Powering Your Brain Metabolism For Success

Beverly Yates, ND

Hi, everyone. Welcome. Welcome to the Reversing Type 2 Diabetes Summit. I am your host, Dr. Beverly Yates, ND. For this episode, it is my distinct honor and privilege to interview Dr. Austin Perlmutter. He is a wonderful expert. He is the doctor that we all wish we had. One of his areas of focus has been realm immunology and boosting the immune system—having the body work for you rather than against you. Also with brain health. Today he is going to talk to us about brain metabolism and how it intersects with blood sugar and blood sugar dysregulation. But before we dive into that, Dr. Austin Perlmutter, would you please introduce yourself to our audience?

Austin Perlmutter, MD

I would be happy to. Beverly, thank you so much for having me. This is such an important topic, and I am honored to be here and participate in the conversation. A little bit about my background: I trained as a conventional MD. I did my medical training in Miami, and then I did my internal medicine residency in Portland, Oregon. Beautiful Portland, Oregon, at OHSU. But I think I realized early on, because I had access to resources through family members and my father is a relatively well-known functional neurologist, that there was more to the equation than just prescribing medications to try to slow the rate of decline of people’s diseases. That seemed so intuitive for all of you out there listening. You probably said, Of course there is more to it.  Yet that is really not the way that conventional medicine looks at health. As I was realizing there was more to this puzzle and that I wanted to be involved with prevention of disease and not just maintenance of people’s chronic disease management, I needed to look elsewhere, and I had the opportunity to work on a number of different projects with some really amazing people.

 One of those was a book called Brainwash, which I wrote with my father, and we were privileged to have that become a New York Times bestseller. We’ve had it published in around 20 countries around the world. But beyond that, I have been able to do research with others, and I guess just independently trying to look at what mechanisms are driving people to be so unhealthy today and what we can do beyond just telling people to exercise and eat healthier is actually going to work. That has led me to try to understand the brain, how it becomes influenced by our lifestyles, and what we can do to empower ourselves and the people around us to change our brains. In doing so, we take back control over our lives and our health. That, for most people today, unfortunately, has been taken out of our hands and put into a place where chronic, preventable diseases are the norm. I thank you, Beverly, and I think we can do a whole lot better. That is why I am excited to be here.

Beverly Yates, ND

That is so great to know. Thank you. Austin. I could not agree with you more. I think we have come to normalize illness, and we have got to turn this around because it is not sustainable for the health of humanity for our current generation or for the kids and all the people who come into the future. We look at the big picture and think about the impacts of blood sugar on our brains and our energy systems. Please share with us how our brains are powered. We all know they have energy. Where does it come from, and how does all that work?

Austin Perlmutter, MD

Well, I guess it is first of all important to understand that, as much as we tend to ignore this, our brains are part of our bodies. Because of this, our thoughts, our actions, and our mental health are part of our brains and therefore part of our bodies. It is not your thoughts; your mental health is powered by some magical energy. It is the same energy production that occurs throughout the rest of your body. It is the same ATP that you need in your brain to be able to power yourself to think clearly and potentially even to feel good about your day, that you need in your muscles to keep them moving, and that you need to keep your liver metabolizing. Why is that so important? Because the brain is uniquely dependent on a ton of energy. If you think about it by weight, the brain is roughly 2% by weight of our body, but it requires about 20% of our energy and resources, which means it is actually using up over 20% of the glucose that we consume in our meals to keep it running. That alone, I think, is a statistic that should force all of us to pay attention to how we get the brain consistent, high-quality energy. But the other thing, Beverly, that I learned recently that I think changes the whole calculus is that the brain does not have all that much empty stored space where we are using our brains to work on memory. Its purpose is to process data.

So, unlike, for example, our muscles and, for example, our fat cells, we do not have big energy stores in our brains. There’s no room for extra glycogen, and there’s no room for fat storage. It means that our brains need that energy to be produced and available on demand. So unlike other parts of our body, it is thought that this is one of the reasons why our brains are sensitive to changes that happen with fluctuating blood sugar levels. All of these reasons speak directly to the point of this conversation, which is that if we are looking at blood sugar issues in the world today or in the United States and you say statistically how many people have blood sugar issues and then remember that blood sugar is so vital to healthy brain function, how many people are at risk of having brain issues because of that? These are statistics that I am sure are not the first time people are hearing them, but I think it is important to say we have one in ten Americans with type 2 diabetes. It is pretty much the majority being type 2 diabetes. The statistic that we all need to pay attention to is that one in three Americans has pre-diabetes, and 80% of these people are not aware that they have it. When you layer all this together and you say, Hey, we, I think, care about making sure our brains work, well, I would argue it is the most important thing. You want to enjoy your day. You want to think clearly. You want to show up for your grandkids, for your spouse, for your other partners, for your friends, and for yourself. You need your brain to work well. Then you need to power your brain with fuel. If you are saying, Well, fuel is only as good as our blood sugar regulation, and one in three Americans at least has pre-diabetes, those numbers are actually increasing, unfortunately. Then basically everybody needs to be paying attention to this message, which is: how does the blood sugar in your body connect with your brain health? What can you do today to help enhance the quality of the energy that gets to your brain?

Beverly Yates, ND

That makes total sense. Your brain is central to how you function every day. I think sometimes, because some of these processes are often silent, people may not understand how much chronic issues with blood sugar completely undermine their brain health. They might have more information, frankly, about connections with heart disease and other things around inflammation. But probably not the brain. I just think we cannot say this enough. What are the specific links between blood sugar dysregulation and brain issues?

