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Today on The Fundamentals, our guest Dr. Martin Myers, Director of the U-M Elizabeth Weiser Caswell Diabetes Institute, discusses diabetes research in the context of Ozempic, Wegovy, and other drugs that are changing how people think about weight loss.

Learn more about Dr. Myers, and you can follow the department of molecular and integrative physiology @UMPhysiology on X. 

Resources

• Find out more about the research stories mentioned at the top of the show at the links below:
  • Diabetes linked to functional and structural brain changes through MRI
    Investigators also found that diabetes complications are linked to these changes in the brain
  • A diabetes device that makes a lot of “Sense”
    A young patient's design helps people with diabetes live easier lives
• You can learn more about The Fundamentals on our website.
• Learn more about other exciting research happening at the University of Michigan, by checking out Health Lab, Michigan Medicine's daily online publication featuring news and stories about the future of healthcare.

Transcript

Kelly Malcolm:

Welcome to The Fundamentals, a podcast where we will celebrate the research and the people behind the research at the University of Michigan Medical School. I'm your host, Kelly Malcolm.

Jordan Goebig:

And I'm Jordan Goebig. And today we're going to be discussing a topic we haven't touched on yet, but that impacts the lives of many, diabetes. This episode's guest did a fantastic job of explaining the fundamentals of this disease, and on the whole, the University of Michigan is doing a lot of innovative research about diabetes. One study I wanted to highlight, led by Dr. Evan Reynolds, a postdoctoral fellow in the Department of Neurology, found that the longer a person has type 2 diabetes, the more likely they are to experience changes in their brain structure.

Kelly Malcolm:

And another diabetes-related story that really tugged in my heartstrings is about an eight-year-old boy named Jackson, who is trying to help others with type 1 diabetes, manage their condition with a device called a SensePod.

Jordan Goebig:

We discuss it in the podcast, but for those interested in learning more, whether you're curious or because you are actively pursuing research, U of M is home to the Elizabeth Weiser Caswell Diabetes Institute, which is leading cutting-edge research into the causes and potential therapies for diabetes. And as always, we plan to provide links in the show notes, and we hope you enjoy reading more. Now let's get onto the show.

Kelly Malcolm:

In the studio today we have Dr. Martin Myers. Dr. Myers is the Director of the Elizabeth Weiser Caswell Diabetes Institute, the Maryland H. Vincent Professor of Diabetes Research, Professor of Internal Medicine and Molecular and Integrative Physiology, and an affiliate of the Michigan Neuroscience Institute. Welcome, Dr. Myers.

Dr. Martin Myers:

Thank you. Thank you for having me.

Jordan Goebig:

Yeah, we're so glad to have you here today. Before we dive into our questions, I'd love to hear more about your path to Michigan?

Dr. Martin Myers:

So I'm an MD-PhD. I did my MD-PhD at Harvard Medical School, and I did my research in a lab at the Joslin Diabetes Center. I, at some point in time realized that I really, really, really loved research. And so when I got done with the MD-PhD, I actually went right back to the lab and started my own lab at the Joslin Diabetes Center. And then my wife, who was a postdoc at the time, needed to find a real job. And so we did a nationwide job search and for a variety of reasons decided that the University of Michigan was the absolute best place that we could go. And I have to say, I think we've been right.

Jordan Goebig:

Well, we're very happy that you're here and that we have you here. So I'm going to dive into some of our questions. You had mentioned when we were speaking previously that you do research in diabetes as your introduction states and then also in obesity. So I just was curious, nearly one in three adults in the US is overweight. So assuming that our biology hasn't changed over the past 40 years, what has changed in our environment to lead to this increase?

Dr. Martin Myers:

So you're right. Our biology is pretty much the same as it was 40 years ago. The main thing that has changed is the availability of really tasty, palatable, high-energy food that you can get without really having to do any work for it. And also, the ability to live your life without doing much exercise.

Jordan Goebig:

Yeah. Yes. My husband and I check quite a bit about just the changes we've seen from when we were kids to now that we're feeding a toddler, the abundance of food.

Dr. Martin Myers:

Yeah, I know. It's absolutely crazy.

