The Peter Attia Drive
#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.
Mon, 24 Feb 2025
View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter Ralph DeFronzo is a distinguished diabetes researcher and clinician whose groundbreaking work on insulin resistance has reshaped the understanding and treatment of type 2 diabetes. In this episode, Ralph shares insights from his five decades of research, including his pivotal role in bringing metformin to the U.S. and developing SGLT2 inhibitors. Ralph explores the impacts of insulin resistance on specific organs, the pharmacologic interventions available, and the gold-standard euglycemic clamp method for measuring insulin resistance. This episode is a masterclass in the pathophysiology and treatment of type 2 diabetes, featuring an in-depth discussion of GLP-1 receptor agonists, metformin, and a lesser-known class of drugs that opened Peter’s eyes to new possibilities in diabetes care. We discuss: Metabolic disease as a foundational driver of chronic illness [4:00]; Defining insulin resistance: effects on glucose, fat, and protein metabolism, and how it varies between healthy, obese, and diabetic individuals [8:15]; The historical significance of the development of the euglycemic clamp technique for measuring insulin resistance [11:45]; How insulin affects different tissues: liver, muscle, and fat cells [15:00]; The different ways insulin resistance manifests in various tissues: Alzheimer’s disease, cardiovascular disease, and more [25:00]; The dangers of hyperinsulinemia, and the importance of keeping insulin levels within a physiological range [29:00]; The challenges of identifying the genetic basis of insulin resistance and type 2 diabetes [37:00]; The “ominous octet”—a more comprehensive model of type 2 diabetes than the traditional triumvirate [45:45]; The kidneys’ unexpected role in worsening diabetes, and how SGLT2 inhibitors were developed to treat diabetes [55:45]; How insulin resistance in the brain and neurocircuitry dysfunction contribute to overeating and metabolic disease [1:04:15]; Lipotoxicity: how overeating fuels insulin resistance and mitochondrial dysfunction [1:07:30]; Pioglitazone: an underappreciated and misunderstood treatment for insulin resistance [1:10:15]; Metformin: debunking the misconception that it is an insulin sensitizer and explaining its true mechanism of action [1:19:15]; Treating diabetes with triple therapy vs. the ADA approach: a better path for diabetes management [1:24:00]; GLP-1 agonists, the Qatar study, and rethinking diabetes treatment [1:31:30]; Using a hyperglycemic clamp to look for genes that cause diabetes [1:45:15]; The superiority of measuring C-peptide instead of insulin to assess beta-cell function [1:46:45]; How GLP-1-induced weight loss affects muscle mass, the benefits and risks of myostatin inhibitors, and the need for better methods of evaluating functional outcomes of increased muscle mass [1:51:30]; The growing crisis of childhood obesity and challenges in treating it [2:02:15]; The environmental and neurological factors driving the obesity epidemic [2:07:30]; The role of genetics, insulin signaling defects, and lipotoxicity in insulin resistance and diabetes treatment challenges [2:11:00]; The oral glucose tolerance test (OGTT): detecting early insulin resistance and beta cell dysfunction [2:18:30]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube
Chapter 1: What are the key components of metabolic dysfunction?
Hey everyone, welcome to The Drive Podcast. I'm your host, Peter Attia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, and we've established a great team of analysts to make this happen.
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If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of a subscription. If you want to learn more about the benefits of our premium membership, head over to peteratiamd.com forward slash subscribe. My guest this week is Dr. Ralph DeFranco.
Ralph is a distinguished diabetes researcher and clinician known for his pivotal work in advancing the understanding and treatment of type 2 diabetes. He's widely recognized for his groundbreaking contribution to the concept of insulin resistance, which has reshaped the understanding of type 2 diabetes and its progression.
He played a very important role in bringing metformin to the United States as a standard treatment for the disease nearly 40 years ago, along with the discovery and development of SGLT2 inhibitor, a class of drugs you have no doubt heard me discuss many times before.
