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The Melanie Avalon Biohacking Podcast Episode #96 - Casey Means (Levels)

Casey Means, MD is a Stanford-trained physician, Chief Medical Officer and Co-Founder of metabolic health company Levels, and Associate Editor of the International Journal of Disease Reversal and Prevention. Her mission is to maximize human potential and reverse the epidemic of preventable chronic disease by empowering individuals with tech-enabled tools that can inform smart, personalized, and and sustainable dietary and lifestyle choices. Dr. Means’s perspective has been recently featured in Forbes, Entrepreneur Magazine, The Hill, Metabolism, Endocrine Today, Endocrine Web, Well + Good, and Dr. Michael Greger’s (author of How to Not Die) video series. In 2020, she has been a guest on the podcasts Veggie Doctor Radio, Healthy Human Revolution, Work for Change, Mindhub and others, speaking about metabolic health. She is an award-winning biomedical researcher, with past research positions at the NIH, Stanford School of Medicine, and NYU.

@unlocklevels on Twitter and Instagram 


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2:50 - IF Biohackers: Intermittent Fasting + Real Foods + Life: Join Melanie's Facebook Group For A Weekly Episode GIVEAWAY, And To Discuss And Learn About All Things Biohacking! All Conversations Welcome!

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9:25 - Casey's Background

14:20 - What Is A CGM?

20:50 - What Is the Levels Experience Like?

21:20 - how is the prescription accessible?

23:10 - the application process

25:15 - what is it measuring?

26:20 - what is insulin's role in the interstitial fluid?

27:15 - how accurate is it?

28:40 - the highest saturation levels

30:15 - CGM compared to a finger prick and/Or a lab draw

31:30 - why the 14 day time limit?

33:00 - recommendations for placement 

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35:20 - placing a patch over the sensor

35:50 - night-time accuracy

40:45 - what is a good range? 

48:10 - CRP (C-Reactive Protein) and inflammation

50:00 - the negative affects of glycation

51:20 - insulin resistance

53:30 - metabolic fitness

54:40 - the most insulinogenic foods

55:50 - the "area under the curve"

1:00:00 - reactive hypoglycemia

1:02:35 - how to bring back carbs after HFLC

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1:10:15 - the differences in glucose response person to person

1:11:50 - glucose levels in a diabetic individual

1:12:35 - the influences on insulin resistance

1:16:15 - berberine

1:16:50 - glucose lowering Probiotics

1:18:50 - Is 2 weeks enough time to learn your patterns?

1:21:50 - can listeners Subscribe to levels?

1:23:30 - using the app and the zone score

1:25:30 - how the zone score is valuated

1:28:10 - updates to the app

1:28:45 - data storage of the sensor

1:31:00 - calibration

1:31:20 - the bluetooth and EMF

1:31:50 - the difference between glucose levels, HbA1c and Serum fructosamine

1:37:20 - testing gestational diabetes

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Melanie Avalon: Hey friends, welcome back to the show. I am so excited about the conversation that I'm about to have. It is a topic that you guys have been begging, begging to have a show on. Here we are and it comes with my personal experience for the past few weeks of trying out this device. I really feel like in the whole biohacking world, there's something that's becoming increasingly more popular every single day, and it's something that's been around for a while, but not really available to the general public, and that is continuous glucose monitors, or CGMs. We're going to obviously dive deep into what that actually is.

I have been wearing one for the past two weeks, learning a ton about myself. You can learn so much about how you react to foods, how you react to fasting, to sleep, there's just so much to learn here, so much potential. What's really exciting is that there are companies like Levels who I am here today with the cofounder and the chief medical officer of, Dr. Casey Means. There are companies like Levels that are, like I said, making CGMs available to the general public and integrating apps so that you can really interpret the data that you have and make it really beneficial to your life, so I am so excited. I have so many questions. Dr. Means, thank you so much for being here.

Casey Means: Thank you so much for having me, Melanie. I'm thrilled to be here.

Melanie Avalon: I'll let listeners know a little bit about you. Like I said, you are the chief medical officer and the cofounder of the company, Levels, that we're going to talk all about. You are a Stanford-trained physician. This is so exciting. You're the associate editor of the International Journal of Disease Reversal and Prevention. That's when you know you’re a biohacker when you get really excited by journal people, but you are an award-winning biomedical researcher, you've had a lot of other past research positions at the NIH, at Stanford School of Medicine and at NYU. Your work has been all over the place, Forbes, Entrepreneur, The Hill, Metabolism, Endocrine Today. You've even worked with Dr. Michael Greger who listeners might be pretty familiar with he wrote How Not to Die. He has nutrition video series, which I've actually watched quite a few of those when I was doing a nutrition certification program. In any case, that's a little bit about you. To start things off, would you like to tell listeners a little bit about your actual personal story, and I'm dying to know what brought you where you are today with CGMs and with Levels and all of that?

Casey Means: Sure, absolutely. Thank you so much for the kind introduction. My background actually starts-- now it's in digital health and metabolic optimization, but it actually started in surgery. I trained as a medical doctor, I was at Stanford for medical school and then came up to Oregon for my residency training in head and neck surgery, ear, nose, and throat. It was there that I was treating a lot of conditions that were fundamentally inflammatory in nature. A lot of things that end in itis, like sinusitis, thyroiditis, things that are fundamentally inflammation, and the immune system being revved up, and upregulated. We treat a lot of these conditions with steroids, which tamp down the immune response. Then, of course, antibiotics. Then really late stage, we'll turn to surgery. After about four and a half, five years in this world of ENT, I became really interested in stepping back and saying, “Why is there so much chronic inflammation? Why are people dealing with these chronic inflammatory disorders that seem to persist and come back even after rounds of steroids and antibiotics and even surgery, a lot of repeat surgeries you see in the hospital?” That really led me on a journey towards trying to understand the root causes of chronic inflammation.

One of the key ones there is metabolic dysfunction and how we handle blood sugar and how efficiently we're processing various substrates into energy in the body. Really became interested in how to metabolically optimize people. I saw in my patients that so many of them that were dealing with chronic ENT disorders were also dealing with other issues of metabolism. Things like obesity and diabetes, and many of the other sequelae that are associated with insulin resistance and poor glucose control, things like liver disease, chronic kidney disease, depression, anxiety, brain fog. There's so many things that are linked to metabolic disease. I was seeing a lot of this in my patient base, but also noticing how people who had poor metabolic function did worse after surgery. Wounds don't heal as well when your blood sugar is not controlled, and you just have trouble bouncing back. It was very important to me to address this and think about this more deeply.

