The Peter Attia Drive - #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

00:00:00.000 Hey everyone, welcome to a sneak peek, ask me anything or AMA episode of the drive podcast.

00:00:16.500 I'm your host, Peter Atiyah. At the end of this short episode, I'll explain how you can

00:00:20.460 access the AMA episodes in full, along with a ton of other membership benefits we've created,

00:00:25.440 or you can learn more now by going to peteratiyahmd.com forward slash subscribe.

00:00:31.140 So without further delay, here's today's sneak peek of the ask me anything episode.

00:00:39.160 Hey everyone, welcome to ask me anything AMA episode number 20. As always, I'm joined by

00:00:46.820 Bob Kaplan. And for this AMA, we do something a little bit different. We actually devote the

00:00:52.460 entire episode, which is a little bit longer than usual to sort of the deconstruction reconstruction

00:00:58.960 of a podcast that many of you have said was simultaneously one of the most interesting

00:01:05.760 and yet difficult to comprehend, specifically the podcast with Gerald Shulman, which is the

00:01:11.740 masterclass on insulin resistance. We felt because this content is just so important,

00:01:17.660 meaning understanding insulin resistance is just paramount to being healthy. As I hopefully make

00:01:23.820 the case in this podcast, you simply can't be healthy if you're insulin resistant. And tragically

00:01:28.760 about 88% of people harbor some amount of insulin resistance or metabolic dysregulation, maybe more

00:01:34.640 broadly. This is something everybody really needs to understand. So we go really deep on trying to

00:01:41.660 explain a lot of the stuff that was discussed in this podcast and hopefully doing so in maybe a

00:01:47.640 slightly less technical manner and also spending a little bit more time on things that we in the

00:01:52.500 podcast probably glossed over a little bit quickly. So if folks enjoy this format, this might be

00:01:57.720 something worth doing a little bit more of where we take some of the more complicated and important

00:02:02.480 subjects covered on the podcast and revisit them in this way. So without further delay, please enjoy AMA

00:02:09.180 number 20. Peter, ready for another exciting AMA? I am, Bob. This is a different one. And this is the

00:02:21.220 first time I think we've embarked on what we're about to do. And if folks like it, maybe it's an

00:02:27.600 interesting thing to do every once in a while. But why don't you give folks a sense of what we're about

00:02:32.560 to do today and why we're going to do it? Sure. So you did a podcast with Gerald Shulman,

00:02:39.020 which I thought was amazing. Stop, just stop. You might've said it best in the intro for that,

00:02:47.700 where you said this was, this was fascinating. And you didn't say this, but you said it before

00:02:53.480 is probably like drinking through a fire hose, that there is a lot of information, a lot of mechanisms,

00:02:58.000 a lot of stuff coming in and that you would have to go back and listen to it probably a few times

00:03:03.500 to gain the insight from it. And a bunch of listeners, I think express those thoughts. It

00:03:09.420 was like more or less people would say that was amazing. I wish I could understand it, which means

00:03:15.840 like they probably understood it to a certain percentage, but there was probably a lot there

00:03:20.920 that they thought if this could be a little bit simpler to understand and synthesized, that would be

00:03:27.100 awesome. And that is, I think one of your superpowers. So not to put you on the spot, but

00:03:32.860 actually to put you on the spot or us on the spot. I think the goal today is to try to synthesize this

00:03:39.580 information and make it a little more digestible. And what are the insights? What's the so what

00:03:44.080 from all of this? Yeah, I think you're absolutely right. I think people probably deserve more credit

00:03:49.220 than they're giving themselves. And the comments on social media and such were, oh my God, this is such an

00:03:56.160 amazing discussion that Shulman was able to give all of these insights, but I'm going to have to

00:04:02.440 listen to this three times and I'm not sure I'll ever fully understand it, which probably says, look,

00:04:06.360 I understand enough of this to know how important it is, but it would be great to revisit this maybe

00:04:11.940 with a slightly different lens. So I think that's what we're going to try to do today. I think we're

00:04:15.720 going to basically go through the important points of that podcast, slow it down a little bit

00:04:21.360 and sort of unlock a little bit of that stuff. So if folks like this, I think every once in a while,

00:04:28.860 maybe, I don't know, every 10th podcast, I think is a Shulman like podcast where the subject matter 0.68

00:04:34.420 is so important to health that it's worth investing in it. And if we can do anything to facilitate that

00:04:40.780 beyond the interview itself, then I think we need to think about it. So I guess the other thing to

00:04:46.340 explain is how you and I thought about preparing for this, which is putting together a bunch of

00:04:52.060 notes, right? We kind of went through the podcast and pulled out various ideas that Jerry discussed,

00:05:00.200 coupled them at points with slides, either figures that we found separately or more often figures that

00:05:05.980 he had used in his Banting lecture, which often spoke to the same points. And so when appropriate,

00:05:12.200 I guess when we talk about that, we can reference slides so that people could actually go back and

00:05:17.060 look at various figures. Yeah. Yeah. And I think this, this will probably be like as a standalone,

00:05:23.320 probably good. And it makes sense to probably to go back and listen to the Shulman podcast.