Austin Perlmutter, MD

Well, Beverly, you are so spot on, which is that we have made some connections over the last few decades that link blood sugar issues with other diseases. I think this is a more general issue as it relates to the brain. For example, if you see people out jogging, they might say they are doing that to improve their cardiovascular health. I think that is probably the case if they are going to say this is the reason I do it from a health perspective as well. I am jogging because running is good for my cardiovascular health. But how many of those people are out there saying, I am jogging because it is good for my metabolic health? How many of those people are out there saying, I am jogging because it is good for my brain health?  Yet we know that physical exercise is one of the most powerful, if not the most powerful, things that we can do to improve our metabolic health, reduce our risk for, and even reverse aspects of diabetes. It can help lower our chances of developing conditions like Alzheimer’s disease as well as potentially have a preventive and therapeutic effect on depression.

But let us talk more specifically about the connection between blood sugar levels and the risk of brain conditions. There is some very clear data from the research. For example, pre-diabetes and diabetes are risk factors for all causes of dementia, including Alzheimer’s, dementia, and vascular dementia. That  there needs to be a broadcast of pre-diabetes and diabetes issues with blood sugar regulation. Our risk factors for the development of Alzheimer’s dementia right now, as we sit here and talk, there are no solid therapeutic modalities from a pharmaceutical perspective for Alzheimer’s disease. All of the drugs that are out there are not designed to significantly impact and do not significantly impact the progression. They might slow it a little bit, but nothing’s really getting to the root cause mechanism. Even with the amyloid drugs, we are not necessarily seeing the level of improvement we would expect to see. Now, our best bet for Alzheimer’s is preventive strategies, including exercise, metabolic regulation, and food. Basically, things that connect to blood sugar seem to be the strongest data set. Again, to recap, prediabetes, diabetes, and risk factors for Alzheimer’s dementia as well as Alzheimer’s disease. But moving one step forward, which is one step back, I guess you could say, is really where so many of us need to be focusing our attention. It is not just once you get diabetes that matters; it is not just when you get Alzheimer’s that we need to care about this. The precursor, or well-established precursor, to Alzheimer’s dementia is mild cognitive impairment. If you think about this on the spectrum of a person who is really not able to remember anything about what is happening around them, somebody with advanced dementia walked that back about a decade, and you might see a person who is having trouble remembering where they put things is having trouble remembering names. It is getting a little bit more lost, but it does not necessarily need some advanced care and certainly has not gotten an overt diagnosis of dementia.

So what the research shows here is that this mild cognitive impairment, which is again a precursor to full-blown dementia, increases along with the severity of diabetes. What we are talking about here is almost a dose response graph where the worse your blood sugar management, the higher your risk of developing this precursor issue to dementia or Alzheimer’s disease. The last thing I will mention here, and maybe something we can jump into in a little bit more detail, is that I have been thinking about this a lot, which is that we tend to say things are very clear when they are not quite as clear. We say things are not clear when they are, but is there a very clear dose-response mechanism between blood sugar regulation and brain function so we can jump into what it means to be hangry? There are a lot of people who are often talking about being hangry. We will see the Snickers commercial. You are not you when you are hungry. 

There is a connection between the food we eat and how we feel. But I do not think it is exactly the way that it is portrayed. What I do think is the case is that if you work in a hospital, especially in an ICU, and you were just saying, What happens to a person when their blood sugar level crashes? What happens to a person when their blood sugar level goes really, really high? So here we are not talking about maybe just the little ups and downs that happen during the day, but rather if your blood sugar plummets or if your blood sugar is in the hundreds, much higher than it perhaps should be with regular regulation. What is your brain’s health going to do? It is absolutely true that if a person’s blood sugar is 4030, they are going to have some brain issues. That is not debated; that is well-established medicine.

 On the flip side, people coming in with diabetic ketoacidosis or a condition that occurs more often in Type 2 diabetics, which is basically hyperosmosis or hyperglycemic state, will regularly have brain issues and confusion. There are also a number of other brain states that come along with it. The point I am making here is that, in the bigger picture, blood sugar, regulation issues, diabetes, and pre-diabetes correlate with risks for brain health conditions. We can talk about mental health as well, but dementia is, I think, a really important place to start. Sure, this could just be an association, meaning it just so happens that people who have blood sugar issues also have a higher risk for brain issues. Maybe that is because they eat an unhealthy diet. They do not exercise. But when you look at this additional data, which says what happens if you take an otherwise healthy person and crash their blood sugar or spike it up really high and you absolutely see changes in their brain function, then we start to say, Well, maybe there is some causal mechanistic work at play here that tells us this is more important than just a casual association.  Instead, maybe one of the core mechanisms that links what we do with our lifestyles with our risk for brain health issues

Beverly Yates, ND

That totally makes sense. What I am hearing you say now, Austin, is that if the brain is subjected to a whipsaw, the rollercoaster, the peaks of high blood sugar, the tops of the glycemic issue, and then the bottoms as well, low blood sugar, hypoglycemia, they are at risk. So the more time people spend outside of what is considered a healthy blood sugar range, the more risk they may experience. This could show up in various aspects of brain health, whether it is mild cognitive impairment or perhaps risks for various kinds of dementia. Is that right? 