Really what it comes down to is improving-- moving the needle on metabolic function really has to do with behavior change. It has to do with changing the hundreds of micro-decisions we're making every day on how we eat and when we eat, and how we respond to stress and how much we're sleeping and how much we're moving. Those are all choices we're making every day. We really don't have a lot of time in our 15-minute visits with patients to really get deep into this and be really, I think, effective agents of behavior change in the standard practice of medicine as it is now. I just became just laser focused and fascinating on how could we leverage other tools to really scale behavior change in regard to metabolic health, how can we use our digital tools, our phones, wearables, things like that, to really move the needle on this aspect of health that’s so fundamental towards all aspects of our health and well-being. That got me really interested, and that topic, and ultimately drove me to start Levels, which does just this. It's a program to help individuals understand and improve their metabolic health rapidly.

Melanie Avalon: I love all of this so much. Yeah, I think especially with metabolic health and blood sugar, for example, my audience in general, people in general are pretty familiar with the problems with blood sugar regulation issues, but I think a lot of people, it caps out at thinking it's just about like weight loss or hunger or appetite, but it goes so far beyond that and affects so many things. I know, for me when I first changed my diet, and stopped the standard American diet was when I went low carb. I wasn't testing my blood sugar at the time but the benefits that I experienced seemingly on my blood sugar levels, and having that regulated was so huge. I've made a lot of tweaks since then.

More recently have been-- I don't know, I've been feeling like- I've been struggling to get my blood sugar quite where I like it and getting the CGM was so validating because it was showing a lot of things that I was suspecting about myself, suspecting that my fasting blood sugar might be higher than I like, I was feeling intuitively that I was getting reactive hypoglycemic responses after meals, which is something that we can talk about. Yeah, that was a whole winded way of saying that I think everything that you're doing is so incredible. For listeners, the CGM, until really recently-- because when did you found Levels? When did you start that?

Casey Means: We started the company last summer, so it's been around for just over a year.

Melanie Avalon: It's really recent that this is becoming a thing where people can have access to this device. I guess just to start with, what a CGM is because often prescribed for diabetics-- what is it? I can tell listeners about the experience of putting it on, which was not nearly as scary as I thought it was going to be. What is it? Why is it prescribed for diabetics normally, and how is it now being made available to us?

Casey Means: Yes, so this technology of continuous glucose monitors, otherwise known as CGMs, this has actually been around for over 10 years. Like you said, this is a technology that has been traditionally used for individuals with diabetes. This is a prescription-only FDA-approved device for the treatment of type 1 and type 2 diabetes. What it is, is it's a tiny wearable sensor, you can think of it like Fitbit for glucose. You're sticking this quarter-sized sensor on the back of your arm and it's got a tiny little 4-millimeter hair like probe that goes just under the skin painlessly. It is tracking glucose anywhere from for every 5 and 15 minutes. Those data points are being sent to your smartphone, and you can see a continuous reading of this internal biomarker, which is fascinating because for sleep monitors, activity monitors, stress monitors that are looking at heart rate and HRV and things like that, these are not internal biomarkers, not things inside our body. These are more just transmitted through the skin. This is an internal biomarker that you're sensing painlessly 24 hours a day and getting this super-rich data stream.

For individuals with diabetes, this was a total game changer. Because prior to that, they were having to prick their fingers anywhere from one to four or five times a day to see what was happening to their glucose after meals, and really to manage medications, particularly insulin, and track progression of the disease. But you can imagine the difference between four data points a day and hundreds of data points a day, it's just monumental and then taking away that finger prick component, which is not fun and painful. It's bloodless, and it's just huge acceleration of the technology.

Then, you bring it into our current culture where people are really interested, even people without diabetes and understanding their metabolism, and you see this with the keto movement and you see this with non-diabetic individuals starting to prick their fingers, so they can better understand where they sit on the metabolic health spectrum because we know that so much now that the way glucose impacts insulin and other hormones in the body and the way other hormones like cortisol affects our glucose, all these things are so interrelated, and if we stabilize and manage our glucose, we have this huge opportunity to really just up-level our current lives in so many ways, improve our energy, improve our mood, improve our cognitive performance, our memory, our athletic endurance, and, of course help prevent this movement toward so many of the chronic conditions down the roads that are associated with dysregulated blood sugar. People have been interested in this. We certainly see that with the movement towards these types of low-carb diets.

Now, there's this technology that tracks glucose in real time, can tell people exactly where they stand every single day, in terms of metabolic health. Really, it's just about getting that technology to a wider market and then building tools that help people, health-seeking individuals to interpret that data and understand the data stream. It's not just about food in terms of what impacts glucose levels. It’s food, it’s food combinations, it’s food timing, it’s stress, it's sleep, it’s exercise, all these things directly feed in to our glucose curve. If we want to keep that curve flat and stable for optimal health, then having software that really integrates data and helps us understand where we're at and how to make actionable changes and close the loop between these decisions and actions and what's happening to our health in real time, that's just a game changer.

For this wider population, this is really completing that health stack. We've had stress sleep activity monitors, but we've never had a real-time wearable sensor that closes the loop on nutrition that has not existed. The best we've had is maybe six months from now, you'll get a fasting glucose level, or you'll get a cholesterol check, or maybe you'll weigh yourself the next morning. But there's not really a closed loop between those outcomes and the exact thing that you did to cause them, and so now we do have that. We have that really closed loop biofeedback for nutrition. It's just a super exciting time to bring this technology to a much wider population and pair it with intelligent software that really parses out the drivers of glucose control, and then helps people move in the right direction consistently.