With over five decades of research in the field, Dr. DeFranco has received numerous prestigious accolades, including the Banting and Claude Bernard Awards, the highest honors that can be given to a diabetologist. This episode with Ralph is really a masterclass in the organ-specific aspects, the pharmacology, the diagnosis of type 2 diabetes, and it draws from his vast experience.
Now, if you listened to my conversation with Jerry Schulman a few years ago on insulin resistance, what amazed me was how little overlap there was, not because the information is not congruent, but because of how much we were able to go into different topics.
So the discussion with Jerry Shulman, which I would encourage everyone to listen to if they have not, really focused on one of the areas that insulin resistance manifests itself, which is in the muscle. What we talk about here is about all of the other organs. Spoiler alert, there are seven that are impacted by this condition.
And therefore we go into much greater detail there in addition to the pharmacologic interventions. And I just have to say, I learned more in this podcast than I do in most podcasts. It's one of the few that I had to immediately go back and listen to, and my notes from this podcast are so voluminous that they even provided substrate for internal meetings with our team in the practice.
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Chapter 2: How is insulin resistance defined and measured?
Even at three and four weeks of starvation, glucose was, if my memory serves me correctly, still providing about a third of the brain's energy. Your memory is very good.
The brain did switch over to ketone metabolism. And believe it or not, I didn't do the 40-day fast, but I was one of the people who fasted for five to seven days. If you fasted for three days, you could get paid $50. And I thought I was the richest guy in the world from this study. I can assure you that the physical specimens in this study were phenomenal. What did the 40-day fasting students get?
I don't know, but I'm sure he paid them a lot of money. That's amazing. In order to do that. The interesting thing about that is you realize that we have so much energy stored in the human body. Who would have thought that you're a lean type person, you can fast for 40 days. But the real problem is at some point you start to break down muscle.
And then if you start to break down cardiac muscle, then prolonged fasting at that point becomes a problem. But you have a lot of energy stored in fat and you can starve for a long time. And obese people easily can go for three, four months with all of the reserves that are in the body.
Let's maybe talk a little bit about what insulin resistance is. We'll get into what causes it, but let's just maybe define for people this term that gets thrown around constantly. And let's explain what it is from a technical standpoint.
Basically, every time you eat a meal and your blood sugar level goes up, you're going to release insulin. And insulin is sort of a master regulator for all biochemical processes in the body. One of the things that insulin is going to do is going to talk to your muscles and say, take up glucose and burn that glucose.
What we need to know is in a normal person, when I infuse insulin, how much of the glucose is taken up by the muscle. And then we could look at someone who is, say, overweight, or we could look at someone who's diabetic. And I actually developed the gold standard technique, which is the insulin clamp technique to look at this. So we could take an obese person or a diabetic or a normal person.
We raise the insulin. And then I'm using muscle as an example, how much glucose is taken up, disposed of by the muscle. And then I can compare if you're overweight compared to the lean person. Obese people are very insulin resistant in terms of muscle glucose uptake. I could look at the diabetic. They're even more insulin resistant. But there are many processes that insulin control.
So insulin regulates how much fat is released from your fat cells. And obese people, unfortunately, insulin keeps the fat in your fat cell. But in obese people, insulin doesn't work so well. So instead of keeping the fat in the fat cell, even though your insulin is high, you're breaking down the fat. So you have to look at each individual process that insulin is controlling.
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Chapter 3: What is the euglycemic clamp method?
define insulin resistance, but basically whatever the particular process you're looking at, you're comparing what would be the normal response in a normal healthy person compared to what might happen in a diabetic person or an obese individual.
So one of the challenges with the term insulin resistance is, as you said, it's a vague term and it's nonspecific because the actions of insulin are so many.
It has an action in the liver, it has an action in the muscles, it has an action with response to glucose, it has an action with response to amino acids, and it has an action with response to fat, both in the liberation of fat, lipolysis, and presumably in response to oxidation. Absolutely. We'll go through all of these, but let's maybe start with how the euglycemic clamp test is done.