Jordan Goebig:

Yes. Yeah, things I've literally never heard of.

Dr. Martin Myers:

Right.

Jordan Goebig:

And it's been such a short timeframe that it's changed.

Dr. Martin Myers:

Yeah. And our brains have a mechanism for controlling our body weight, but the systems in our brain that do that, were never evolved to deal with the kind of environment that we have now. So even though we've got this great system in our brain that says, "Oh, you should be this hungry or that hungry and eat this much or not eat that much," it gets short-circuited by all of the calories that we have in the environment.

Kelly Malcolm:

So I know that you mentioned that you love research, which is great, and that took you down this path to studying diabetes. What type of research do you do in particular, and I think people don't really think about weight as a function of your brain, but can you tell us a little bit more about that?

Dr. Martin Myers:

Absolutely. So my own research focuses mainly around the homeostatic system in the brain that actually helps us decide how much we should eat and what our body weight should be. So where I usually start with this is to try to actually give people a little bit of the data that supports that there's a system in our brain that actually decides how much we're going to weigh. And there are a couple pieces of data. One of them is that you can take, so two different strains of mice that have slightly different genes, and you can put one on what we call a Western diet and it will gain a ton of weight, and we can put another one on that same diet and it actually won't gain very much weight at all. So that suggests that there's a genetic basis for body weight. And in fact, if you take animals, or for what it's worth, if you take humans and you decrease their food intake and decrease their body weight, that's what happens when we have a diet.

What happens is if you limit the amount they eat, they obviously lose body weight, but as soon as you stop limiting them and you let them eat as much as they want to, they go right back to the body weight that they started at. And you can actually do that experiment in the opposite direction. You can take humans or animals and you can overfeed them and then hold them at that overfed body weight, like 10% or 20% above the body weight that they would normally be at. And then if at some point in time you say, "Okay, now just eat what you want," they stop eating. They'll literally stop eating for a couple of days and then very rapidly over a week or so, their body weight will come right back down to where it was. So there is a system in our body that controls how much we eat and helps us decide how much we're going to weigh.

Now, it's like the blood pressure system though. If you think about the control of blood pressure, it's not like a thermostat. There's not some number set in your brain that says, "Oh, your blood pressure should be 120 over 80." Right? That's just where it ends up based on all of the factors that are pushing on it. And it's the same for food intake and body weight. You have a system in your brain and it pushes your food intake and your body weight to be where it is. And then if you change something, like if you change diet, if you go from what we think of as our Western diet to, "Hey, you can only eat shredded wheat," people are going to lose 10% or 15% of their body weight. And that's not because they're making a conscious decision. It's just because it's not as fun to eat that kind of stuff. Right?

Kelly Malcolm:

Okay. So does that mean everyone has a set weight that's in their genes or what's playing a bigger role?

Dr. Martin Myers:

So it's not a set weight, but it's a tendency toward a specific body weight or a tendency to gain weight or to lose weight, and that is actually in the genes. So there are these studies that are called genome-wide association studies that have been done, well, in a variety of places around the world where you basically take 10,000, 20,000, 100,000 people, and you look at their genome and you map places in the genome that correspond to either having higher body weight or lower body weight. And it turns out when you do that, there are about 250 genes in the genome that we can say have something to do with the control of body weight. And if somebody has 200 of those genes that predispose to having a high body weight, they're going to have a high body weight. And if they have 200 of them that predispose to having a low body weight, they're likely to have a low body weight.

Now, if you take those same people and you change their diet, the food that they have access to, that's going to change their body weight as well.

Kelly Malcolm:

Right. So it's a mixture of genetics and the access to food or what types of food you have access to.

Dr. Martin Myers:

Exactly. Exactly.

Kelly Malcolm:

Okay.

Dr. Martin Myers:

It's like one is your right leg and one is your left leg, genetics and environment, and you can't really separate the two. Right? You got to have both of them.

Jordan Goebig:

I actually think this is a perfect segue into what is more important, genetics or lifestyle when it comes to diabetes risk factors?