Melanie Avalon: I think listeners can now see why I'm so excited by all of this. I'm also the host of The Intermittent Fasting Podcast and my cohost on that show, Gin Stephens, she went through using a CGM, and it was for the PREDICT 2 study I believe, so they sent her one for that, which was I think I a gut microbiome related study. In any case, the thing, like we both-- I feel like we're both the CGM fangirls, like half the episode now, we just talk about our CGMs. One of the biggest epiphanies from all of this is seeing your pattern throughout the day and throughout the evening, like you said, 24/7 is just really, really incredible because I've always been testing myself. In the past, I pretty much check my blood sugar every night once in the evening, then it will usually be around the same. Wearing the CGM, I've realized even if it's smaller fluctuations, just how much my blood sugar does fluctuate, even if it's within a range. What I think is so interesting about that is it made me realize, if I'm getting blood tests, and my number that I get from that blood test, it could be substantially different if I had gone-- I think, even five minutes later. There's just so many factors. It just really made me realize how much more there is to know and how much just having one marker for blood sugar tells you-- It tells you that one marker at that one moment, but it doesn't tell you that much honestly.

For listeners, because I want to give them an idea of what the experience is like. Levels, you guys don't actually make the CGM, correct? You're using the FreeStyle Libre?

Casey Means: That's correct. We're using off-the-shelf hardware. Our real core competency is the software overlay, so helping people understand the data stream and we are integrated with Abbott and with the FreeStyle Libre, which is one of the three pieces of hardware on the market. There's three different types of CGMs and soon to have a Dexcom offering as well.

Melanie Avalon: How are you making this prescription accessible? Does anybody qualify? Can anybody get it? What is the process to get the CGM?

Casey Means: Currently, we are a general health and wellness product. We're not a medical product. We're not treating any diseases or conditions. We're really just helping people understand their current level of health and optimize that. This is really a product targeted towards health-seeking individuals without clinical conditions who want to optimize their metabolic fitness. The way that works for a Levels customer is that they would purchase this one-month metabolic awareness experience. It's one month of really experimenting and testing lots of food you love and understanding how to optimize to get that lower and flat glucose curve.

The first thing that happens is you're connected with a telemedicine physician in our network who evaluates the person for a CGM. This is actually a very, very quick process. It's basically filling out a short questionnaire that the doctor in your state then reviews, and if a person, if it's safe for them to get a CGM, a CGM is then shipped from our partner pharmacy to the person's house, two sensors, each sensor lasts on the arm for 14 days. Together, those two sensors make a 28-day monthlong experience. Then, access to the Levels app which interprets the data and helps make it really engaging and understandable. That's how the prescription products are made accessible to this population is through our telemedicine network and shipment of these sensors from a pharmacy to their homes.

Melanie Avalon: I take my blood sugar a lot, like finger pricks, I will do subcutaneous injections of crazy things like glutathione. I'm not scared to stick things into my body. That said, it just looks intimidating the applicator to put it on, but, oh my goodness, you don't feel it at all. I was very much surprised. For listeners, it's not painful to put it on even though-- it's inserting it right beneath the skin, the sensor?

Casey Means: Yeah, it's a 4-millimeter sensor, it's less than a millimeter in width. It's almost like a piece of dental floss that's 4 millimeters in length. It's very, very tiny, super flexible, but just like you, I had the exact-- the very first time I put one on a year and a half ago, I've been wearing one now for that entire time. It's really intimidating because you see this thing and you're like, “Wait, I'm about to impale this thing into my arm? Is it there going to be a needle in the arm? Is it going to be rigid? Can I lay on it?” So, many questions. I think I watched probably 15 YouTube videos to just see people applying it to see what it was going to be like. Then, of course, just like you, I finally did it. I think I had my Bose headphones on blasting music while I was doing it, just to gear up. Then I did it, I just started laughing because I was like, “I could not feel it.” Pretty much, no one feels it. A lot of people actually don't even think that the applicator has functioned properly because they didn't feel anything happen. It's so quick. Then once it's on, you just forget it's there. Then, I think it's also really reassuring when people take the sensor off after two weeks, because then they can actually see that little probe that was inside for the two weeks and feel it and just realize how hairlike and flexible it is. You could just lay on it and it's just going to bend. It's so flexible. It's really, really reassuring.

I've created some of our sensor application videos and made sure to really press on the probe, use the sensor, and show people how flexible it is because I think it takes away some of the fear factor there. Have you taken yours off, your first one off yet?

Melanie Avalon: No, I have two days left. I'm really excited to see it. Gin said, my cohost, she was like, “It was really exciting to take it off and see what it looked like on the flip side.” Yeah, so no need for any fear surrounding it. As far as what it's actually measuring, so it's not actually testing your blood. Correct? What is it measuring?

Casey Means: That's correct. Yeah, it's measuring interstitial fluid, which is the fluid in between your cells. You can imagine under the skin, there's all your skin cells. In between each of those cells, there's fluid, which is the interstitium. Glucose basically leaks out of blood vessels into that tissue, as glucose travels to the cells to be taken up. That is the fluid that glucose is being tested from. Because of that, there is said to be basically a slight delay between a blood reading and an interstitial fluid reading that can be about 10 to 15 minutes as that glucose from the blood diffuses into the interstitial fluid. Yeah, I've certainly found that to be true on some days. But then other days, I'll eat something and within 5 to 10 minutes, I'll see my glucose starting to rise on my sensor. I think it sometimes happens really, really quickly. Yeah, there's a little bit of a delay getting into the interstitial fluid, but that's not going into your blood, just going in the general tissue.

Melanie Avalon: Okay, so the interstitial fluid, is it still on the outside of the cell?

Casey Means: Yes.

Melanie Avalon: The insulin receptors, are they on the cell? The leaking from the blood to the interstitial fluid, is that at all dependent on insulin or does that happen regardless of everything?

Casey Means: Yeah, that's just going to happen regardless. The insulin receptors are sitting on the surface of these cells and glucose is going to come out of the bloodstream into the interstitium, then it's going to be insulin binds to a cell that's going to allow the glucose transporters called glute channels to go to the surface of the cell and then soak up that glucose from the interstitium. It's measuring in that area. Really, you can just imagine that what's happening in the blood is reflecting almost identically in the interstitium, just with a time delay.