Let's assume that I'm a healthy enough individual that we can use me as a proxy. I come into your clinic. What are we going to do? How do you run this test?
Let me bring you back in time when I was a fellow because at that time, we didn't really have a good measure of insulin sensitivity. So what people would do is you do an oral glucose tolerance test and the insulin level would go up. Some people would say, I'll look at how much insulin comes out compared to the rise in glucose. And that's a measure of beta cell function.
And then someone would just turn it around and say, look, I'm going to see how much the rise in glucose was per insulin. And that's a measure of insulin resistance. And it was very clear to me, well, this is insane. You can't take two variables and then just depending upon how you want to look at them, switch denominator and numerator.
So I said, we need to develop something that is really more specific.
Just to be clear, Ralph, I mean, unfortunately... We as clinicians are not able to do euglycemic clamps. Correct. We are still looking at oral glycemic tolerance tests. We are still giving people oral glucose and sampling glucose and insulin every 30 minutes and trying to impute what we can, which I'd love to come back and talk about interpretation, but carry on with the limitation.
We actually have done a lot of work on how you interpret that. So what we said is, why don't we develop a serious way? And so we developed a technique where I could take 100 people and I would infuse insulin initially as a priming dose and then just clamp the insulin level. So I give a prime continuous insulin infusion.
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Chapter 4: How does insulin resistance affect different organs?
You are going to have to infuse both insulin and glucose into each of my arms. The reason is, when you said a moment ago, you're going to steadily increase my insulin and take it to a steady state of 100... IU per ml. That's a staggeringly high insulin level. Not so high. In your eye, after a meal, it would be maybe 60. Obese people very commonly get to 100.
Sure, sure.
For a healthy person, would never see an insulin level that high. And if you were not simultaneously running glucose into them, you would kill them within minutes. Yeah. Hopefully not. Yeah, but to get to the point, they would become so profoundly hypoglycemic that they would cease to exist.
And it should be obvious that if you're very sensitive to insulin, I have to infuse a lot of glucose. But the other beauty of it, as I said, when I was a young guy at Yale, there was a a physician in New York, Dr. Altshuler, he was the first one to use treated glucose to trace metabolic pathways. And I said, this is astounding. So I actually went to visit Dr. Altshuler and learned how he did it.
So all of the insulin clamp studies that we did, we were the first people to use treated glucose in humans. and to show that the ability of insulin to shut down the release of glucose from the liver was markedly impaired.
Sorry to interrupt, but just to make sure that people are following us, the reason you wanted to use tritiated glucose there was not to quantify the total amount of glucose disposal. You could do that on mass balance. You wanted to determine the ultimate fate of glucose. How much became hepatic glycogen, if any? It sounds like the answer is none. How much became muscle glycogen?
Sounds like you said about 90%. And how much ultimately got converted through de novo lipogenesis into adipocyte or free fatty acid? Sounds like that's about 10% under the euglycemic condition.
Yeah.
Is that correct?
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Chapter 5: What are the genetic factors in insulin resistance and type 2 diabetes?
Jesse Roth, very famous diabetes person, maybe 50 or 60 years ago was the first to describe insulin receptors in the brain. And this is an area that's now starting to unfold. It may have some relationship to neurodegenerative disease, Alzheimer's disease. Some people say that Alzheimer's disease is diabetes type three. I'm not sure. Brain diabetes. Yes.
So the insulin resistance is a very important concept. Let's say we're going to talk about diabetes. even though there's an ominous octet that I developed that's used everywhere in the world for the pathophysiology of type 2 diabetes, if we really wanted to solidify it and say, what are the two big concepts? Insulin resistance would be here, and the other hand would be impaired beta cell function.
So if you are insulin resistant, and your beta cells work well, they know how to read the insulin resistance. They'll make enough insulin. You won't become diabetic. Hyperinsulinemia can damage you in other ways, but you won't become diabetic.