Dr. Martin Myers:

So with diabetes risk factors, again, there are two things that make a difference. So the first one is environment. And so body weight for type 2 diabetes makes a huge difference, but only about a third of people who have what we call class one obesity or higher will ever develop diabetes. So there's something different about the two-thirds of people who don't develop diabetes compared to the one-third of people who do. And actually, that comes down to genes as well. And again, people have done these genome wide association studies and identified a bunch of genes that determine whether or not you're likely to get type 2 diabetes. Unlike the body weight genes, which mostly map to the brain and into the circuits that help us decide whether we're hungry or not, the genes that control whether you're going to get type 2 diabetes or not actually map to the insulin producing cells in the pancreas. So the actual cells that help us control our blood sugar.

Jordan Goebig:

So when I was doing some research on you for this episode, I sent Kelly a message because I'm like, "The word leptin keeps coming up."

Dr. Martin Myers:

Oh, yeah.

Jordan Goebig:

With your name, which I'm sure is great. That's exactly what I should see, it seems like when I am researching you. So I'm curious if you could explain what that is to me and how that influences diabetes?

Dr. Martin Myers:

Absolutely. So leptin is a hormone and it's secreted specifically from fat cells. And the more fat you have stored, the more leptin you make. So you can think of leptin as the fat cell signal to the rest of the body that says, "This is how much energy you have stored and therefore you should behave this way." And leptin controls actually a whole host of different functions that have to do with food intake and how many calories you burn and so on and so forth. But I think the important thing to realize is that if you take leptin away from a human or an animal, they become voraciously hungry even though they may be obese. That's because this unconscious system in the brain that controls food intake and body weight thinks that there are no calories stored, basically thinks that the animal is starving to death. And so just drives hunger.

And similarly, if you take an animal that has no leptin and you give leptin back, all of a sudden they stop eating. They're just not that interested in food anymore because they know they've got lots of calories stored. I study it because it's an important part of the system in the brain that helps us regulate food intake and what we call energy balance, body weight. The other thing is it turns out that leptin does have something to do with the control of blood sugar, which is of course, the basis of diabetes. And animals that have no leptin are not only very, very hungry and so become very, very obese, but they also get type 2 diabetes at a very rapid rate. And it turns out that's not just because of the obesity. It turns out that leptin does something to actually control blood sugar. And one of the things my lab is trying to do is to figure out how that works.

Jordan Goebig:

Really interesting. So shifting a little bit, but this is something you're trying to figure out and something that you probably face very regularly as a researcher or challenges. So I'm curious to find out what are some of the biggest challenges facing research who are focused on diabetes and obesity?

Dr. Martin Myers:

Wow.

Jordan Goebig:

You could just succinctly summarize that question.

Dr. Martin Myers:

Yeah. So the biggest challenges that we face in diabetes research specifically, well, I'd say if you look at it across the board, across the University of Michigan, we are probably in the best place to do diabetes research in the world. But if I had to pick a specific hurdle that we have, it's that we need even more researchers that can work with the teams that we already have. Because research is one of those things that although we often think of the lone brilliant scientists working out there by themselves, research is really team science. And as we develop more techniques and more insights into the way the body works, it becomes more and more important to do team science where you bring people with different expertise together.

Jordan Goebig:

Yeah, yeah, absolutely. And Michigan is a good place for that.

Kelly Malcolm:

Yes.

Dr. Martin Myers:

It's wonderful. Yeah, absolutely.

Kelly Malcolm:

So I anticipate that a lot of our listeners are familiar with a couple of new drugs that are very popular now, Ozempic, Wegovy, I think they're probably some others. Can you explain to us how they work?

Dr. Martin Myers:

Absolutely. So Ozempic and Wegovy are the trade names for a drug called Semaglutide. There's another similar drug out there called Mounjaro, and its generic name is called Tirzepatide. So these are all members of a class of drugs called GLP-1 receptor agonists, which just means that they work by binding this thing that's in our bodies called the GLP-1 receptor. And the way they work is by... Well, let me take a step back. So when you eat food, your gut senses that you have food, senses that there are nutrients. It senses that there's all of this stretch happening and the gut sends a signal to the back part of the brain that says, "Hey, there's all of this stuff going on." And then your brain receives that information and a couple of things happen. One of them is there's a reflex that heads back down and says, "Oh, you need to change gut physiology so you can absorb all of these wonderful nutrients."