Melanie Avalon: Would that also mean that it might be slightly less accurate when you're at a really low blood sugar level, because there's less glucose to be leaking into the interstitial fluid? I know that's really granular, but--

Casey Means: No, it's a good question. Actually, the sensors are less accurate at lower values. It's actually a perfect question. There is a specific range for which the sensors are the most accurate. That's about 100 to 200, really, a range that is going to be really relevant to the diabetic population. Then as you get down to glucose values between 60 and 80 or so, things are a little bit less accurate compared to blood, which may very well have to do with the lower concentration in the fluid. There's actually an enzyme protein that is stuck on to the sensor. This is what actually happens, is that there's a chemical reaction between the glucose and then this enzyme that's on the sensor called glucose oxidase. The glucose oxidase does a chemical reaction with glucose that converts glucose into a secondary byproduct. In that process, it creates basically an electrochemical charge that's picked up by the sensor and transmitted as the glucose level. So, you can imagine how at lower values, that chemical reaction may not be happening as robustly, but it's still very, very accurate. You do see a little bit of a decline at the very, very low values.

Melanie Avalon: That's so interesting. Is there a saturation level that happens in the interstitial fluid, or does that happen in the blood as well? Where there can't be any more?

Casey Means: That's an interesting question. The glucose can get very, very, very, very high. There are people who have glucose readings in the 300s, 400s, 500s. The sensor will not pick up that high. in terms of just like biologic plausibility, you can have glucose levels that high, and sometimes you'll see that in patients who are coming in with diabetic ketoacidosis. That is certainly an area, a range that we never ever want to get in, we want to stay much, much lower than that. One thing I'll say just accuracy wise, if you look at the FreeStyle Libre, they've done tons of research on basically comparing glucose at all values to the blood reference range. They've found that the mean agreement with reference tests for FreeStyle Libre compared to blood, so the difference between blood and the Libre readings on average, is about 9% on average. There may be an up to sort of 9% on average difference between what you'd see in the blood and what you'd see read by the FreeStyle Libre. Interestingly, this is actually very similar to other consumer wearable devices, like Fitbit, which is also in the range of about 9%. That's fairly accurate.

Given that this product, especially in the nondiabetic population is not intended for treatment decisions, we're really looking at trends and the delta between before and after of an intervention and seeing what happens. Certainly, that's a range that we feel really comfortable with as still being very useful for someone using it.

Melanie Avalon: How does that compare to pricking yourself and then also like a lab draw?

Casey Means: In the research that was done that's reported, the research that basically had to be done for FreeStyle Libre to be approved by the FDA, this is looking at a lab draw, so like a blood draw in the vein compared to the FreeStyle Libre. Then for the finger prick, that's going to sort of also vary depending on the finger prick monitor that you're using. These home monitors also have their own degree of variability between a lab test that's done in a lab versus the fingerprint. That one, it's hard to know exactly what the difference is going to be between the Libre and your home fingerstick glucometer because each one is a little bit different, whether using One Drop or Keto-Mojo, or any of these companies, so yeah.

Melanie Avalon: When I've been using it, I've been checking it against-- well, I had a Bayer and then I just got the brand-new Keto-Mojo. I was testing everything altogether. They were all typically around within like 10. I should know it's measured in 10.

Casey Means: Oh, milligrams per deciliter.

Melanie Avalon: Yeah, okay, 10 milligrams per deciliter. I always just use like numbers. Really quick, random rabbit hole question. Since using the enzyme in the sensor to detect the level of glucose, is that why the sensors only last two weeks? Is it because of something like in the sensor not “expiring?” Or, there's just a two-week time limit?

Casey Means: Two reasons, actually. One is what you just said, which is the enzyme. A big part of making bio-wearables, like internal sensors that measure lab values in real time that you're wearing is stability of the enzymes used to test these things. Enzymes can be very, very fragile and basically, it won't work. That's why we aren't seeing a ton of bio-wearables on the market that are testing-- basically doing lab tests at home. A lot of it has to do with enzyme stability. Glucose oxidase just happens to be this brilliant enzyme that's really stable. We can do it for two weeks. Yes, that that may decline over time. The second thing is actually your body's reaction to the sensor. This is a foreign object under the skin. So, over time, you also could develop an immune response to that and potentially create, theoretically like a capsule around it inside or create inflammatory tissue around it. The two weeks, it's just this perfect amount of time where you're not really mounting an immune response to it. In the vast majority of people, the glucose oxidase is stable, and it's going to stay really accurate. Right now, the two main sensors on the market, Dexcom and FreeStyle Libre, Dexcom is a 10-day sensor, and the FreeStyle Libre is 14. These are right around the sweet spot. Certainly, longer sensors, we're really hopeful that these will come online to just ease the use of this.

Melanie Avalon: Taking it out, and then putting it in another location, it's like starting afresh?

Casey Means: Yeah, that's what I tend to recommend is do it, at least like a centimeter off from your last sensor or switch arms. To me, and this is really-- I don't have like evidence for this, but to me, that makes a lot of sense. Give the tissue on one arm some time to just heal and forget that this ever happened, and then do it on the other arm for the second sensor. But if you prefer one arm, if it's easier to scan your sensor with your phone on your left arm, if you're right-handed, we would just probably recommend moving a centimeter down from your prior insertion so that the probe is in just a slightly different area.

Melanie Avalon: For listeners, like we said, it's a really small sensor, but then for Levels, there's a patch that you can put over it and it actually made me really happy because-- this is crazy, in order to get rid of decision fatigue, I have five copies of the same outfit that I wear every single day, it's black with a white logo. The cover for the CGM with Levels is black and white. I was like, “This is perfect, matches my outfit every single day.” Super random. One more question about accuracy while we're talking about that. I was talking with Tom at your company about the accuracy because I noticed at night that I tend to be pretty late, which may or may not be ideal, but I do, and I've always, like I said, sort of felt I was getting reactive hypoglycemia. I definitely saw that reflected in the CGM data. But I also noticed a few nights that it would drop ridiculously low, like 40s. I was like that seems a little bit low.

I was talking with Tom and he was saying that, if you lay on the sensor while you're sleeping, that might be cutting off circulation, which can be a problem. He was also saying that there haven't been a lot of studies actually on glucose levels all throughout the night. We don't even really know what might be normal for nighttime levels. If people do have it, have you seen people experience dips in general at night and could it possibly be from laying on the sensor or something like that?