But what happens is if you're insulin resistant, particularly if you have a genetic predisposition, if your beta cells have to continuously pour out insulin, they start to exhaust. And insulin resistance is a disaster for someone who has a genetic predisposition. It's going to bring out the diabetes. Insulin resistance, in my opinion, is intimately related to cardiovascular disease.
That is why when you see a diabetic patient, 10% of them, you walk in, you have diabetes, first time I see you, 10%, 15% of the people already have a clinically significant cardiovascular disease. And if you look carefully, virtually 100% of them do.
And sorry, Ralph, do you think that that is a result of the hyperinsulinemia or the untreated or poorly treated hyperglycemia?
All of the above. More importantly, what we showed, and we were, again, the first people to show this, and the cardiologists, they're hemodynamically oriented. They're looking at vessels. Stenosis, yeah. But if you look at the insulin signaling pathway, Insulin has got to bind to its receptor. And then there's a signaling pathway. I can tell you all the molecules in there, which I'm not.
And then glucose gets transported in the cell. We were the first people to show in humans that that pathway doesn't work normally. Insulin will bind to the receptor. It will activate the receptor. But the next molecule, IRS1, PI3 kinase, all those molecules don't get activated. So glucose doesn't get into the cell. That's diabetes. That same pathway activates nitric oxide synthase.
And that generates nitric oxide. Nitric oxide is the most potent vasodilator in the human body. It's the most potent anti-atherogenic molecule in the human body. So this defect that's in muscle. and it's in cardiac muscle, and it's in skeletal muscle. This is all human data that I'm talking about, not animal data.
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Chapter 6: What is the ominous octet in type 2 diabetes?
You go back to 1950, the incidence of diabetes was 2%.
I've seen even data that says it was 1% as recent as 1970. It's very low. Yeah.
But these people were all lean and they're insulin resistant. So there's a genetic cause of the insulin resistance.
And you think, Ralph, that the greater genetic effect is on the insulin resistance side or on the beta cell fatigue side? Both. Okay. So let's tackle each. Since you started with insulin resistance, let's go there. Let's talk about what we know about the genetics of insulin resistance. That's easy. Nothing.
Truly nothing. I joke. Let's say 20 years ago, we got involved in one of the biggest genetic studies called the VEGAS study, Veterans Administration Genetic Epidemiologic Study. And we were convinced that we were one of the people to do the first GWAS studies, that we would define all the genes that are responsible. Well, we were not very successful.
Even if you took the subset of people with type 2 diabetes who were lean and you compared them to people who were lean and non-diabetic versus obese and diabetic, a GWAS was not able to identify a signal in those three cohorts?
We identified several and remember their associations. Of course. and they're in non-coding regions. The TCF7LT2 gene, we found that, but that had already been described by Dr. Michael Stern in San Antonio many years before. So we repeated what Michael showed, and other people have shown that. So there are a number of associations. Again, if you ask me, how many genes have we truly established?
that are really important in terms of causing type 2 diabetes? I would say very, very few. I know the genetics people out there probably hate this, and they'll say that we can put together a genetic score. But when they talk about a genetic score, it's not that they've causably associated a gene with diabetes. It's an association. It's an association. We have a whole different approach.
If you want, I can tell you what we're doing that may give some insight. And then people have started to think about rare diseases. that maybe the problem is in one family, you have this particular genetic mutation. Another family, you have a different genetic mutation. A third family, a different genetic mutation. And then when you do the GWAS study, you got this mixture of individual genes.
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Chapter 7: How do SGLT2 inhibitors work in diabetes treatment?
So you asked me mechanism. So we know that at least for the GIP, the glucotoxicity is impairing the ability of the beta cell to respond to the GIP. But not necessarily GLP-1. No, no. And that doesn't correct the GLP-1 problem. So there's true resistance still, even though I normalized the glucose in terms of GLP-1. So this incretin axis, the gut, is a very important endocrine organ.