00:05:30.520 And that said too, when I, when I say it's like really, people said it was really complicated or

00:05:36.040 difficult to comprehend. I will say that it is, although I'll also give Dr. Shulman credit that

00:05:43.120 I think that he put together a really compelling episode. And also he gave a lecture. We'll probably

00:05:49.520 link to that as his Banting Memorial lecture, where, I mean, this guy's been doing this,

00:05:53.800 studying this for 35 years. So I think part of it is like, he knows this stuff backwards and front.

00:05:58.620 And, and sometimes he might, you know, he throws out terminology and things like that that people

00:06:03.380 might not understand or, or kinases and proteins and things like that. But just that being said,

00:06:09.300 I think, I think this will probably be a good standalone. We'll be able to explain things, but

00:06:13.800 it'll help if you go back and listen to the podcast. If you have.

00:06:18.140 So let's set the stage for what we want to talk about. Cause I think you could, and by the way,

00:06:21.840 I went back and listened to the podcast for the first time two days ago and getting ready to prepare for

00:06:27.840 this discussion. And I was on my bike listening to it. So I listened to it during a zone two workout.

00:06:34.080 So I was upregulating all of that insulin independent glucose uptake in my legs while

00:06:40.420 listening to this. And I got to tell you, like the, I had to really pay attention. The little

00:06:46.540 go back 15 second button on my phone was used a lot. You know, it was really great to go back and

00:06:52.260 listen to it. Cause you understand a podcast much more when you're not interviewing somebody,

00:06:55.780 when you can actually just listen. In many ways, this discussion comes down to a couple of things.

00:07:01.060 How does insulin work under normal circumstances? What is insulin resistance really mean? How do you

00:07:07.180 even measure it? We didn't talk about that in the podcast, but we're going to talk about it today.

00:07:10.480 Cause I think those terms get thrown around a lot. How is insulin resistance manifested in muscle?

00:07:17.200 How is it manifested in the liver? How are those the same or different? And what are the consequences

00:07:22.780 of this? In many ways, that's basically what you want to be able to get out of this.

00:07:29.220 There's a lot more stuff we might get into if we have time today, but if you understand these things,

00:07:35.020 you'll really then understand what I guess is the single most important takeaway, which is what should

00:07:39.840 you do about this? Cause once you understand the consequences of this, you'll appreciate how central

00:07:45.360 this is to your health. Maybe we'll start with the first thing you learn in medical school about

00:07:50.900 insulin is some of the basics. So insulin is secreted as what's called a pro peptide. So the

00:07:59.640 pancreas, which is this spongy little organ behind the stomach secretes something that is inactive

00:08:08.780 and it gets split into insulin and C peptide. And then insulin is the active thing. And you can think

00:08:18.220 of insulin as a very anabolic hormone. Anabolic is just a fancy way for building or growing. So insulin

00:08:28.020 generally makes things grow. So it drives glucose into muscles where it can be turned into glycogen.

00:08:39.380 I'll explain what glycogen is in a second. It plays a role in glycogen synthesis in the liver,

00:08:47.200 though, as we will discuss, insulin is not necessary for glucose to get into the liver the way it is

00:08:52.840 necessary for glucose to get into the muscles. They have different transporters.

00:08:56.020 It turns down the process of the liver giving up glucose and it increases fatty acid uptake

00:09:09.540 into fat cells. So it makes fat cells more fat. It makes muscle cells more glycogen rich and it makes

00:09:16.800 the liver more glycogen rich. So that's one way to think about insulin. It's a pro building hormone.

00:09:23.700 So where should we go next? We should probably define what we're talking about in terms of

00:09:29.320 what is insulin resistance? Because if you ask 10 people, you might get 10 different answers,

00:09:34.500 10 experts. You're right. And this is one of those things that is very difficult to get a handle on.

00:09:40.580 But I think Jerry, his work plays such an important role in our understanding of this.