Casey Means: Yeah, that's a great question and definitely one that we get a lot because people get very alarmed by seeing values in the 40s or 50s, or 30s, so there's three things I would say. The first is what Tom mentioned, which is there is this very well-established phenomenon called pressure-induced sensor error. Quite a few publications on this where basically, if you lay on the sensor and put your full body weight on it, which many of us side sleepers are going to do, that can create complete error in the sensor. There have been studies where people have been wearing these in hospitals and a research assistant will basically-- they'll have video cameras on the patient and then see when their glucose goes low and it's sends a correlate really identically with when they rolled on their side, so they'll monitor the videos and the glucose response and they've seen a correlation with that. Then, I believe double-checked it with like an actual lab draw at that time. It's not actually that low. Really, really big lows, often are likely, I think, going to be the pressure-induced sensor error.

The second thing to know is that glucose does actually go lower during sleep. During REM sleep in particular, we tend to have glucose levels that are about 5% lower than in other sleep stages. There may be just natural dips that we're seeing in glucose. The third thing is that, like Tom mentioned, we don't exactly know what's normal for a healthy person at night because, first of all, we haven't really cared that much about glucose levels in nondiabetic individuals traditionally. We were sort of a system that really focused on things like once the disease has emerged, so there's just not a ton of data looking at what over 24 hours is the normal glucose levels for nondiabetic individuals. There's about six or seven papers that have looked at that but it's not an abundance of research and would be happy to talk a little bit about what those papers found.

Specifically, in terms of lows, something that's been seen is that, we may spend anywhere from 5% to 10% of our day below values of 70 milligrams per deciliter, which would be traditionally called hypoglycemic. In these large populations of healthy people, it seems like they're spending many, many minutes, if not hours a day dipping below often asymptomatically, without symptoms of hypoglycemia. So, it may be somewhat normal that we will intermittently dip into the 60s or whatnot. That might be totally, totally normal. Certainly, as more nondiabetic, healthy individuals were these overnight, we’ll have much, much more information about what is normal.

Then, very last thing is what you're eating late at night may have a really big impact on the curvature and the shape of the glucose line overnight. People who are eating a high-carbohydrate meal late at night are going to have the downstream insulin response of that, and potentially could get into a situation where they have this big insulin surge, and then a big dip in their glucose, then leading to reactive hypoglycemia, and then that could lead to this little bouncing throughout the night of a little bit of hypoglycemia, and then recovering, and then back and forth. Certainly, not eating high-carbohydrate meals, or more specifically, not eating foods that for your particular body are going to cause a glucose elevation, because it's going to be different each person, that's a good way to keep glucose levels a little bit more stable overnight.

What's more, people who have glucose spikes at night tend to sleep more poorly, so it can cause you to sleep hotter if you have a glucose spike at night, it changes thermal regulation. We know that people who sleep hotter tend to sleep worse. It's been associated with just general insomnia. Keeping the glucose spike really minimized towards the end of the day, I think, is a really super low hanging fruit for getting the best sleep possible. Those are some of the reasons for the lows potentially at night, and some ways to potentially mitigate that.

Melanie Avalon: That ties into another just huge foundational thing to talk about, which we talked about how it's measured in milligrams per deciliter for blood glucose. What is a healthy range? You just mentioned that technically going below 70 is hypoglycemia, but during the day some people eat meals and people snack, a lot of my listeners practice intermittent fasting, so they have some sort of fasting period during the day, what is a good range? What qualifies as a spike? What do we want to see? What do we not want to see? What should it look like?

Casey Means: Yeah, I guess just backing up for people, the part of the reason we don't want these glucose spikes is because high glucose can cause just a number of things in the body that we just don't want. The first is that it can generate inflammation like I was talking about in the very beginning. A big glucose spike can tell your body that something's off, something's a little wrong, and cause you to up regulate immune chemicals like cytokines, TNF alpha, CRP, interleukin 6, things like that. We don't want that. It can also cause oxidative stress, so create free radicals in the body that can be damaging, and it can also cause glycation. When blood glucose concentrations are high, glucose can stick to proteins and other structures in the body and cause dysfunction. Glycation is a process that is sometimes called-- when the body becomes almost caramelized. It's literally changing the proteins. It's not a good thing, so we don't we don't want glycation, oxidative stress, or inflammation.

Then, of course, glucose spikes are going to cause corresponding insulin spikes. The higher the glucose spike, most likely, the higher the insulin spike. Insulin spiking frequently, we really don't want because what happens is, when that occurs over and over and over again and insulin is required to get the glucose shuttled into the cells, our body becomes a little bit tired of that and becomes resistant to that insulin signal. The body then has to actually make more insulin to get the same amount of glucose into the cells. Now, you've got higher insulin, higher glucose, and this process of insulin resistance is fundamentally the root of so many medical conditions that we see today. Also, it is a big problem with weight loss and obesity because when insulin is high, it's a signal to the body that glucose is around, we've got this ready source of energy, we don't need to use other sources of energy. Of course, that means we don't need to use fat for energy. So, insulin is a direct block on fat oxidation. You can imagine if you're trying to lose weight or if you're trying to have a lot of endurance with a workout and just really want to be tapping into fat oxidation, insulin being high, big problem. Those are just five of the reasons why we don't want glucose spikes to set the stage for then where should we be aiming.

The short answer is that for nondiabetic individuals, we don't exactly know where people should be shooting for, for optimal glucose levels. This is interesting, because right now, all we've got is some criteria that are put out by the American Diabetes Association that say, “If you're above this range of glucose, you're in the prediabetic or diabetic categories. If you're below, you're nondiabetic,” but that actually doesn't tell us what's best for health. If you just looked at that criteria, what we would know is that we want our fasting glucose first thing in the morning to be less than 100, to be considered non-diabetic. If it's between 100 and 125, you're prediabetic, and if it's 126, or above, you're considered diabetic. There's another test called the oral glucose tolerance test, which is where individuals will chug 75 grams of glucose in this standardized drink, called Glucola. Then they'll have their blood sugar measured at various intervals two hours after that drink. If your glucose is below 140 milligrams per deciliter after that drink, two hours afterwards, you're considered nondiabetic. If it's above 200, you're considered diabetic. If it's between 140 and 200, that's prediabetes. From that standardized clinical information, we'd say, “Okay, well, we should shoot for a fasting morning glucose below 100. We should plan to be less than 140 after meals.” I personally think this is much too lenient and doesn't really tell us where we really ought to be for best health and avoidance of future disease.

