Type 2 Diabetes

G Alexander: I don't want people to think that type two diabetes means that you're you're necessarily not obeying good lifestyle principles. You may be doing the right thing. You may be eating relatively well. You may not be overweight. You still could have type two diabetes.

Brent: Welcome to Death Clock. I'm your host, Brent Franson. The mission of what we're doing at Death Clock is trying to help 100 million people live ten years longer. We do that through this podcast. We try to bring experts onto the show that can help us understand how to be healthier and live longer. The show is supported by the Death Clock app.

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Brent: Download the Death Clock app and let us know what you think. Today we speak with Dr. G. Alexander Fleming, who spent over a decade as a leader at the FDA and helped approve landmark drugs like metformin, the first statin, and the first insulin analogs. He's an endocrinologist who's spent decades at the intersection of metabolism, aging, and regulation. We talk about what type two diabetes is, how it's different from type one diabetes, and the biomarkers that we use to understand our risk of type two diabetes.

Brent: What should you ask your doctor to order to understand these things for yourself, how to prevent it? And a little bit of the public policy around metabolic health. It's such an important topic. Diabetes and type two diabetes is preventable, and it's at the center of our health. If we are at risk for type two diabetes or we have type two diabetes, we are at higher risk of heart disease, Alzheimer's, cancer.

Brent: It really has a systemic impact. He's a wonderful guest. I hope you enjoy.

Brent: Dr. G. Alexander Fleming, welcome to the show.

G Alexander: My pleasure, Brent. Glad to be with you.

Brent: So the topic today is diabetes, specifically type two diabetes, understanding the disease and understanding how we can prevent it. This is obviously center of the bull's-eye of preventative health and longevity. Diabetes is one of the four horsemen of death, so it will be good to chat with you about it.

Brent: Before we do that, can you give us a sense of your background, your bio?

G Alexander: Well, I am an endocrinologist by background, so I specialize in hormonal diseases, diabetes being the major one from a public health standpoint. But I've been involved in other subjects of endocrinology as well. I was pursuing an academic career at NIH and was invited to come to the FDA to help them out.

G Alexander: I thought it would be on a temporary basis, but long story short, I ended up staying for a good number of years, being responsible for diabetes treatments. This was back in the late '80s when I started. Soon after getting there, I approved the first statin, and later went on to approve all of the diabetes treatments that came along at that time, including insulin analogs and metformin, which is, of course, a commonly used drug for type two diabetes.

G Alexander: At the time, that approval was very controversial, so it's interesting that it is now the first-line treatment for type two diabetes. It's also being put forward for preventing multiple chronic diseases and slowing the aging process. We might come back to that in a moment. But just to say, I started off when we did not even know if it made a difference to control blood sugar for people with diabetes.

G Alexander: This was back when we were testing blood sugar by doing a dipstick in the urine and saying it was high or low, and maybe you should or shouldn't do something about that. That was just how crude things were in that day. It's kind of like I was with the Wright brothers and now I'm in a 747—there's been that much change in the field.

G Alexander: And that's all for the good. But what is exciting is the prospect of actually preventing diabetes and other chronic diseases.

Brent: Let's start by defining diabetes. In particular, let's talk about the difference between type one and type two. What is diabetes, and what is the difference between type one and type two?

G Alexander: Well, what binds those two forms of diabetes is simply high blood sugar if you don't do something about it. But the causes are very different. For people with type one diabetes, we typically think of that as a childhood disease, but actually many adults are struck with type one diabetes at any point.

G Alexander: It can occur at any age. The reason type one diabetes occurs is because of an autoimmune attack on the cells in the pancreas that secrete insulin. Those cells are wiped out by the autoimmune process, and eventually people with type one diabetes lose all ability to secrete insulin. If you don't give them insulin, they would die.

G Alexander: So insulin is essential for people with type one diabetes. Now, that's not the case for type two diabetes. People with type two diabetes may start to lose their insulin secretion over time, and after many decades they do lose a lot of that ability. But the main problem for them is the ability to respond to insulin—what we call insulin resistance.