Austin Perlmutter, MD

I think let us jump into that for a second, because if we are considering how a person actually gets in touch with their blood sugar levels, for most people, there are two ways this would happen. One is what is called a fasting blood sugar level in a typical lab that you will get from your doctor. The other one is a screening test called hemoglobin A1C. A1C test is the shorthand for it. Fasting blood sugar is a snapshot in time. It is your blood sugar at the level that it was drawn at that morning of the doctor’s appointment, if it was actually a fasting blood sugar. I know people sometimes do not know exactly what that means as far as what it is or what their real fasting blood sugar is. But the other piece of this, and I would say when I was seeing patients more consistently, would be the A1C that we would look at. This is a screening test that basically looks at how much glucose has been added to your hemoglobin molecules. hemoglobin red blood cells; these live for about three months. The red blood cells have a life span of about three months. Measuring the amount of exposure to high blood sugar through these red blood cells gives you a sense of what the average blood sugar levels were over the last three months. 

Generally speaking, we know that at a higher A1C, first of all, the diagnostic for both prediabetes and diabetes has its own correlations with risk for a number of other conditions, the overt manifestations of which we know very well in the case of diabetes are cardiovascular issues, microvascular issues, and other issues. Kidney problems are very common, with a higher risk of infections and amputations. They are also very common, with a higher risk for heart disease or stroke. Obviously, stroke is a brain-related issue. Vascular issues in the eye are very common. All of this is well known. What we do know is that, on average, people have higher blood sugar levels. What we were talking about here in the upper hundreds, two hundreds, was that there is a strong correlation with the risk of disease. But what you are alluding to here, which I think is so important to understand around the brain, is that it may not just be a question of whether the blood sugar is high, but rather how consistently our brain is getting access to the amount of glucose it needs to allow it to function appropriately. Because, coming back to what we have already established, the brain does not have a whole lot of reserve blood sugar, which means it really needs to have access to consistent levels of blood sugar from the blood stream. If the blood stream levels are going up and down exactly as you described, whipsawing, there is concern that this may actually be an independent issue. Even if this is so important, your A1C is completely normal. You could have half the time too low, half the time too high, and all of the time going way up and down, and it would still read normal, which is really interesting to think about. Even though the hemoglobin A1C is in theory a snapshot of what happens over a three-month window, it is still only a slice, and it does not tell you any real-time data as to what is happening on any given day.

Let me take this just one step further. This all seems mechanistically to be a concern, but there was a paper that was published recently by Yale researchers, and it suggested that when blood sugar levels whipsaw, that variability is connected with oxidative stress and inflammation. So having highly variable blood sugar levels is thought to have a negative impact on our bodies and on our brains by basically increasing the risk for oxidative stress and inflammation. These are pretty well established to be true of the mechanistic processes by which our cells and, importantly, our brains get damaged, increasing our risk for a number of conditions, including dementia, depression, and other mental health conditions. The point you make is a really good one, and it is all the more reason to start paying attention to what is happening in your body at a level greater than what you can get from just a simple point in time once every couple of years.

Beverly Yates, ND

Exactly. Thank you for doing a great job of walking us through and peeling back the layers here. I think that the information people get around their fasting morning blood sugar numbers and their A1C is part of the puzzle. It is not the whole story. Thanks for the detail around why if you get a pat on the back from your A1C and they still might not be telling you what you really need to know, if you are on that blood sugar whipsaw, that roller coaster, that is not good. Hangry should not be the new normal. What are the pathways by which blood sugar issues, poor glycemic regulation, or just a variable blood sugar response are caused? How can they do damage to our brains?

Austin Perlmutter, MD

Yes, well, this is a really interesting question as well. I think when we talk about the brain, it is important to understand that even though it is part of and absolutely connected to what is happening in the bloodstream in the rest of the body, there are some interesting, unique aspects of how the brain gets access to data from the bloodstream in the body. The best example of this would be that we now understand there is a gut-brain connection, and so data in the gut is able to change what happens in the brain, not necessarily because the molecules in the gut directly get into the brain, which can be the case. But because there are a number of pathways, for example, the vagus nerve and the immune system, by which data can be translated from the gut into signals that the brain can respond to. While we have talked here about the glucose part of this, I think that it is not just the actual access to the fuel in the brain that is a reflection of what is in the bloodstream. That is important to talk about. It is probably the case that what is happening is that a lot of things are happening in the rest of the body as a response to the metabolic dysfunction that then leads to issues with the brain.

Let me give you an example. One of the core mechanisms that is well established in diabetes is type 2 diabetes. You build up resistance to the molecule insulin, and in a homeostatic state or in a state of non-diabetes, you would release insulin in response to higher blood sugar levels. That would happen after a meal. That insulin facilitates the removal of glucose from your bloodstream and pulls it into cells as people become more and more diabetic. It is thought that the cells themselves become resistant to insulin, meaning the insulin’s there knocking on the door saying, Hey, we are here; we have got the glucose; are you ready? The person behind the door in the stall says, No, no, we are good for now, and we do not need the extra fuel.  Also, I am not listening to your signal. The combination of these two things leads to high levels of glucose and insulin in the bloodstream. What is interesting about this is that insulin resistance could develop within the brain. 

There are now researchers—Suzanne Lamontagne is one of those researchers we had a chance to talk to a couple of years ago—who have proposed that Alzheimer’s disease actually represents type three diabetes in that there are shared mechanisms between diabetes and Alzheimer’s disease that relate to insulin resistance. We do not know how much insulin is produced. It is possible that a little bit is produced within the brain, but it is almost certain that the vast majority of it is produced outside the brain and needs to get into the brain to do its task. Now, here’s the thing that most people do not know: we think of insulin as the key to regulating blood sugar levels and maybe regulating fat deposition. It is another role.