Then, you have to turn into some more nuanced literature. These are the studies where they've put CGMs on healthy populations, and just looked at 24-hour patterns. What you see in that research is that healthy people without diabetes with CGMs on, will typically spend about 92% of their day between glucose values of 70 and 120. That starts tightening up the range a little bit, but likely we want to be between about 70 and 120. For Levels customers, this is really what we encourage people to shoot for, like, don't just shoot for below 140 after meals, probably we should be shooting for more 70 to 120.

For fasting glucose, there's been some really interesting research sort of breaking down this normal range of less than 100 milligrams per deciliter, fasting glucose being normal. What you actually find is that people in the lower range of normal do much better than the people in the higher range of normal. People who have fasting glucose between really about 70 and 85 have much lower risk for future diabetes, future heart disease, other health conditions than people whose fasting glucose is between 85 and 100, which is also considered normal by our standard criteria. Actually, you start seeing this very steep slope of the line of increased risk of future disease, so we also encourage people to really think about tightening up their fasting glucose parameters, and really shooting between about 70 and 85, not just 70 to 100.

Summing that all up, we should probably be spending the vast majority of our day between a fairly tight range of 70 to 120. When we wake up in the morning, seeing our glucose between 70 and 85. Really, ideally, I would say after a meal, we don't want to see our glucose go up more than about 15 points. So, a little gentle rise and then back down. What a lot of people find when they start checking their glucose is that some of their favorite foods might spike their glucose 80 points, 100 points. We've seen people eat normal oatmeal, and their glucose goes up literally 80 to 100 points, or our CEO had a Chick-fil-A sandwich and a soda, and his blood glucose went up to 210. There are lots of foods that we just consider our “normal” that don't even keep us remotely in that range that I'm talking about. What is next is to-- now that we are thinking more about metabolic health for the for the general population, we need to be doing more research to understand what ranges are associated with best current physical and future-- current physical performance, and then of course, risk for future disease. I would guess that we're going to see that it's these tighter ranges that we should shoot for.

Melanie Avalon: This is so fascinating. Yeah, intuitively, that's how I've always felt. I've always felt blood sugar in the 70s is when I feel good, and I’ve been suspecting that it's been creeping up. It's still not that high, but the 80s and 90s. I just feel better on the lower side of that. A few different things you touched on that I just have to ask you about really quickly. Okay, one is actually not really blood sugar related, but I'm just dying to ask you, you mentioned CRP, and for listeners, that’s C-reactive protein. If it's really low, can you still be in an inflamed state?

Casey Means: That's a great question. I think the answer is, yes, inflammation is a very complex set of pathways, and CRP is just one snapshot of looking at that. It is a very, very, very good snapshot. But I think it's possible that you could have other inflammatory processes going on without the CRP necessarily being elevated, but we just don't test a lot of the other inflammatory cytokines that are directly related to health, especially things like IL6, IL11, TNF alpha. Some really longevity-focused doctors are testing these things. Certainly, getting that broader panel if it’s something you're really interested in might be interesting to do. But by and large, if CRP is really low, that's a great thing. It's definitely associated with better cardiac outcomes, and we want it to be lower. But theoretically, yes, I think it's possible, it could be low and there could be other inflammatory pathways that are still perturbed, but I don't know that for sure.

Melanie Avalon: It's a super random question. It's just because I'll feel this state of inflammation going on, but whenever I test my CRP, it's ridiculously low. It's like zero, or like point one. I'm, like, “Huh? I'm so confused, I feel inflamed.” Okay, some other questions that you touched on, about blood glucose levels, and things like that. Glycation, a lot of people on low carb diets, may be in carnivore diets. I feel I see a lot of reports of people having higher blood sugar levels, even while being potentially even severely low carb. Can the negative effects of glycation occur on a carb-free diet if blood sugar levels are still high?

Casey Means: Yeah, so if blood sugar levels in the blood are high, glycation can occur, because really, it's like how much glucose is in the bloodstream, and if that's able to then stick to things in the body. If it's high in the blood, it can glycate things. At the Levels that people might be talking about on the carnivore diet, they still might be like fairly low glucose levels, like 90s or 100s, that might be higher than that, what they want to see, I'm not sure what levels they're necessarily referring to, but I assume they're kind of still fairly, fairly low, certainly, glycation is going to happen at the much higher glucose levels. I imagine is going to be really a linear increase from the lower levels to the higher levels, in terms of like, glucose going up and how much glycation happens. But yeah, if it's in the blood, it can do some of these deleterious things.

Melanie Avalon: Yeah, that makes sense. Then also, while we're still in the low-carb world, people often think that the most insulinogenic things are carbs, but I think meat and protein can release a substantial amount of insulin, even if it's countered by glucagon. Can a person get insulin resistance from just releasing a lot of insulin, even if the insulin is not shuttling blood sugar necessarily into cells? Can that still create that insulin resistance problem? I know that's also diving into the world of like, physiological insulin resistance that a lot of people say might happen on lower carb diets? Yeah, so that whole world of insulin and low carb-diets, and oftentimes people go on low-carb diets, and they feel like they can't quite bring back carbs or they can't tolerate carbs the way they used to. We can talk more about how maybe people can practically use a CGM and learn more about themselves with all of this, but what are your thoughts on all that, on all the issues that can go awry with insulin?

Casey Means: Yeah. Foundationally, we want to be really optimally insulin sensitive and keep our insulin levels low. Low insulin levels are where we want to be. This is not a lab test that we are often checking in standard practice, unfortunately, but I would really highly recommend that people push their doctors to get a fasting insulin level, because it can give you so, so, so much information. I typically like to see people in a range of two to six or so, which is quite low but you can have people out there who have “normal glucose levels” in the blood, they don't meet criteria for prediabetes and diabetes, but have insulin levels up in the 20s, and 30s fasting. Someone with a fasting glucose of 85, who has a insulin level of two is very different from someone who has a fasting glucose of 85, who has a fasting insulin of 25. Because that person with a fasting insulin of 25, their body appears to be pumping out so much more insulin to keep that glucose level at 85 than the other person, which means likely they have gone down the pathway of insulin resistance and their cells just need so much more to drive that glucose in, and that's not a state that we want.