G Alexander: People with type two diabetes typically have some degree of insulin resistance, and they may also have insufficient insulin secretion. Any combination of the two can result in elevated blood sugar. That's when you start to be classified as having type two diabetes. One important point is that there are a lot of people who don't have elevated blood sugar, but they do have high insulin resistance.

G Alexander: Many of them will go on to develop type two diabetes, but some don't. The point, though, is that these people are at risk, and having insulin resistance itself causes other issues, including cardiovascular disease and contributing to the risk of heart attacks. Insulin resistance is a very pervasive problem in our society.

G Alexander: It goes along with obesity. Not every person who is overweight has type two diabetes—many eventually do, but they start with some degree of insulin resistance. It's that insulin resistance that is more or less the root cause of type two diabetes.

Brent: Just to be clear, type one and type two are very different. Type one diabetes is when you're not producing insulin due to an autoimmune issue, which doesn't have to do with lifestyle or behavior.

Brent: It's genetic. With type two diabetes, you're creating insulin normally, but you have a resistance to that insulin, and that resistance is very unhealthy. Type two diabetes is almost exclusively and directly related to lifestyle.

Brent: Eating the wrong things, not exercising, or being overweight can contribute. We put type two diabetes in the preventative health category because if we do the right things in our lives, we can prevent getting this disease in the first place.

Brent: So for type two diabetes, how do we diagnose it? How do we measure it? What are the biomarkers that we care about? How do we determine if someone is approaching type two diabetes, has it, or doesn't have it?

G Alexander: That's a key question. Let me emphasize that all people with type two diabetes have some degree of insulin resistance, but it's a spectrum—some have much more than others. It is true that excess weight tends to cause insulin resistance.

G Alexander: That in turn can lead to type two diabetes. But there are plenty of people with type two diabetes who are not overweight. They still have some degree of insulin resistance, but they may have beta cell failure, where the insulin-secreting cells are not putting out enough insulin. So I don't want people to think that type two diabetes necessarily means you're not following good lifestyle principles.

G Alexander: You may be eating relatively well and not overweight, but still have type two diabetes. Most people with type two diabetes are overweight, and people who are very overweight tend to eventually get type two diabetes, but it's a bit more complicated.

G Alexander: Ultimately, genes are behind it as well. We have genes that make us more or less susceptible to the disease, so having type two diabetes doesn't mean you're a bad person, and that's clearly not the message we want to send.

G Alexander: Well...

Brent: I'd like your perspective on this. To come back to biomarkers, type two diabetes feels like a modern disease borne out of abundance.

Brent: If we were to go back and study cavemen from a couple thousand years ago, we probably wouldn't find a lot of type two diabetes. They ate meat and vegetables and were very active as a natural part of their lives. But because we've figured out how to create something like sugar in excess and put it in everything we consume...

Brent: We've got these caveman bodies evolutionarily that aren't designed to handle this amount of glucose. We're getting it in pasta and added sugars, and that's where type two diabetes comes from—it's a disease of the modern abundant environment.

Brent: Do you agree with that?

G Alexander: That's very fair. I think that is 90% the case—that people with type two diabetes might not have had it if they were working in the fields 100 years ago, being physically active and eating less refined sugar. You're absolutely right about that.

Brent: A lot of people have heard of blood glucose and hemoglobin A1C. I'd like to get your perspective on things like fasting insulin or an OGTT. How do we diagnose it, and how do we know if someone is at risk of type two diabetes or has it?

Brent: Or if somebody has it?

G Alexander: Going back to ancient times, we used to diagnose type two diabetes by tasting the urine. But then we progressed.

Brent: You mean dip sticking?

G Alexander: Literally tasting the urine. By the early 20th century, we started to measure blood glucose and understood that diabetes was related to high glucose in the blood. Fast forward to about 40 years ago, and we started using hemoglobin A1C.

G Alexander: It was just getting started when I came to the FDA, and we started to approve drugs based on that biomarker. Hemoglobin A1C is a way of understanding average blood glucose over a period of time, because glucose binds to hemoglobin in red blood cells in proportion to its concentration in the blood.

G Alexander: It turns out to be a very good way of determining average glucose levels. For diagnosing type two diabetes, an elevated hemoglobin A1C can pretty much determine whether a person is classified as diabetic or pre-diabetic. It's an easy test that can be measured every three months.