But the other thing that happens is at some point in time, the circuits say, "Hey, you've eaten enough. If you keep eating, you're going to get sick." So it turns out that there's a whole bunch of GLP-1 receptor on those circuits. So if you take these GLP-1 receptor agonists, it pushes on those circuits and makes you think you're full even if you actually haven't eaten anything or even if you haven't eaten very much. And so that's another one of those things that changes the set point on how hungry you are and what your body weight is going to be. And it turns out these circuits when we push on them, are very effective at making us not very interested in food at all. And so it makes people not eat. And when people don't eat, they lose a lot of weight.

Kelly Malcolm:

They sound like miracle drugs, but they have side effects too. Right?

Dr. Martin Myers:

They do. So let me start by saying they are in fact miracle drugs. Up until these drugs came on the market, there were no medical therapies. Absolutely no medical therapies for weight loss. So people were really just stuck with dieting. And as we talked about earlier, dieting doesn't work because it just makes you hungry. They do have side effects though. So it turns out that some of the circuits that these GLP-1 receptor agonists push on just make you feel full. But it turns out some of those circuits actually make you feel nauseous as well. And so, one of the big side effects that affects probably 20% or 25% of the people who take these drugs is nausea, sometimes vomiting and some other GI distress issues can be constipation or diarrhea.

And it sounds funny, but actually, some of these side effects can be so severe that people have to go to the hospital and end up discontinuing the drug. So for people who don't get the nausea and stuff with these drugs, they're absolutely fabulous. For the people who have those side effects, we need to find something better.

Kelly Malcolm:

So have the availability of this class of drug changed what receptors or what types of drug targets researchers in your field are looking at? Or is this just one type and there's other promising types out there that you're looking at?

Dr. Martin Myers:

Great question. So actually, one of the things that my lab works on is... So we talked about the leptin stuff, but we're actually very interested in the circuits and the hindbrain that mediate satiety, the feeling of fullness that causes you to cease eating. And there is GLP-1 receptor on a bunch of these circuits, but it turns out there are a bunch of other receptors too. And one of the things that we're working on with the laboratory of a guy named Tuna Pears, who's over at the University of Copenhagen in Denmark, and then some of our close collaborators here at the University of Michigan are trying to identify the circuits that you can activate that cause people to not be interested in eating without making them nauseous. And there are a few classes of drugs like that that are starting to come down the pipe, but I think we need to develop more of them.

Kelly Malcolm:

Yeah. The other drawback I've read about is that these drugs are really expensive, so not everyone is going to be able to afford them.

Dr. Martin Myers:

Right. Access is a huge issue with these drugs, and there are two flavors of access here. One of them is so the drug company that makes semaglutide can't make enough of it, just absolutely cannot make enough of it. So there are serious shortages, even though they keep building manufacturing plants to make more and more of this stuff. And so as a consequence, even if you have lots of money, it's hard to get. But as you might imagine, because this stuff costs anywhere between $1,000 and $1,600 a month, there are a lot of insurance companies that don't want to pay for it. And there are a lot of people who either have no insurance or inadequate insurance and they can't afford these things. So there are real equity issues in terms of who can actually take advantage of these really amazing new medicines and who can't?

Jordan Goebig:

So speaking of the disparity in income and access, I'm just generally curious if there are other folks? I tongue in cheek made a joke about being overwhelmed with the food choices when I go to the grocery store, but I also have the privilege of being able to spend the time reading the labels and having a wonderful partner who is a master gardener who can provide me and my child with fresh fruits and veggies, but not everybody has an Adam in their life who's gardening for them and the financial resources and the time and the access to better grocery stores and things like that, and all of these things can contribute to diabetes. I'm just curious if at Caswell, you have folks who are looking into the health disparities that impact folks and being diagnosed with diabetes?

Dr. Martin Myers:

Absolutely. We actually have a huge team of researchers that's very focused on those questions. The team that I'm thinking of right now is actually run by Gretchen Piatt out of the Department of Learning Health Sciences and Michele Heisler out of the Department of Internal Medicine. And they have a huge number of outreach programs to the City of Detroit and elsewhere to try to understand all of the factors that influence the ability to get fresh and healthy foods, and also the predisposition to diabetes and as importantly, the ability to access treatments for diabetes.