00:09:46.280 Insulin resistance is probably best defined as an impaired ability for insulin to do some of the

00:09:52.520 things I just described, right? So if insulin's job is to take glucose into a muscle so that a muscle

00:10:00.620 can make glycogen, when that gets impaired, and we're going to talk about this in great detail,

00:10:06.800 that is insulin resistance. And it's important to differentiate between what is insulin resistance

00:10:12.060 and how do you measure that or how is that manifested? We're going to talk about that more

00:10:16.680 clearly. But insulin resistance in the muscle is what I just described. When we get to fat cells

00:10:24.620 and liver cells, it turns out there's a slightly different explanation or manifestation of it.

00:10:32.160 So let's focus right now just on the muscle. And let's maybe talk about how these things are measured.

00:10:38.520 So there are a couple of really fancy ways to measure and quantify insulin resistance that are

00:10:48.540 done in clinical trials. So that is to say, these are not tests you will ever have done at the doctor's

00:10:56.660 office. I've had these tests done to me, but again, they've not been part of any regular checkup you

00:11:06.300 would do. They've been, you know, part of me being enrolled in studies and having an IRB approval to

00:11:12.600 have these things done. They're very invasive and truthfully they can be dangerous if not done

00:11:16.840 correctly. Speaking of insulin resistance heavyweights and some issues with some of these

00:11:23.080 tests, was it Gerald Riven? So he did a, he also did a Banting Memorial lecture. You've done these tests

00:11:29.740 and I think you've talked about it, but it might be worth stopping and maybe talking a little bit about

00:11:34.440 your, I'll explain my insulin suppression test at Stanford that Jerry was kind enough to do on me.

00:11:39.740 So let's start with something called the euglycemic clamp. Okay. So first of all,

00:11:45.040 euglycemic means normal glycemic. The way this works is plasma insulin concentration is raised to a

00:11:56.000 pretty high level. So the patient has two IV lines, one that's running insulin into them and the other

00:12:01.880 one that's used for glucose. So the first thing you do is you run a very high amount of insulin into

00:12:09.000 them and you maintain insulin at a very high level, 100 micro units per milliliter. So you have a

00:12:15.920 continuous infusion of insulin. It's at a high level physiologic, but a high level. Okay. So this is

00:12:22.960 10 times higher than what you'd want your fasting insulin level to be in the morning, but not so high

00:12:28.940 that it's not something you'd see postprandially. Okay. Meaning after a meal. Now at the other IV,

00:12:35.600 glucose concentration is also being held constant by a variable glucose infusion. And this is done

00:12:43.900 until you achieve a steady state. So if you think about that for a moment, so that's why it's called

00:12:49.520 euglycemic. You get to a normal level of glucose by a fixed level of insulin. So if you had four people

00:12:57.660 doing this test side by side, they'd all have the same insulin level of a hundred micro units per

00:13:02.520 milliliter, but they might all achieve a very different steady state glucose. So what would

00:13:09.280 it mean? Well, what this test tells you is once they get to a certain level, that steady state of

00:13:17.760 glucose, you can calculate what their glucose disposal rate is. And that's usually calculated in

00:13:23.780 milligrams of glucose per meter squared of surface area of the body per minute. Again, you don't have

00:13:30.960 to pay attention to those minute details. The point here is you can normalize how much glucose a person

00:13:37.460 is able to put away. And that's almost exclusively into their muscles per unit time, per unit glucose,

00:13:46.020 per size of body. And therefore, if you think about it, the more insulin sensitive you are,

00:13:54.360 the higher that glucose disposal rate will be. Does that make sense, Bob? Did I explain that in a way

00:14:00.780 that you think folks will get? Yeah, I think so. So we're looking at a picture of glucose disposal

00:14:06.760 rates in different people, in a normal person, in a type 2 diabetic, and then a type 2 diabetic taking

00:14:11.400 insulin. So ignoring the third one. So maybe you would look at like a curve like this and think

00:14:16.680 like, whoa, the normal ones, the numbers, the data points are high. Is that good or bad? And you'd say,

00:14:21.540 well, I mean, it depends, but it's relatively good here because you're disposing of more glucose

00:14:26.420 under these conditions compared to a type 2 diabetic. So the figure you're talking about is

00:14:31.300 actually showing glucose disposal, not glucose. It's important to understand that distinction.

00:14:35.800 And that's why the more insulin sensitive person at a fixed level of insulin requires more and more

00:14:43.660 glucose to maintain glucose homeostasis. So that's how a euglycemic clamp works. I think of it as the

00:14:52.220 reciprocal test is called the insulin suppression test. And here you also have two intravenous lines.