G Alexander: That's the standard of care to see how a person is doing. But it is just an average; it doesn't tell you how your blood sugar goes up and down during the day. We now have continuous glucose monitoring technology to see blood glucose changes every five minutes. Remarkably, we find that even people without diabetes have major shifts in glucose that we previously had no idea were happening in the general population.

G Alexander: Some people without diabetes have these big shifts more than others. Some people use continuous glucose monitoring as a way to improve health by avoiding diets that cause high spikes. CGM is very important for people with type one diabetes because they're at risk of hypoglycemia from using insulin.

G Alexander: Most people with type two diabetes do not require insulin, so they don't have the same need to monitor glucose levels minute by minute, but we have that ability. Consumer versions of continuous glucose monitors are available to buy for various purposes, particularly preventing diabetes.

G Alexander: That's the state of the art for monitoring diabetes at home. It's still important to use hemoglobin A1C, but CGMs are often helpful even for people without diabetes.

Brent: Blood glucose is a blood-based biomarker included in commonly ordered blood tests like a basic or comprehensive metabolic panel.

Brent: You typically do it in a fasted state in the morning. Below 100 mg/dL is considered normal, 100 to 125 is pre-diabetic, and above 125 is considered diabetic.

Brent: The drawback is that if I ate cake yesterday, it gives a snapshot of the last 24 hours that might not be representative of my overall lifestyle. That's where hemoglobin A1C comes in, giving a percentage reflecting a three-month view.

Brent: Below 5.7% is considered normal, 5.7% to 6.4% is pre-diabetic, and 6.5% and above is diabetic. That three-month average is the gold standard in blood tests for visibility into diabetes risk.

Brent: Continuous glucose monitors can show minute-by-minute spikes that might not show up clearly on a normal A1C, providing further insight.

Brent: What about fasting insulin? My A1C is 5.7%, which is on the line, but my fasting insulin is healthy. How do you view fasting insulin or the oral glucose tolerance test (OGTT) in measuring insulin resistance?

Brent: How do you think about the role of fasting insulin, or the oral glucose tolerance test (OGTT)? Those tests can give a sense of insulin resistance as well, correct?

Brent: How do you think about the role of fasting insulin, or is another test that pregnant women will be familiar with? This called the oral glucose tolerance test the og t. It's a more involved test, but that can give you a sense of, insulin resistance as well, correct?

G Alexander: That's right. Taking those in reverse order, the oral OGTT is an old test used for a long time. It remains standard of care for looking at diabetes risk in pregnant women.

G Alexander: Taking a standard glucose load and measuring blood sugar is a reliable way of determining where you are on the spectrum of normal, prediabetes, or diabetes. We don't do it as much as we used to because we rely on A1C and fasting or postprandial glucose levels.

G Alexander: The average doesn't tell you everything. Those high spikes that occur in some people can be harmful. You can have a normal A1C because it's an average, but high spikes can cause tissue damage over time.

G Alexander: That's something to keep an eye on. Coming back to insulin levels, insulin resistance drives not just diabetes but multiple other diseases. It's a good idea to know if you have insulin resistance, even if your body weight is normal, you are active, and your glucose is normal.

G Alexander: If you have a high insulin level, that indicates insulin resistance. It may or may not lead to diabetes, but it increases your risk of heart disease, fatty liver disease, and neurodegenerative diseases like Alzheimer's and Parkinson's. It's really good to know whether you have insulin resistance.

G Alexander: A simple way to check is to measure insulin and glucose levels at the same time. The ratio gives an indication of insulin resistance. It should become more of a standard of care to check this, even in people who look normal, to evaluate complications of insulin resistance early.

Brent: So three good measurements are blood glucose, hemoglobin A1C, and fasting insulin.

Brent: The ratio between A1C and fasting insulin really matters. You might have a healthy A1C, but elevated insulin indicates higher insulin production to compensate for resistance. Across these three markers, we can learn a lot about metabolic health.

Brent: Maybe because of a resistance. And so the ratio between those two things can allow us to go a level deeper. But across these three markers, we're going to be able to tell a lot about your metabolic health or your, you know, the amount of blood of glucose in your blood and the amount of insulin resistance.

