial lecture where I mean, this guy's been doing this, studying this for 35 years. So I think part of it is like he knows this stuff backwards in front of and sometimes he throws out terminology and things like that that people might not understand, or kinases and proteins and things like that. But just that being said, I think this will probably be a good standalone. We'll be able to explain things, but it'll help if you go back and listen to the podcast, if you have.

So let's set the stage for what we want to talk about, because I think you could. And by the way, I went back and listened to the podcast for the first time two days ago and getting ready to prepare for this discussion. And I was on my bike listening to it. So I listened to it during a Zone two workout. So I was upregulating all of that insulin independent glucose uptake in my legs while listening to this. And I got to tell you, like the, I had to really pay attention. The little go back 15 second button on my phone was used a lot. You know, it was really great to go back and listen to it because you understand a podcast much more when you're not interviewing somebody, when you can actually just listen. In many ways, this discussion comes down to a couple of things. How does insulin work under normal circumstances? What does insulin resistance really mean? How do you even measure it? We didn't talk about that in the podcast, but we're going to talk about it today because I think those terms get thrown around a lot. How is insulin resistance manifested in muscle? How is it manifested in the liver? How are those the same or different? And what are the consequences of this? In many ways, that's basically what you want to be able to get out of this. There's a lot more stuff we might get into if we have time today. But if you understand these things, you'll really then understand what I guess is the single most important takeaway, which is what should you do about this? Because once you understand the consequences of this, you'll appreciate how central this is to your health. Maybe we'll start with the first thing you learn in medical school about insulin is some of the basics. So insulin is secreted as what's called a propeptide. So the pancreas, which is this spongy little organ behind the stomach, secretes something that is inactive, and it gets split into insulin and C peptide, and then insulin is the active thing. And you can think of insulin as a very anabolic hormone. Anabolic is just a fancy way for building or growing. So insulin generally makes things grow, so it drives glucose into muscles where it can be turned into glycogen. I'll explain what glycogen is in a second. It plays a role in glycogen synthesis in the liver, though, as we will discuss. Insulin is not necessary for glucose to get into the liver the way it is necessary for glucose to get into the muscles. They have different transporters. It turns down the process of the liver giving up glucose, and it increases fatty acid uptake into fat cells. So it makes fat cells more fat, it makes muscle cells more glycogen rich, and it makes the liver more glycogen rich. So that's one way to think about insulin. It's a pro building hormone. So where should we go next?

We should probably define what we're talking about in terms of what is insulin resistance. Because if you ask 10 people, you might get 10 different answers, 10 experts.

You're right. And this is one of those things that is very difficult to get a handle on. But I think, Jerry, his work plays such an important role in our understanding of this. Insulin resistance is probably best defined as an impaired ability for insulin to do some of the things I just described. So insulin, if insulin's job is to take glucose into a muscle so that a muscle can make glycogen, when that gets impaired, and we're gonna talk about this in great detail, that is insulin resistance. And it's important to differentiate between what is insulin resistance and how do you measure that, or how is that manifested? We're gonna talk about that more clearly. But insulin resistance in the muscle is what I just described. When we get to fat cells and liver cells, it turns out there's a slightly different explanation or manifestation of it. So let's focus right now just on the muscle, and let's maybe talk about how these things are measured. So there are a couple of really fancy ways to measure and quantify insulin resistance that are done in clinical trials. So that is to say, these are not tests you will ever have done at the doctor's office. I've had these tests done to me, but again, they've not been part of any regular checkup. You would Do. They've been part of me being enrolled in studies and having an IRB approval to have these things done. They're very invasive, and truthfully, they can be dangerous if not done correctly.

Speaking of insulin resistance heavyweights and some issues with some of these tests. Was it Gerald Reeven? So he also did a Banting memorial lecture. You've done these tests. I think you've talked about it, but it might be worth stopping and maybe talking a little bit about your.

I'll explain my insulin suppression test at Stanford that Jerry was kind enough to do on me. So let's start with something called the euglycemic clamp. Okay, so first of all, euglycemic means normal glycemic. The way this works is plasma insulin concentration is raised to a pretty high level. So the patient has two IV lines, one that's running insulin into them and the other one that's used for glucose. So the first thing you do is you run a very high amount of insulin into them, and you maintain insulin at very high level, 100 micro units per milliliter. So you have a continuous infusion of insulin. It's at a high level physiologic, but a high level. Okay, so this is 10 times higher than what you'd want your fasting insulin level to be in the morning, but not so high that it's not something you would see postprandially. Okay, meaning after a meal. Now, at the other iv, glucose concentration is also being held constant by a variable glucose infusion. And this is done until you achieve a steady state. So if you think about that for a moment. So that's why it's called euglycemic. You get to a normal level of glucose by a fixed level of insulin. So if you had four people doing this test side by side, they'd all have the same insulin level of 100 micro units per milliliter. But they might all achieve a very different steady state glucose. So what would it mean? Well, what this test tells you is once they get to a certain level, that steady state of glucose, you can calculate what their glucose disposal rate is. And that's usually calculated in milligrams of glucose per meter squared of surface area of the body per minute. Again, you don't have to pay attention to those minute details. The point here is you can normalize how much glucose a person is able to put away, and that's almost exclusively into their muscles per unit time, per unit glucose per size of body. And therefore, if you think about it, the more insulin Sensitive you are, the higher that glucose disposal rate will be. Does that make sense, Bob? Did I explain that in a way that you think folks will get?