What we really focus on at Levels is improving metabolic fitness, which we like to think about it like going to the gym. It's like you put in your reps to get stronger at the gym and you have to put in your reps to get more metabolically fit. How do you put in the reps? Well, you decrease your glucose spikes day after day, and each day that you are minimizing your glucose spikes, your cells are seeing less insulin, and so they are going to perk up to future insulin signals and so your body is going to have to produce basically less of it to get the same amount of bang for your buck and get the glucose in. Each day that we're keeping those spikes minimized, we are letting the cells hear the signal of insulin more loudly, and ultimately regain our insulin sensitivity. It's not something that happens overnight, it's something that is going to potentially take weeks and months to really, really get those pathways back on track. Long story short, insulin being lower is where we want to be. Insulin affects every cell in the body in lots of different ways and drives a lot of disease processes that are very, very well established.

Like you mentioned, there's other things within glucose that can increase insulin. Specifically, ranking them, glucose and carbohydrates are going to be the most insulogenic. They're going to produce the largest and quickest spike in insulin, followed by protein, which can also increase insulin levels, and then fat very, very, very little, and borderline non-insulogenic. Yeah, so it is possible if we're eating a very, very high protein, low-carb diet, we're actually going to be generating some of that insulin output and potentially moving down that pathway of insulin resistance. You can imagine then-- so if you're focusing on low carb, high protein, and let's say you are maybe a little bit insulin resistant, eating some carbohydrates then might actually show you a higher glucose level than you might imagine, because you're on a low-carb diet. It's pretty interesting. Definitely, more research needs to be done in this area, but yeah, definitely would put a plug in for people asking their physicians to test this. It's one of the most valuable pieces of information that we can get from a standard lab, in my opinion.

Melanie Avalon: Yeah, we talk about this a lot in The Intermittent Fasting Podcast, about testing insulin, and we just think it's really sad that it's not on a standard lab test. Yeah, that's a whole another topic. You're speaking about the spikes, and you mentioned the area under the curve. I wonder about this a lot. Is there something that's better or is one worse--? Oftentimes, we are told, or it's suggested to have meals that lead to a slower, longer glucose response, and I guess, maybe lower compared to like a spike that goes up and comes down shortly or quickly. Is that okay? Say a person eats a meal and it spikes high, but then it goes down pretty fast, and then they're back to baseline, compared to it spikes a little bit, it doesn't go quite as high, but then it's actually-- then their blood sugar that was elevated for longer, but lower, is one of those more beneficial or better, do you know what I'm asking?

Casey Means: Yeah, absolutely. Couple things that brings up. One is just this general discussion of area under the curve. I know your listeners know a lot about metabolic health. I normally don't get into this concept because it's a little bit nuanced, but I think it's actually really important to think about. Basically, if you have a continuous glucose monitor, you can imagine it's picking up data points every five minutes or so. You're going to eat something. Over the course of the next two hours, you're going to build this like bell curve essentially of what happened to your glucose after that. If you shade it in everything under that curve, and just shaded that in, that's going to be some area. You can imagine, you’ve got a couple different scenarios that could happen. You could go straight up and straight down like a super sharp peak, and that area to the curve is going to be medium, it's going to be not super long in the time dimension, but it's going to be high. Then, you could have a really high peak that lasts for an hour and a half. It's a much wider curve, that's going to have a much greater area under the curve. Then, you could have like a really low-carb meal that barely spikes you and comes right back down. That's going to be like a virtually negligible area under the curve. Tiny little spike comes right back down. Then, you could have more of a sustained carb that's a low spike, but it lasts for maybe an hour and a half or so and then comes back down and that's going to be a medium area into the curve.

Melanie Avalon: You said that's so much better than me. That was perfect.

Casey Means: No. I think about it as exposure to glucose. How much exposure is our body having to this? Is it having a lot for a long time or a little for a short period of time? Certainly, I think the one that's best for health is going to be that little spike for a very short amount of time. Basically, no spike, just a little gentle up, maybe 5, 10 points after a meal, 5, 10 milligrams per deciliter, and then comes back down within like an hour and a half. Very little exposure of the body to glucose, and probably very little exposure to insulin as well. Versus the worst-case scenario, which is it goes way up, and it stays up for an hour and a half, and then comes back down. That's just going to be a lot of glucose exposure to the tissues and a lot of insulin exposure.

But then, there's that question of the high peak that comes right back down. My feeling is that that is actually problematic, even though it's recovering quickly. For instance, you have a donut and a piece of cake, and you've had very little protein or fat, you're just eating straight, simple carbs, and you go up to maybe like-- let's say, you're starting at 80 milligrams per deciliter before that food and then you go up to 170, 180, go up 100 points, but you've got a good insulin sensitivity and good insulin response., you come right back down. Well, the problem with that is, one, you have just slammed your pancreas, you have made your pancreas do so much work and just put out so much insulin to soak all that back up really quickly. That's an insult to your body. You're throwing that all on the cells and they have to respond to it and clear all that. That's a lot of work. What also can happen when you have that big insulin surge is that you can overshoot, you can basically suck up too much glucose into the cells and have that episode of reactive hypoglycemia. This is where you actually overshoot your baseline and go lower than you were before the meal.

Reactive hypoglycemia is problematic for a few reasons. It's been associated with that post-meal slump feeling, like having to go take a nap after a meal, sort of brain fog, and also anxiety, like mood lability. There's been very small observational studies that have been published about people who had generalized anxiety disorder and when they moved their diet to one where it was less spiky and less glucose spikes, and much more stable glucose levels, the anxiety really improved. That's not surprising. If you're putting your body on a glucose roller coaster, you may also have energy, mood, cognitive rollercoaster going on. What I love about continuous biofeedback and why I think it's really the future of medicine, is that right now we may have a meal, maybe a doughnut in the morning, because someone brought them to the office and have them in the workroom. We eat a doughnut, and then a couple hours later, we don't feel great, we feel maybe a little bit jittery, we maybe feel a little bit tired, maybe feel a little bit anxious, and you have no idea what to attribute that to. You're like, “Is it because I didn't get good sleep last night? Is it because I just wrote a stressful email? Is it because I ate the donut? What is it, just my personality? What is it?” It's very hard to make a change if you can't attribute the cause. But if you have the glucose monitor, you can say like, “Okay, this is how I feel. This is what happened to my data. It went to 170 and then crashed down to 55. This is what I did, I ate the doughnut.”