G Alexander: That's right. A clinical lab test measuring insulin resistance is worth considering to characterize your metabolic state.

Brent: You can ask your doctor for an insulin resistance panel, which often includes cardiovascular biomarkers highlighting how interconnected these things are. Diabetes increases risk for Alzheimer's, heart disease, and cancer.

Brent: Regarding diagnosis: is measuring hemoglobin A1C precise enough? For heart disease, elevated cholesterol or ApoB indicates correlation, but diagnosis comes from looking inside arteries for plaque.

Brent: High cholesterol doesn't mean I have heart disease the way that we know whether or not someone has heart disease is we look inside their arteries and we look for plaque, and the presence of plaque would indicate heart disease. And you can have healthy cholesterol and lots of plaque in your arteries. And then you can have unhealthy cholesterol and no plaque in your arteries.

Brent: Do we have something similar for diabetes? Saying someone with an A1C of 6.5% has diabetes feels like simplifying a complex system.

G Alexander: All of these metabolic measures are interrelated—glucose, triglycerides, lipids, and blood pressure. Insulin resistance contributes to all of them.

G Alexander: To reduce root causes like insulin resistance, lowering caloric intake and losing weight if overweight is the fastest method.

G Alexander: Physical exercise improves insulin resistance. You can take actions to lower these risks through lifestyle changes.

G Alexander: GLP-1 receptor agonists cause significant weight loss, and surgery can also help achieve remission in type two diabetes.

Brent: If you are pre-diabetic or diabetic based on readouts like hemoglobin A1C, take it seriously. The foundational steps are sleep, diet, exercise, and weight loss.

Brent: We know what to do: eat healthy, get regular exercise, and maintain good sleep routines. But forming those routines can be difficult.

Brent: Mostly plants. Or try to Mediterranean diet and get, at least 150 minutes of exercise a week. And, you know, go to bed at the same time and, and get up at the same time. That's great. I think we all know what we need to do, but the doing it and getting into the routine of it is very difficult.

Brent: Do we have learnings from public health on what actually works outside of medications?

G Alexander: There's no doubt lifestyle interventions make a difference. Sleep is increasingly recognized for cardiometabolic health, as is diet and weight management.

G Alexander: Physical activity helps, especially weight-bearing exercise. As adults, we gradually lose muscle mass over time, which is an important issue.

G Alexander: Muscle loss can be exacerbated by GLP-1 agonists. We can monitor progress with biomarkers, weight scales, and blood pressure monitoring at home.

G Alexander: If you have hypertension, it's very important to keep it well controlled.

Brent: High blood pressure.

G Alexander: Hypertension requires medication or lifestyle adjustments to bring blood pressure down, as it's a key driver of cardiovascular risk.

Brent: Yeah. I mean, it feels we had, chatted with somebody who was talking about this and some studies related to increasing physical activity without the use of any medications. And it's very hard. I think there was a trainer and you got this great support structure around the participants in the study, and the average increase was 18 or 20 minutes a week or something.

Brent: Seeing biomarker data directly provides motivation to adjust habits. Good sleep helps preserve willpower for healthy diet choices and regular exercise.

Brent: I do personally, I find there's something pretty motivating about that. Sleep is an interesting one because obviously sleep is good for us in and of itself. But for at least for me, the main benefit of sleep is I have more willpower. I find it easier to eat the right things and to convince myself to exercise. If I've slept well, you know, think about when you're hung over.

Brent: You're not having a great day. The next day after you're hung over, you've got no willpower to do anything. You're eating the burger and you're laying on the couch. And so, you know, so you can think about it as filling up your your willpower bank. But it does seem broadly that we're lucky to have what seemed to be, I say, cautious.

Brent: Let's start with metformin. What is metformin, how does it work, and how effective is it?

G Alexander: Metformin was developed decades ago but was approved in the US in 1993. A related drug, phenformin, caused serious side effects, leading to safety concerns around metformin that turned out to be unfounded.

G Alexander: It's now the first-line treatment for type two diabetes because it's safe, inexpensive, and generally well-tolerated after initial mild stomach upset.

G Alexander: It lowers blood sugar, has mild weight-reducing effects, and offers broader metabolic benefits.