Jordan Goebig:

That's wonderful. What would your messaging be for people who are struggling to lose weight?

Dr. Martin Myers:

My message to people who are struggling to lose weight would be diet, but diet in the context of medical therapy. There are a bunch of medical therapies available now. Not all of them are as expensive as the ones that we've been talking about, but that can help lose weight. And it's important to realize that losing weight isn't just about eating fewer calories. That is the bottom line, but in addition to eating fewer calories, you also need to make sure that you're eating a healthy diet that will give you all the vitamins and micronutrients that you need.

Kelly Malcolm:

What about exercise? Because I do think a lot of people think, "Well, I just need to go to the gym and then I'll lose weight." What role does that have with weight maintenance really?

Dr. Martin Myers:

Well, so exercise by itself is not going to help you lose weight very much. And the reason for that is if you exercise and start burning more calories and lose weight, as we talked about earlier, that's going to make you hungrier. So people initially lose a little bit of weight and then get hungry because they've lost weight, and then actually start eating and their body weight comes back to normal. That having been said, exercise is one of those things that's really, really, really important for the battle against type 2 diabetes. So just as it's important not to just take these new drugs and lose weight without eating the right foods, it's also important to not take these drugs and lose weight without getting exercise.

Kelly Malcolm:

Right. Okay. We've mentioned the Caswell Diabetes Institute. Are there any specific projects that you want to mention or collaborators that you want to give a shout-out to?

Dr. Martin Myers:

Absolutely. So I'll start close to home because one of the things that I have found makes doing research on obesity and type 2 diabetes at the University of Michigan just a ton of fun and really empowering is that there are teams of us that are focused around specific problems. So my own lab is in a team of a total of six labs. We call ourselves the Amigos Group. It's Ali Affinati, Martin Myers, Carol Elias, Paula Goforth, Dave Olson and Randy Seeley. So it's not actually the Spanish way of spelling Amigos, but it's close enough. And we all do research on very related things and collaborate extensively. We trade reagents back and forth. We help each other do this assay or that assay based on what somebody's particular expertise is. And working in a super team like that is just an amazing experience.

As regards to the Caswell Diabetes Institute, in a larger sense, we have a lot of programs going on. Not all of them are just the basic science research that we've been talking about earlier, but we have a bunch of clinical and translational research projects. Probably the most important one to point out is one that's running out of the School of Public Health, it's run by an investigator named Briana Mezuck. And what she's interested in is how having diabetes, either type one or type 2, impacts your mental health, and also how mental health impacts your ability to care for diabetes, whether you have type one or type 2. And that is a really important project starting by focusing on patients here at Michigan Medicine. But the hope is that as we identify gaps in care and things that we can do better, that we'll actually be able to get that information out into the larger, wider world so that everybody can benefit from the experience that we have.

Kelly Malcolm:

Yeah, that'd be great. I know diabetes takes an enormous toll on a lot of Americans, so it'd be good to add to the knowledge base about that and have people live better lives.

Jordan Goebig:

I don't have anything else, unless there's anything else you want to make sure to add in here before we wrap up?

Dr. Martin Myers:

I'll say this one thing. I don't know whether there'll be time to splice it in, but I actually have to say that the Caswell Diabetes Institute itself has an absolutely spectacular leadership team. Not just in terms of faculty members, but in terms of the staff and their commitment to battling diabetes.

Jordan Goebig:

We're very fortunate to have you on this campus and all of the researchers doing this. I really appreciate you coming and spreading the good word about collaboration. I've only been at Michigan for about a year. I did come from another Big 10 institution. I won't name names.

Kelly Malcolm:

We won't mention it.

Jordan Goebig:

But there is something different about being here. I moved all the way to Michigan because of how wonderful everybody is and how much I already believe in this place. So it's been really great to learn from you. Thank you so much.

Kelly Malcolm:

Yeah, thank you for coming.

Dr. Martin Myers:

Thank you for having me.

Kelly Malcolm:

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