Yeah, I think so. So we're looking at a picture, picture of glucose disposal rates in different people. In a normal person, in a type 2 diabetic, and then a type 2 diabetic taking insulin, so ignoring the third one. So maybe you would look at a curve like this and think like, whoa, the normal ones, the data points are high. Is that good or bad? And you'd say, well, it depends. But it's relatively good here because you're disposing of more glucose under these conditions compared to a type 2 diabetic.

So the figure you're talking about is actually showing glucose disposal, not glucose. So important to understand that distinction. And that's why the more insulin sensitive person at a fixed level of insulin requires more and more glucose to maintain glucose homeostasis. So that's how a euglycemic clamp works. I think of it as the reciprocal test is called the insulin suppression test. And here you also have two intravenous lines, and in one of them you're sort of infusing epinephrine, propranolol and insulin, and in the other one you're infusing glucose. So the epinephrine and propranolol suppress your endogenous insulin release. So we want to take that out of the equation because different people will have different amounts of that, especially people who have sort of, you know, what we call beta cell fatigue. You want to have a steady state level of glucose and insulin. So the way this test works is kind of the opposite, which is you fix the level of glucose and you're trying to see how much insulin is required to do that. You made a point earlier about my experience with this when I did this test. I don't want to spend too much time on this story. Basically, I got very, very hypoglycemic and it got a little dangerous. I'll just leave it at that. But I spent all this time explaining those things because you hear about them in research. But the reality of it is you're never going to have one of these tests done on you. So what's done in the real world? Well, I mean, fasting insulin and fasting glucose are generally talked about as ways that people pay attention to insulin resistance. But the reality of it is those things are such late players to the game that I generally don't consider those to be great tests. And even something called the homa IR which people have probably heard of called the homeostatic Model Assessment of Insulin resistance, which is basically just a formula that looks at fasting insulin and fasting glucose. So it's fasting insulin times fasting glucose divided by 405. If they're in the units we typically use in the US that's borderline about as helpful as fasting insulin level. So I don't find that test helpful. We don't do that test on our patients in isolation. The thing that we do on our patients is an oral glucose tolerance test. And we find that to be by far the best thing you can do clinically to a sense of insulin resistance. And that is what much of the research that Jerry Shulman talked about. And then we're going to get to here. That's how it was done. So for that test, patients show up fasting, and you draw a blood level, glucose and insulin. They ingest a standardized drink called Glucola, which consists of 75 grams of glucose and nothing else. And then every 30 minutes for two hours, you draw blood, checking glucose and insulin, and you generate then two curves. What's their glycemic response? Meaning how does their glucose change over the next two hours, and what's their insulin response?

Is there generally like a time cap or how long are you supposed to take to drink that glucola?

You chug it. It's pretty small volume, but under ideal.

Conditions, it's actually, you want to take that in as quickly as possible. You're throwing 75 grams of glucose into the system.

That's right. Essentially, you don't nurse that. It's not a sipping beverage, and you don't do anything during this period of time. That's the thing that's important. You can't go off and exercise or do anything else that would interfere with glucose uptake. What you're really trying to measure is while you're sitting there, how much glucose gets taken up into the muscles. And that's being measured by the glucose level over time, and then how much insulin was required to do it. And so the earliest indication of insulin resistance is an elevation of those what we call postprandial insulin levels. So we see patients all the time that have normal glucose levels, but their insulin levels are sky high. So the typical progression you see from normal to abnormal normal would be glucose stays relatively low after the ingestion, and so does insulin. The first thing that you see that typically goes wrong is insulin goes up while glucose stays down. Then you see glucose goes up while insulin stays up then you start to see fasting glucose going up and then fasting insulin going up. And once fasting glucose gets high enough, you're very close to getting towards diabetes. Other things that people use to predict whether someone is insulin resistant is of course to look at something like the syndrome for metabolic the criteria for metabolic syndrome. So there are five of these and I think it's worth everybody knowing what they are because one should aspire to have none of them present. Bob, isn't it about the case that 90% of Americans have at least one of these five factors present?

Yes. Yeah, it's like 88%. It's almost 90%.

And if you have three or more of them present, you are technically defined as having metabolic syndrome. And all of a sudden your risk for metabolic disease, all metabolic diseases, cancer, cardiovascular disease, Alzheimer's disease, obviously type 2 diabetes, just goes through the roof. So what are these five criteria?

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