But in the brain, insulin turns out to be involved with neuroplasticity. It is an anabolic growth factor, which we know, but in the brain, it is neurotrophic. That means that insulin is a signal for neurons to both grow new neurons and make connections between them. Why does that matter? Well, if we are starting to get insulin resistance and that resistance gets to the brain and our brain has relatively low access to the insulin it needs because it is just maybe saying, Oh, we do not need so much of you, the receptors do not get as sensitive to it. You could be missing out on the signals that you need to create connections between neurons and create new neurons, both of which are essential mechanisms in the prevention of Alzheimer’s disease. It turns out that there may be key mechanisms in mental health conditions. Mechanism one, I guess I would say, is the interplay between higher blood sugar levels and insulin resistance that may translate into brain problems. There are a couple of other ones that we could get into, and some of these are a little bit more technical. I think inflammation is an important one to discuss, so we can jump into that one. There’s also more of a mitochondrial issue and a metabolic issue, and there are a couple of different pathways by which this may develop, but we can go to whatever you think would be most helpful next. I think the inflammation one is particularly interesting because it speaks to mental health and Alzheimer’s disease.

Beverly Yates, ND

Okay. I think talking about both of those, why do we not start out with inflammation and then mitochondria, because we have had some of the speakers talk a little bit about inflammation from a completely different angle and about mitochondria, but again from a completely different angle? We want to give people as much information as we can while we are here.

Austin Perlmutter, MD

Great.  Let us jump into the connection between inflammation, blood sugar metabolism, and brain health outcomes. Most people have heard about inflammation. They generally think about it with a negative connotation, which is that inflammation is bad. I really wanted to make sure that we dispel this myth that information is bad without inflammation; we would probably each die within 24 hours because inflammation is not good or bad. It is just an essential part of our immune system. It is saying T cells are bad or B cells are bad. You need those. They’re essential. Can they create problems with autoimmunity? Of course they can. It does not necessarily mean that we should label them as good or bad, and inflammation is just that. Inflammation is a natural process in our body in which our body responds to a perceived threat. It creates a symphony of different molecules, activates a whole bunch of different blood cells, and, in the best of scenarios, addresses the threat and removes it. In the worst of scenarios, it does not address the threat and continues to feed on itself, creating this low-level smoldering inflammation that is strongly associated with the risk of basically every chronic disease, as well as dying early and disability. All the things we do not want, and that is the version of inflammation most people are talking about when they are just painting it with a negative lens. It is just important to recognize that the goal is never to shut off inflammation. It is simply to have it respond to what is necessary and then go back to a more quiescent state.

With that said, how does inflammation map to metabolic health? We’ll say first metabolic health, and then we’ll go to the brain. Depending on who you listen to and depending on the study you read, there is either a directional relationship between metabolic health and increased inflammation, meaning worse metabolic health increases inflammation, or inflammation increases or decreases metabolic wellness. I am going to go ahead and say yes and yes. It seems that both of these things are happening. There are some pathways that we could talk about by which these things seem to occur. But the bottom line is that people with metabolic dysfunction tend to have higher levels of inflammation. People with higher levels of inflammation have a higher risk of metabolic dysfunction. If you are a person with poor metabolic health, there is not a slight chance that you will have some degree of smoldering, low-level inflammation. Maybe one of the best ways to demonstrate how solid that connection is by talking about fat cells. Before I get into this, I am just going to say that I think the way that we have talked about fat and obesity tends to be blaming people for having extra weight, and I do not think that is helpful in the least.

But what I do think is helpful is saying that, just like in every other part of your body, you can have cells that are healthy or unhealthy, and that the cells themselves are basically their repositories of energy, and this is an important thing. They also do a number of other things within our body. They produce a number of chemicals that send signals throughout the body and to the brain. These are called adipose fat cell molecules that transfer signals depending on how the state is deposited. Depending on where it is deposited, those signals from the bad cell can be healthy or unhealthy. When they are unhealthy, they tend to be inflammatory signals. If a fat cell is packed full of fat in the wrong spot, and in this case, it is usually when we have overwhelmed all the other fat storage places where we have filled up all of our muscles and other places, well, I should say we filled up our typical fat stores with energy. Now we are putting the fat where it should not be. We are putting fat in our muscles. We’re putting the fat in our liver. We’re putting fat around our organs. That is the fat that tends to be more inflammatory. That is a reflection of a number of things. But it is the emblematic signal of metabolic dysfunction.

When we get into these scenarios where the fat cells are being put in the wrong spaces, where they are getting the wrong signals and therefore are producing unhealthy signals, this is strongly associated with inflammation. It is thought that this may be one of the reasons why there are connections with a higher BMI, which is a very imperfect measurement of these fat cells, but specifically fat cells that are around organs. We call these visceral fat production and risk factors for brain health issues, and it is the inflammation produced by those fat cells that seems to increase our risk for brain health issues. Here we have said that metabolic health is connected to inflammation. One mechanism is through the production of inflammatory molecules that come from fat cells that are overloaded because there isn’t anywhere else to put them. Also because sometimes there is a correlation between our dietary choices and how that fat gets deposited. I know it is a little bit technical, but that is one of the major pathways.