00:14:59.540 And in one of them, you're sort of infusing epinephrine, propranolol, and insulin. And in

00:15:07.020 the other one, you're infusing glucose. So the epinephrine and propranolol suppress your endogenous

00:15:12.080 insulin release. So we want to take that out of the equation because different people will have

00:15:17.280 different amounts of that, especially people who have sort of, you know, what we call beta cell

00:15:21.480 fatigue. You want to have a steady state level of glucose and insulin. So the way this test works

00:15:29.060 is kind of the opposite, which is you fix the level of glucose and you're trying to see

00:15:37.940 how much insulin is required to do that. You made a point earlier about my experience with this.

00:15:44.800 When I did this test, I don't want to spend too much time on this story. Basically, I got very,

00:15:50.180 very hypoglycemic and it got a little dangerous. I'll just leave it at that. But I spent all this

00:15:57.040 time explaining those things because you hear about them in research. But the reality of it is

00:16:00.740 you're never going to have one of these tests done on you. So what's done in the real world?

00:16:06.920 Well, I mean, fasting insulin and fasting glucose are generally talked about as ways that people pay

00:16:13.280 attention to insulin resistance. But the reality of it is those things are such late players to the

00:16:20.040 game that I generally don't consider those to be great tests. And even something called the

00:16:25.920 HOMA-IR, which people have probably heard of, called the homeostatic model assessment of insulin

00:16:31.060 resistance, which is basically just a formula that looks at fasting insulin and fasting glucose. So

00:16:37.440 it's fasting insulin times fasting glucose divided by 405 if they're in the units we typically use in

00:16:43.580 the US. That's borderline about as helpful as fasting insulin level. So I don't find that test

00:16:50.180 helpful. We don't do that test on our patients in isolation. The thing that we do on our patients is an

00:16:55.740 oral glucose tolerance test. And we find that to be by far the best thing you can do clinically to

00:17:02.700 a sense of insulin resistance. And that is what much of the research that Jerry Shulman talked about,

00:17:08.840 and then we're going to get to here, that's how it was done. So for that test, patients show up fasting

00:17:14.680 and you draw a blood level, glucose and insulin. They ingest a standardized drink called glucola,

00:17:23.140 which consists of 75 grams of glucose and nothing else. And then every 30 minutes for two hours,

00:17:30.180 you draw blood, checking glucose and insulin, and you generate then two curves. What's their

00:17:36.040 glycemic response? Meaning how does their glucose change over the next two hours? And what's their

00:17:40.680 insulin response? Is there generally like a time cap or how long are you supposed to take

00:17:46.020 to drink that glucola? You chug it. It's pretty small volume.

00:17:49.740 Yeah. But like under ideal conditions, it's actually, you want to take that in as quickly

00:17:52.780 as possible. Like you're throwing 75 grams of glucose into the system.

00:17:56.780 That's right. You don't nurse that. It's not, it's not a sipping beverage.

00:18:01.960 And you don't do anything during this period of time. That's the thing that's important. You can't

00:18:06.140 go off and exercise or do anything else that would interfere with glucose uptake. What you're

00:18:10.860 really trying to measure is while you're sitting there, how much glucose gets taken up into the

00:18:16.020 muscles, and that's being measured by the glucose level over time, and then how much insulin was

00:18:22.900 required to do it. And so the earliest indication of insulin resistance is an elevation of those,

00:18:32.180 what we call postprandial insulin levels. So we see patients all the time that have normal glucose levels,

00:18:38.880 but their insulin levels are sky high. So the typical progression you see from normal to

00:18:45.760 abnormal, normal would be glucose stays relatively low after the ingestion, and so does insulin.

00:18:52.940 The first thing that you see that typically goes wrong is insulin goes up while glucose stays down.

00:18:58.520 Then you see glucose goes up while insulin stays up. Then you start to see fasting glucose going up,

00:19:06.800 and then fasting insulin going up. And once fasting glucose gets high enough, you're very close to

00:19:12.880 getting towards diabetes. Other things that people use to predict whether someone is insulin resistant

00:19:22.440 is of course to look at something like the criteria for metabolic syndrome. So there are five of these.

00:19:29.740 And I think it's worth everybody knowing what they are, because one should aspire to have none of them

00:19:37.320 present. Bob, isn't it about the case that 90% of Americans have at least one of these five factors

00:19:44.720 present? Yes. Yeah. It's like 88%. It's almost 90%. And if you have three or more of them present,

00:19:52.660 you are technically defined as having metabolic syndrome. And all of a sudden,

00:19:57.000 your risk for metabolic disease, all metabolic diseases, cancer, cardiovascular disease, Alzheimer's disease,

00:20:04.860 obviously type 2 diabetes just goes through the roof. So what are these five criteria?

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The Peter Attia Drive - February 15, 2021

#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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