G Alexander: We also have SGLT2 inhibitors. These drugs cause the kidneys to excrete excess glucose in the urine, effectively lowering blood sugar levels.

G Alexander: They also help reduce the risk of heart disease, which is a major complication for people with type two diabetes.

G Alexander: Then there are GLP-1 agonists like tirzepatide and semaglutide. They reduce appetite via pathways in the brain to drive significant weight loss.

G Alexander: While effective, they can lead to lean muscle loss. Preserving muscle mass is crucial for long-term health and mobility.

G Alexander: And so that in itself is another separate public health problem that has come to be more recognized. Just because these super effective drugs for diabetes are bringing that issue more public. And so.

Brent: Muscle loss usually accompanies weight loss in general. Carrying less body weight requires less muscle, though active resistance training helps preserve lean mass.

Brent: Oh, if you're carrying around more weight, you need more muscle to carry around that weight. If you lose the weight, you're carrying around less weight. And so you lose the muscle. You don't need as much muscle to carry around the weight. And so there's some muscle loss either way. I think is that correct?

G Alexander: If people stop taking these medications and regain body fat without regaining muscle, they may end up with a net muscle deficit.

G Alexander: And often people just stop taking them after a year because they can't afford them anymore. And so we know that a lot of people are not continuing to use the drugs. And after they stop taking them, they regain the weight they lost. It comes back pretty quickly. But the muscle loss does not come back. In other words, you're left with a muscle deficit and you may get back to the same weight you had.

G Alexander: So you net out essentially a negative. And that's the limitation with these these drugs is that once you receive the benefit, you need to more or less keep on them to preserve that benefit. On weight and the other benefit. There are other benefits. Cardiovascolare is one like the CO2 inhibitors. They also reduce heart risk, at least in people with type two diabetes and probably and people with weight are with obesity.

G Alexander: The point is, if you stop taking them, then you may be worse off than you were when you started taking them.

Brent: Strength training is essential as we age to maintain muscle mass, whether using GLP-1 medications like Wegovy or Ozempic or not.

Brent: There's not a great way around it. The reason I think people find it annoying is because going from not strength training to strength training is not enjoyable at all. And I can say, as somebody who's been tall and skinny, most of my life, that that I understand that. But if you get past the hump, strength training is actually great.

Brent: It's a very different high than a cardiovascular high. You know, the workout high, it's a different high. It's a great high. You feel really good. It really improves your mood. You feel confident. You see yourself in the mirror. Wow I got some good muscles. I'm working it here. But the going from not doing it at all to making it a habit is not fun.

Brent: You got to take it slowly and you feel weak and you don't feel like you're making gains, but it's strength training particularly important if you are on these drugs. They are miracle drugs of sort. But like any drug they've got, they've got their trade offs. But, you know, strength training, you got to be doing it either way.

Brent: So it's something we all need to be doing. Either way. You can't just hike, you know, regularly. And to be healthy.

G Alexander: Muscle mass peaks around age 30 and gradually declines. Strength training helps mitigate this decline and lower the associated risks of injury or mobility issues.

G Alexander: So that's a public health issue. We haven't really paid enough attention to it. And to your point, this can be done. I mean, the doing strength training is doable and it's not just for bodybuilders, it's not just for young people. It actually is a good thing for older people to be doing. And particularly if you're on one of these drugs, because we've got good data that show that strength training will prevent that muscle loss.

G Alexander: That's associated with it with, GLP one agonist.

Brent: What is your perspective on current public health regulatory discussions and initiatives like MAHA?

G Alexander: It's important to rely on strong scientific evidence and maintain trust in public health institutions and proven preventive measures like vaccines.

G Alexander: But measles vaccines come on. We've had kids die because they didn't get measles vaccines. It's just crazy to be denied. But, measles is not going to be, prevented by vaccines or that there's some risk of taking these vaccines. That completely negates the benefit of preventing the measles. So I'm really worried about this. We're going to have another surge in Covid.

G Alexander: This winter may not be that noticeable, but it's likely to kill probably 100,000 people twice. What kills the number of people who die from influenza? So an important message to older people like me is take your vaccinations. You need to take, your flu vaccine. You definitely need to take your Covid vaccine, unless you've had Covid recently.