The other question, though, is: how does inflammation then influence the brain? If we want to bring this full circle, how does the brain then influence our metabolic choices? Because our brain, depending on how it is structured, is going to tell us, Am I going to reach for the unhealthy food? Am I going to exercise? I am going to sit on the couch and watch TV for the next 4 hours. Inflammation in the brain is really where I spent a lot of my time the last two years, where I published research. That is where I have tried to bring attention to the mechanisms because we still exist in a world in which we think about the brain as separate from the body. The mind is separate from the brain, and all these things that are myths do not make any sense to me, but I think they make sense when you do not think clearly about what is going on here. If you think about what the brain is, you have, as I said before, about 2% of, let us say, a couple pounds worth of it. This is going to be a network of billions of neurons and other cells, with trillions of connections between these neurons that are powered by glucose as well as, to some extent, ketones and other energy sources that come from our diet.

But this is not some magic process here. It is going to be constantly influenced by what happens in our bodies. What are the signals from our bodies that tell our brains, Here’s what’s going on, and here’s how you should behave differently while inflammation turns out to be a major one? This helps to explain why inflammation is a well-established risk factor for the development of depression and why higher levels of inflammation seem to induce feelings of depression. The example that I always give, because it is one I personally experience and it is very clearly stated in science, is: how is your mood when you get sick? For me, I do not feel great. I do not feel as motivated, interested, or happy. This is exactly what the science is showing us: if you increase inflammation in a healthy person by giving them an injection of what is basically a piece of a bacterium, they feel depressed. It is fascinating stuff. You can create feelings of depression by increasing inflammation. All of this is just saying that this is one example of how we know that inflammation influences brain health. This was a major topic in Brainwash, the book that we wrote. The bottom line here is to understand how what happens in the body influences the brain. Inflammation in the body appears to influence the brain, and one of the drivers of this inflammation appears to be metabolic dysfunction. I know this is a very long-winded explanation of some of these topics, but I think it is important to understand how all of these things come together. Otherwise, we are missing the bigger picture.

Beverly Yates, ND

I agree that it is important to unpack these things and give people a robust, thorough answer, not just a superficial two or three sentences. then they are saying, Well, wait, because you have hit on a lot of the pieces that are often missing so that people can understand that inflammation is not necessarily the enemy. There are normal processes in the body that invoke inflammation. If you cut your finger, you absolutely want it to knit up. Inflammation is how that happens.

With this in mind and as we think about the role of that, I am glad you talked about moods and how people feel because, again, people are often blamed for their problems, and depression can be a prominent part of the health journey when someone has pre-diabetes or Type 2 diabetes, really any blood sugar dysregulation, metabolic syndrome, polycystic ovarian syndrome, etc. Will you please share something you have talked about before? Before we move on to our next question, what are your thoughts about mitochondrial function? The mitochondria are the powerhouses of the cell; they are the organelles. If you could share with us about mitochondria while we are here, that’d be great.

Austin Perlmutter, MD

I mean, I think it is because you cannot really separate metabolic health from mitochondria because, if you think about how nutrients in our food are actually converted into energy, the majority of it is happening, or at least the high-efficiency parts of it, within the mitochondria. These are the primordial bacterial cells that came into our ancient cells and basically came onboard as designated energy production factories. They turn out to do a lot more. For example, when they create steroid hormones, they are involved with cell health. But for the purposes of the metabolic health discussion, you cannot have that metabolic health without good mitochondrial health. So there are a number of pathways by which researchers have identified mitochondria that might be damaged by our modern-day diets and metabolically unhealthy lifestyles.

Maybe the easiest one to understand, and I am not necessarily saying this is the only one, nor is it necessarily the absolute most correct one, but if you just think about the mitochondria and if it is tasked with basically converting fuel into energy and it has an absolute excess of fuel where it is just constantly being inundated with calories and food, you are eating all day long, you are eating very high-calorie foods, and potentially you are eating foods that are by themselves. Not great as far as how cleanly the mitochondria can process them. Then, on the back end of this thing, the mitochondria are going to have a buildup of the waste products of metabolism. On the front end, they are going to have a buildup of energy that cannot be adequately burned because they are just overloaded. 

One of the important things to know about mitochondria is that this is where oxidative energy production occurs. The electron transport chain, oxidative phosphorylation, is the way that we are able to convert a glucose molecule into a bunch of ATP. It is the most effective way to convert basically fuel into a high number of ATP. But in the process, it creates oxidative stress, and this process seems to be exacerbated when mitochondria are overloaded. Oxidative stress by itself may be a driver of metabolic functions so that you might get a feedforward cycle, but oxidative stress, which is basically the buildup of certain tiny molecules that can, in essence, rust your cells more rapidly, is a mechanism by which we think many diseases are worsened. So the bottom line to all of this is that if you are trying to understand metabolism, which is the idea of taking energy from basically outside the body, because we do not know how to do photosynthesis as far as I know, and converting it into basically building blocks for cells, data for cells, and also fuel, then you have to have these mitochondria healthy.

The last thing I will say about this is, again, something that, when I learned it, I was thinking to myself, This is absolutely incredible. When we think about the brain, I mentioned that somewhere in the neighborhood of, let us say, 80 billion neurons, each of those neurons might have a thousand synapses, which means you are in the neighborhood of a billion trillion synapses. It turns out that an individual neuron can have thousands—potentially many more—mitochondria. If you think about how many opportunities there are for something to go wrong when you look at mitochondrial health and brain health, that is the number I looked at. I think it was a quadrillion. It is a whole lot of zeros to try to understand how many mitochondria you have in your brain. To that end, how important is it that they are working well?

