A masterclass on insulin resistance—mechanisms and implications | Gerald Shulman, M.D., Ph.D. (#140 rebroadcast)

**Peter Attia** (0:11)
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Now, without further delay, here's today's episode.
Welcome to a special episode of The Drive. For this week's episodes, we're going to re-broadcast my conversation with Gerald Shulman, which was originally released I think December of 2020
This episode is really a masterclass on insulin resistance. In this, Jerry clarifies what insulin resistance means as it relates to muscle and liver and the evolutionary reason for why it exists. It goes into great depths on the mechanisms that lead to and resolve insulin resistance, the clinical implications of these mechanisms, the role of diet, exercise and pharmacologic agents. While this was one of our most technical episodes, it was also one of the most popular episodes ever. Unfortunately, the complexity of this episode is the price one has to pay if you really want to understand longevity. You're going to have to understand insulin resistance. So to help with this topic better, we then released an AMA in February of 2021, I believe it was AMA number 20, called Simplifying the Complexities of Insulin Resistance.
And in that AMA, I basically sat down with Bob Kaplan and we went through the podcast and tried to explain some of the more complicated areas in it. This is another great resource for people who want to go deeper into this subject matter. So just as a brief reminder, Gerald is a professor of medicine, cellular and molecular physiology and the co-director of the Diabetes Research Center at Yale. In 2018, he received the Banting Medal for Scientific Achievement, which is generally regarded as the most prestigious award one can win in this field. So without further delay, please enjoy or re-enjoy my conversation with Gerald Shulman.
Jerry, thank you so much for making time to sit down virtually with me today. As I said before we hopped on, this is a topic that is near and dear to my heart. And frankly, all roads seem to point to you. And that goes back to, I don't know, at least for me, probably 2011, when I became really fascinated by this topic. And there aren't a lot of topics where I've personally experienced the following problem, which is the more I think I understand it, the less I do. So now when someone says to me, Peter, what's insulin resistance? You know, I can sort of give glib answers to that question, but the reality of it is, I don't think I fully understand what it is. And I don't know that I can represent to the listener that by the end of this, they will fully understand what insulin resistance is. But what I think they'll understand is how maybe we can think about it through the lens of different tissues and what may or may not be going on. And in large part, I think that's due to the incredible work you've done over your entire career. I guess I'd like to kind of just start with a little bit of background. You did an MD and a PhD and you're trained as an endocrinologist, correct?

**Gerald Shulman** (3:36)
Yeah, that's correct. And then I did residency in medicine at Duke, fellowship in endocrinology at the Mass General Harvard. And then I've always been interested in metabolism, diabetes.
I guess probably my father was a diabetologist, went to summer camp. He was the doctor for type one diabetics.
At an early age, I was exposed to problems, type one diabetes in my peers. I was just a camper and saw my peers getting hypoglycemic or getting into issues with ketoacidosis. So I think I was exposed to metabolism at an early age. I'm sure it left an impression on me. My father wanted me to become a radiologist because my physics background, but I ended up staying in metabolism and doing endocrinology.

**Peter Attia** (4:21)
I'm sure you would have done great things in radiology, but I also think we're far better off for the contributions you've made in this field.
When did this particular question of understanding what insulin resistance meant and actually starting to differentiate between some of these phenotypes of what is the fate of glucose in a person with normal metabolism versus what is the fate of ingested glucose in someone with type 2 diabetes? When did that question begin to obsess you? And specifically, now that's a sort of change from the patients that you grew up with with type 1 diabetes.