And that's number five in the ominous octet. Number six in the ominous octet is the alpha cell. I would say the father of hypergluconemia, this is Dr. Roger Unger in Dallas. He was one of the very first people to show that diabetics had very high glucagon levels. Tell people what glucagon does. Yeah, glucagon, it drives hepatic glucose production.
So if your glucose gets too low, your alpha cells will release glucagon. So the alpha cell can sense the glucose. And so if you're hypoglycemic, this is an important defense mechanism. You release glucagon, that stimulates your liver and the glucose production goes up. It returns your glucose to normal. But a diabetic already has a high glucose. We don't want high glucagon levels.
So paradoxically, there's very high glucagon levels in the diabetic and those high glucagon levels are very important contributor to the hepatic insulin resistance because they're driving the liver to make glucose.
And sorry, just to make sure, I'm embarrassed to say I forget this from biochemistry. Is it driving the liver to make glucose out of, for example, glycerol, amino acids or other things?
Gluconeogenic pathway in glycogenolysis. Acutely, so if I acutely give you glucagon, the first thing that happens, you break down glycogen. But very quickly, you get rid of all the glycogen that's in the liver. And so chronically now, you're running on gluconeogenesis. But glucagon stimulates both pathways.
And does it also drive hepatic glucose output?
Yes.
Or does it just drive the creation of gluconeogenesis? No, no, no, in absolute terms. It increases hepatic glucose output as well as gluconeogenesis. Yes.
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Chapter 8: Why is pioglitazone an underappreciated treatment?
I'd probably never have to write another NIH grant for the rest of my life. And then we went on to show, and in fact, this is the first definitive proof of the glucotoxicity hypothesis. So we did all of these studies initially in animals, and this was all published in the JCI. And Luciano Rossetti is one of the fellows at this time. Actually, Jerry Shulman was a fellow on the papers as well.
And what we showed was that you could take different types of diabetic animal models, and you could show that they're reabsorbing excess amounts of glucose. And then if I treated them with fluorazine, because that's what was available, they simply peed the glucose out in the urine. And now all of a sudden their beta cells started functioning normally. Muscle insulin sensitivity improved.
So of course, that's wonderful if you're a mouse or a rat. So we said, well, what about humans? And so the original studies actually were done, there's kind of an interesting story behind this, but the initial studies were done with dapagliflozin. And we showed with just 14 days of treatment with dapagliflozin, we markedly lowered the fasting and postprandial glucose.
We improved insulin sensitivity by 35% and we made a major improvement in beta cell function. Now, the beauty of this, SGLT2 inhibitors are only in the kidney. They're not in your muscle. They're not in your beta cell. And the only thing that the SGLT2 inhibitors do makes you put glucose out in the urine. The only change in the plasma was the glucose came down.
And now insulin sensitivity improved in muscle and beta cell function improved. And this was the first, now in humans, even though the original studies were done in animals, first studies to show an improvement and the reality of glucotoxicity.
What was interesting is that when we started to work on developing this with BMS and AstraZeneca, the company decided, well, we should get some nephrologists in to see about this story. They said, look, if you listen to what Dr. DeFranco says, this will be a disaster. And they said, why? Because you put glucose in the urine, it will glycosylate the proteins, then you'll cause kidney damage.
And they actually held up the development of the SGLT2 inhibitors. And the way we finally convinced them to go ahead was that there's a disease called familial renal glucosuria. From day one of their life, they're bringing out tremendous amounts of glucose. They have perfectly normal kidney function.
How many grams of glucose can be differentially or extra secreted, basically, in the presence of an SGLT2 inhibitor today?
It kind of depends on what the level of your GFR is, but it could be anywhere from 40 to 60 grams up to 120 grams of glucose. And the higher would be in somebody with a higher gradient? Yeah, the higher the glucose. The higher the, yeah. Yes, because you filter more glucose, then there's more glucose to be blocked at the level of the kidney. And these drugs are very, very good.
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