There is now a lot of research focused on interventions that improve mitochondrial health. It ranges from everything from intermittent fasting to ketosis to other strategies that give the mitochondria a break and let them clean themselves up, potentially form new mitochondria, and get rid of the old defective ones. Something else that is interesting about mitochondria is that they are constantly undergoing fusion and fission, which sounds like nuclear reactions, but it is actually just the breaking apart of one mitochondria into two or two mitochondria coming together and fusing into one. Fascinating stuff. The bottom line is that every choice that you make from a lifestyle perspective, whether it is food, exercise, or even sleep, is impacting your mitochondrial health. That is probably one of the major mechanisms by which metabolic dysfunction occurs.

Beverly Yates, ND

Absolutely. Yes. I am thinking of some of my earlier research, information, and learnings about mitochondria and their importance, let us say with cardiovascular function, congestive heart failure, etc., and certainly with diabetes. When it comes to any of the brain health concerns or trying to mitigate damage to the brain or simply protect muscles, athletes, whatever it may be, whatever state we are in in life, the energy functions, the mitochondria, and metabolism are always intimately tied together. Thanks for sharing that with us because I think it is important that people understand, and again, these are not the most direct or common conversations for the general public. I am well aware that probably about 20% of our audience is made up of our fellow colleagues or other health professionals. I am glad that you explained that. Okay, so now that we have gone through these topics and pathways, what are the best ways to restore and protect healthy brain metabolism?

Austin Perlmutter, MD

Yes. You ever get into a topic where, depending on who you ask, people are going to have different perspectives? I think that it is absolutely the case that today we have a polarization in people’s perspectives on anything that is going to touch on diet. Everyone’s got their best diet. I am going to try to be a centrist here and stick to what I know as far as what the research would indicate are the effective strategies that relate to metabolic wellness and specifically to brain metabolic health. I will say at the start that most of the research around interventional trials, meaning where they have taken humans and done something to them before and after measuring things around the brain and brain metabolism, is very limited, meaning we just do not have much data. There. We have a whole lot more data on peripheral metabolic health. Type 2 diabetes, for example, and what we can do to reverse aspects of Type 2 diabetes. Some of what I will say, I guess, is generalized to the brain from what we know happens in the body. But there are a couple of data points for the brain that I definitely want to bring up. The first thing I will say is that, as much as it tends to be complicated, I think that the majority of our health lifestyle is going to be the major driver.

So while I am certainly somebody who has prescribed insulin, I am certainly in favor of looking at medications like Ozempic and Metformin and all these other interventions. I think that as we look at what is happening in the world today, those cannot be the solutions that we are looking for. Because to basically assume that the only scenario that works is that we wait for people to be so sick they require pharmaceuticals is giving up on the most important part of this. How do we live healthy lives that do not require us to get through the end of the race with the diagnosis before we start taking things seriously? What do I know as far as lifestyle modification for metabolic health? It’s really the basics. As much as I would love to say that there is some incredible hack, it is certainly exercise. I think that cannot be overstated. Physical activity is absolutely vital to preserving metabolic wellness, and the reason I say that is because what happens to our bodies when we exercise is so much more than just burning up some extra glucose. In the context of mobilizing, let us say your leg muscle groups, with resistance training, you are actually translocating more glute receptors to the periphery of the cells, which allows you to pull more glucose out of your bloodstream and into your muscles.

These mechanisms are really stunning. There’s another important mechanism, which means that in the context of exercise, you produce muscle-specific molecules that can go out. They’re called Mayokins and actually have an anti-inflammatory effect and potentially increase insulin sensitivity throughout the body and potentially in the brain. Mechanistically, I think it is absolutely vital. I think if a person is looking at how they can improve their metabolic physical activity, it turns out to be so much more than just trying to lose weight because, actually, it is not a very effective weight loss intervention when done on its own. But there is one study that has been done recently, which is an interventional study looking at humans and whether exercise could improve brain metabolic sensitivity. What they found is that in this study, they had people exercise for a couple of months and looked at what happened when they gave them intranasal insulin, which is an interesting thing. But yes, just bear with me here for a moment. We know that insulin has a really important role in the brain. We also know that as people develop metabolic dysfunction, they can become more resistant to insulin. The insulin in the bloodstream has a harder time getting to the brain. One thing that you can do is basically give somebody insulin through the nose to see what happens in the brain.

So in this recent study, they were basically looking at what happens when people exercise. They gave me insulin. What they have shown is that people have different brain responses to this insulin after exercising. Basically indicating that there was an improvement. In a reversal of that, I guess, metabolic dysfunction in the context of physical activity. Again, we do not have all that much data specific to brain metabolism, but that is one of the few studies. I think it is certainly something we should be paying attention to, especially because we know peripherally that it is really helpful and we know that people who exercise have much lower rates of certain brain-related conditions. Exercise is a huge benefit for the prevention of Alzheimer’s disease. It has actually been shown to improve aspects of neuroplasticity and cognition in people with existing brain dysfunction. It is super important. I will say, though, one last thought on this. People all have their ideas as far as what the best exercise looks like. If you are somebody who does not move their body often, as a doctor or as a person, I want to make sure that I tell you that my goal is not for you to get out and run a 5k today. My goal is just for you to find something that you enjoy and that you can do to move your body, and literally, stretching, Pilates, walking—all of that stuff is amazing if you are not somebody who is doing that to start with. I do not want to get stuck in this framework of saying, It has got to be 150 minutes a week; otherwise, it does not matter. I think that is nonsense. Just moving the body seems to be really important for improving metabolic dysfunction by improving insulin resistance, improving glucose uptake, and making you metabolically healthier. That is one I am happy to go into. Any strategies around there, if you had any? But the other big one is obviously diet, and this is where, as I said, things get very controversial, so I guess I will jump into this in whatever way is most helpful for you and let you drive that conversation.