G Alexander: And I did. As a matter of fact, ironically, I went on a trip, overseas and I came back with Covid and, fortunately, it was a mild case. But the point is, Covid is still out there and it can still be deadly. It's killing people. Low numbers right now. But in all probability, we're going to have another surge in, both Covid infections and complications, including death.

Brent: Public health metrics show high rates of chronic disease and obesity. Is there a middle ground where public health focuses more on preventive care and lifestyle factors?

Brent: We've got, we've got epidemics and obesity and diabetes, as we've been talking about here today. We've had major issues. We know on the public health side with things like the food pyramid being totally wrong and influenced by basically, you know, big food. There's there's money being spent there that's, that's negatively impacting public health. And, hey, I've heard RFK talk a lot about preventative health and being healthier.

Brent: He seems to be a healthy guy himself. Didn't we go from like, you know, just five vaccines to 25 vaccines? Do we really need 25 vaccines? Is it all bad or is there some middle ground here? Because even if we say we don't, we don't like RFK and the program. I do think it's a reaction to us not getting something right on the public health side and losing some trust on the public health side.

Brent: So what's the is there no optimism to be seen through through what he's doing? Or if we tried to understand kind of why Maha becomes a thing, is there something to learn about the way that we've managed public health over the last 20 or 30 years?

G Alexander: Well, we're always learning. Let's not throw the baby out with the bathwater for sure. We all violently agree that America needs to be healthier than it is, but it comes down to how does it do it? How do we as a nation become healthier? And we've already talked a lot about what we can do as individuals to be healthier and to avoid chronic diseases?

G Alexander: That's not anything that we're going to, argue with. RFK Jr about. Sure. Let's be sure that we start to improve our health as a nation by doing the logical things. But then when it comes to infighting, to fighting infectious diseases, let's not be ignoring the data. Penicillin does save lives. We use antibiotics. Nobody questions doing that.

G Alexander: If we'd rather not have to use them. In fact, we we do overuse them. That is an issue in itself. But the point is, there is a role for antibiotics. There's a role for vaccines. The fact that we have more vaccines doesn't have anything to do with our deterioration in public health. We've talked about the reasons our public health is decline.

G Alexander: It has nothing to do with having a Covid vaccine vaccination available. So let's, follow the science and and do what makes sense, to protect, individuals. And, and again, does it mean that a five year old should be getting a Covid shot? But I tell you, a 65 year old person should. The data, the scientific evidence is very clear.

G Alexander: The benefit to risk relationship is very positive. And that's what every expert in the field will tell you. And you'll have people who are not experts who offer their opinion. You know, we have freedom of speech, but I would say it's doing damage.

Brent: Yeah. It does seem that basically just follow the science can apply across the board. You know, prior to RFK, I think we've gotten in trouble when it when things became a little bit more politicized, a little bit more opinionated and less just follow the science. And we lost some trust there. And it seems we're doing the same thing now.

Brent: You know, we're, we're we've we've been losing trust on one side. Now the pendulum is swinging and we're losing trust on the other side. And so nobody trusts anybody. And you know, science is just the pursuit of truth. And the scientific process is an incredible thing. We haven't always had it in the course of human history. And if we just stick to the science and objectively and non politically following the science and reporting on what we know about the science and so much of science as well, we think it says and we don't know, okay, let's say that, you know, here's what we think.

Brent: But we don't yet know. But yeah, following the science is the, if we can just follow that theme through multiple administrations, it feels like we'd be in a very good place.

G Alexander: Consult trusted medical professionals and rely on peer-reviewed scientific data when making healthcare decisions.

G Alexander: And mine are trying to do the best, that we currently know how to protect your health. So that's all I say is go to people who you can trust, who are trained, who are open to and interpret science, scientific data to make decisions that are good for you.

Brent: Dr. G. Alexander Fleming, thank you so much for helping us better understand type two diabetes.

G Alexander: Well, thank you. I really enjoyed it. It's important what you're doing, so keep going.

Brent: Death Clock is recorded in Boulder, Colorado, and San Francisco, California. Produced by Patrick Gudino, music by Patrick Lee, and hosted by Brent Franson, founder and CEO of Death Clock.