Beverly Yates, ND

Yes, it’s interesting in today’s world how complicated we have made the entire notion of nourishing ourselves. People have whole wars about nutrition and how to eat, and I agree with you, but your points about exercise make have feel that the best exercise is the one that you actually do. People have pain. They have all kinds of things that sometimes make it complicated. Maybe going out for a walk, a run, or a jog may not be safe where they live. Maybe the weather’s terrible—too hot or too cold. There are all kinds of constraining factors. Maybe their home space is not really large enough to do other things. It might be more complicated, etc. I just think we’ve got to get back to the basics as quickly as we possibly can. When it comes to nutrition, yes, again, people have to find what nutrition works for them. I have personally found there is no such thing as one size fits all nutrition after 30+ years of clinical practice. I have gotten away from giving people a list of thou shalt eat this and thou shalt not eat that. Because from a blood sugar point of view, never mind other things like their mood, whether or not it agrees with their belly, they have a lot of gas and flatulence, or bloating. Everybody does not react the same way to food. We can certainly watch for blood sugar reactions. It is okay. What are your thoughts about CGM continuous glucose monitors? As you can imagine, throughout our Type 2 diabetes reversal summit here, we have been talking on and off about the use of continuous glucose monitors or CGMs to really help people get actionable insights into what their blood sugar is doing. I would love to get your thoughts.

Austin Perlmutter, MD

Well, let me describe the two, which I think are opposing perspectives. On the one hand, the opponents of CGM monitoring would say this was a technology that was developed for people with diabetes. It has not been proven effective for people who do not have diabetes. It creates additional concerns and provides data that is not helpful, and people do not know what to do about it. Also, it may not be as reliable as people think it is. These are always additional costs, or, I should say, reasons why people would be opposed to people using CGM who do not have diabetes.

On the flip side, there are people who would say, Let us look at the rates of prediabetes and metabolic dysfunction. As I said before, we are talking about maybe 100 million people in the United States with undiagnosed prediabetes, in addition to those who already have diabetes. We are not talking about a small fraction of people. We also know that probably about 10% or less of people are metabolically healthy. I think if you want to make the case that, oh well, it is only helpful for people who have a preexisting issue, well, most of us have a preexisting issue. I think that is a tough pill to swallow. But it is true.

One of the most helpful reasons why I have enjoyed CGM is that if you do not do this, you are relying on a health care system that is set up to wait until things get so wrong that you have a diagnosis before it does anything. That fundamentally just does not make sense to me as a strategy. If you are comfortable saying, I am going to wait until I have a diagnosis, until I have a nice disease, you also have to be comfortable working within a system that is not designed to actually get rid of said disease, which is why most people over the age of 50 have at least one chronic disease diagnosis and or are on at least one medication because we have set things up for that to be the norm.

I think if the goal is to be preventive in a real way, then you have to have data that comes in before you have a diagnosable disease. From what I can tell, CGM is one of the best ways to get real-time insight into what your blood sugar is doing. The other thing that I really enjoyed about CGM or have been enjoying since I have used them multiple times is that you can learn what is unique to you, and it is fascinating to know that for me, for example, if I ate some brown rice, my blood sugar went up pretty high. Even though it is brown rice, which is supposed to be super healthy and whole grain, it has all the extra fiber. But when I ate the brown rice with a piece of salmon, it did not really go up that much. These are insights. You think, Oh, well, I did not necessarily know that. It is not necessarily the case for everyone else.

When I am with family members or with my partner and we eat the exact same meal, we have different blood sugar responses, and even beyond the food, let us say, I mean, we are all going to eat food. That is, we are not really going to argue that point. We are going to eat our meal. But then what comes next? That is actually really interesting, and it is only something that you can really learn if you are using CGM. You eat your meal, and you realize that your blood sugar is going up more than you expected. Again, the naysayers would say, Well, maybe that is a normal excursion, but we are now learning that the ups and downs may not be all that helpful. Maybe you say, Well, my blood sugar is going up way more and staying up higher than I would like. Maybe now is an opportunity to go for a walk or meditate. We know that stress has a major role to play in blood sugar regulation. I can see in real time what that does to my blood sugar. I think even beyond the question of what that does for my overall health, it is super empowering to have the biofeedback and know that my actions, my lifestyle actions, have an immediate and powerful effect on what is happening with my blood sugar. 

Where I come down to this is that I think CGM are a really powerful tool. I think there are instances in which they are not great, so certain people may respond to them in a way that increases neuroticism around what you eat and exercise, and that is not a healthy thing. I think that in an optimal scenario, people are doing this with assistance. I think that is really important. I think about even Sleep tech Oura rings and other sleep tech wear or genetic testing that is readily available to the public, and all of a sudden you are getting this data that you do not know what to do with. It can be really stressful. 

I think it is really important to have it set up as a scenario where if you are getting information that concerns you or that you do not understand, there is somebody around to help you walk through that and understand, Hey, this is or is not actually a concerning thing. This is what we expected to see. Maybe the most important part of the whole thing is that if you get a CGM, that is the first time that you have ever actually learned about your blood sugar. How do you know when you need to actually see a practitioner for that? How does a practitioner know how to interpret the CGM? Those last two things are not quite dialed in yet. something that I know many people are working on, but big picture-wise, with those caveats, I am in favor of learning more about our bodies, and I think CGM is going amazingly well.

Beverly Yates, ND

I agree. I do think we were at the forefront of making this more understood, both for the general public and for our colleagues as health professionals and medical experts. I think over the next 5 to 10 years, we’ll really start to close those gaps as we just sort of crowdsource some of this and find out what the best practices are, in particular for those who already have the problem around blood sugar, something that has been diagnosed, as well as those who may have a strong family history and are worried. They are, and I want to dodge this. I do not want this outcome for me. How do I make it different and find out if I am starting to lose blood sugar control, especially around, let us say, menopause for women and reports where men’s testosterone levels really start to vary? We have the bookends of life: in 15 years and puberty in middle school, we get that rise and change in our sexual reproductive hormones. Then, as we exit that window of active hormones, fertility hormones can shift, whether or not we do any bioidentical hormone replacement therapy. Still, our sensitivity to insulin and other things is shifting, so now might be a great time to have a CGM and catch it. You are saying that before we have the problem, which is a different mindset because that is not what gets rewarded now.

Austin Perlmutter, MD

Well, let me just add one more thing to that, because something that I did not necessarily address but that I think is important is that, really, I was talking about the utility of CGM in a person who is either pre-diabetic or just, I guess, what we call a metabolically healthy person. But if you think about what it does for diabetes, it is already being used in that field. That is where it got started. But I do think there is still so much more that can be gleaned from it once we have higher-level algorithms. What I mean by that is that I have had patients come in to download the CGM data, and it is just overwhelming. So you have to parse out trends. You say, Well, it looks like you are having high blood sugars in the morning, or it looks like you are getting low blood sugars at 2 a.m. This is really helpful because, obviously, one of the goals is not to have very low blood sugars for most people with diabetes. That is really the scary thing because low blood sugar, from a brain perspective, is incredibly dangerous.

A little bit higher in the hundreds. Maybe you are not as concerned until it gets much higher than that, but low blood sugars can be deadly. CGM can start telling you where things are getting low and help you mitigate that. But beyond that, where I am really excited is that CGM, when coupled with higher-level algorithms, can start telling you insights about what does or does not work with your body. So much of your diabetes management, at least in primary care, is just trying to cover blood sugar levels with doses of insulin. You have your long-acting insulin, you have your mealtime insulin, and you can get fancier and get a pump that can do all these different things to try to keep things a little bit more steady. But I think what is most often ignored is the idea that each person has an individual response to different types of food. The goal—maybe not the primary goal, but eventually the goal—would be to say, Why is it that you are needing all this different insulin for different types of foods?  To the point, I guess, of the summit, are there things we can do to reduce your insulin dependence, even if it is just reducing the amount of insulin that you need, potentially getting you off of insulin altogether? In order to do that, you cannot just say, Well, the goal is just to make sure that whatever you eat, we are covering you with insulin. That is the first-stage risk mitigation approach. I think CGM gives you some of that opportunity. You can start to say, Well, it is not just that the massive bowl of frosted honey-nut oat clusters in the morning is increasing.

Your blood sugar is so high that we need to give you some more mealtime insulin. It is actually a question of saying, Well, maybe that in and of itself is one of the reasons why you are having such poorly controlled diabetes. Mechanistically, not just that the blood sugar is going up high and we have to chase it, but rather saying that there is that high level of basically crazy glucose, the sugar rush is creating damage to your insulin, and it is creating damage to your inflammation. that by saying we want to actually not just cover that meal with more insulin but change that meal so you do not need as much insulin. We are not unnecessarily creating insulin resistance, which seems important to you. CGM allows for that level of understanding. My hope here is that pretty soon we’ll start getting these algorithms that will be able to tell us, based on your CGM data, what we could recommend as far as a diet and lifestyle modification plan to help reverse the course, get you off of the amount of insulin you need, and potentially take away some of these other medications. What’s super interesting is that we have seen that several groups, including the United States, have now been able to demonstrate that by dietary intervention by lifestyle intervention, you can do just that. I think that is incredible. Removing insulin from a person’s protocols and getting a person to a place of going from being a diabetic to not being a diabetic are things that are happening now and are just so exciting as far as giving hope to and just empowering people to know that there is more that can be done than just constantly chasing blood sugar with insulin.

Beverly Yates, ND

Absolutely. In the case of type 2 diabetes, this is a reasonable approach. I am excited about that progress because I really feel that will be a large part of how people heal so often. Austin, thank you so much for being here with us at the summit. All of your insights, your gems, your tips, and not only your point of view, but your willingness to explain behind the scenes, giving people a real sense of what goes on behind the curtain so they can understand, Okay, where am I relative to this? What did I actually know about this before? What did I just learn? Then, as I have been saying throughout our summit time, friends, as you listen to these wonderful experts, Dr. Austin Perlmutter, please share this time with everyone you know who cares about their health, has this problem, or is looking to prevent it, because we are talking about millions of people around the world who are concerned or who are part of this now. If people want to connect with you often, where can they find you?

Austin Perlmutter, MD

Easy to spot would be my website. AustinPerlmutter.com. Then I sent out a newsletter probably once a week, just filled with all the tips and thoughts I have, primarily around brain health but certainly around metabolic health. Some of the other topics you brought up today.

Beverly Yates, ND

Great. Thank you so much for being here with us. We look forward to all of the things that you are up to now and to other things in the future. I hope people connect with you. Take good care.

Austin Perlmutter, MD

Appreciate it. Thanks for having me.