Then, all of a sudden, it's not a mystery anymore. We have this whole new enhanced body awareness that's basically biofeedback and formed and we can start to close the loop, attribute correctly, and then make changes. That's really, I think, what we've been missing. It's been so much trial and error with nutrition and lifestyle. “Well, maybe I'll tweak this. I'll get off caffeine. I'll sleep a little bit more. I'll maybe try to avoid sweets.” To just have that trifecta of action, data, and subjective experience and be able to link those three things together, I think that's just revolutionary for making sustained, efficient behavior change. It's just something we haven't really been able to do before in the nutrition realm. So, I'm pretty excited about that, the future of biofeedback and form diets.

Melanie Avalon: It's such an empowering tool, especially if you're trying to figure out what foods work for you. I wish I had had one of these for the past 10 years. In any case, like I said, I originally “cleaned up” my diet when I went low carb and didn't really struggle with blood sugar issues, and then I adopted a paleo diet and I went actually pretty high carb, lower fat, high protein. But with intermittent fasting, I felt I had really good blood sugar regulation, went low carb again, and it was still pretty good. Now, I keep trying to bring back carbs. I just feel it's not working for me. This was before wearing the CGM, just intuitively, I felt my blood sugar is not staying stable and I get hungry. When I first put on the Levels, one of my experiments of trying to bring back the carbs again and I didn't really like what I was seeing on the CGM. Like I said, my fasting blood sugar was in the 90s or even 100, and I was like, “Oh, no,” and so I decided to try going back low carb while I had on the Levels. Everything really normalized a lot, which is a bummer for me, because I'm trying to bring back carbs, but I think having this as a tool-- because without it, it's not that this is a shot in the dark, but when you don't have that 24-picture, like you said, it's hard to know what's what. But when you have a 24-hour monitoring, you can literally see how you're reacting to foods. I think especially for people trying to figure out the macros or the foods that work for them that it's just ridiculously empowering.

Casey Means: I would just jump in. One thing that might be fun to experiment with is really trying to figure out what carbohydrates do work for you because this is what's been so fascinating and really motivated me to really work on this and the personalization aspect is that, and I'm sure you know this, but each person will respond to different carbohydrates differently in terms of how much their glucose elevates. There was this great study five years ago out of the Weizmann Institute in Israel called Personalized Nutrition by Prediction of Glycemic Responses, and basically put glucose monitors on a bunch of non-diabetic individuals, and then gave them all standardized carbohydrate meals, the same carbs for each of them and saw that everyone responded differently to the exact same meal. Some people didn't spike at all, other people spiked hugely. Then, they looked at what factors could predict how someone was going to respond to this carbohydrate load. They identified things like microbiome and anthropomorphic features, body type, and how much sleep people had gotten. It could be interesting to experiment a little bit with all these other levers other than just the carb alone that can mitigate a glucose spike.

Let's say a sweet potato, fairly high carb food, for me, that spikes my glucose highly. How I would approach that using Levels is take that carb that's not working for me and start doing the modification. Pair it with fat or protein, both of which are known to mitigate a glucose spike. Adding tahini or an almond butter sauce, or chia seeds and flax that have fiber and fat and see if that [unintelligible [00:57:05] spike a little. Then the second thing would be looking at food timing. If I eat late at night, I'm going to likely have a much higher glucose response that if I eat it in the morning, because later at night, we have melatonin release, which impacts our ability to secrete insulin and so we might actually see bigger spikes with the exact same food later at night than earlier in the day. Then, experimenting with the other lifestyle modifiers. What if I eat that thing, on a day that I did a high intensity interval training workout in the morning, and I know I'm going to be more insulin sensitive that day? Or, make sure I'm not eating it during a high stress day because cortisol can increase our glucose responses. Then, also do it on a day that I got a lot of sleep because even one hour loss of sleep can reduce our insulin sensitivity. It's like looking at that whole toolbox of stuff that can mitigate our personal response to that exact same carb and see how to shape the overall context for which that carb comes into the body. That has been definitely powerful for me.

I'm vegan, and I eat tons and tons of carbs. I'm able to keep the glucose flat really at this point, because of that very much like contextual approach to putting a carb in my body, so yeah, I'm excited to hear what you learn over the course of testing it out. I just really want to say that I think there are ways to turn the other knob so you can still eat those foods you like and maybe not have as much of a glucose spike.

Melanie Avalon: Yeah, 100%. I'm so glad you said all of that because when I was doing the high carb, high protein, low fat in the past, it was all fruit carbs, and that's what I'm trying to bring back. But I did two days ago, tried rice instead. Very, very bad idea. Oh, my goodness, it actually went up to the 200. I was like, “Okay, we're not doing that.” Funny/good thing is that I was stressing a little bit about the fruit initially, but now compared to that, I'm like, “Okay, I think I can work in the fruit world and make this work because at least it wasn't going to the 200s.” In any case, yeah, so much that you can learn from the tool. I think I misspoke because I was saying that, Gin, my cohost who was doing the PREDICT 2 study, and I said it was a gut microbiome study, but I think just that was one part of it was they tested her microbiome. I'm pretty sure it's a follow-up to that study that you just mentioned, which was mind blowing. Things like a banana would have a huge response and somebody and do nothing to another person, and a cookie would be the same way.

Casey Means: Oh, yeah. Two people, like you and I, we could both eat the banana and the cookie, and I could be a huge spike around the banana, and no spike on the cookie, and you could be the opposite. It's just crazy because it flies in the face of the whole low-glycemic diet concept where we have this standardized chart and we should all follow it because we're all going to have the same glucose rise with these foods and it's like this really shows that that there might be so much more to it than that. It's painful to think that there might have been people who are following these diets very strictly and did not see the progress they wanted to. It might have been because of these underlying factors that just, for whatever reason, changed the way that carbohydrate was processed in their body into glucose. That just super excites me about the future of personalized wearables. Over time, these studies like PREDICT and what Eran Segal’s lab is doing at the Weizmann Institute really looking for, if we have big datasets in this stuff, how can we then potentially figure out these types of the predictive models essentially. If you respond this way to X, Y, and Z, this is probably actually how you respond to A, B, and C, which is really exciting.

Melanie Avalon: I have a really random question. Well, not, I guess it is related. With diabetes, is it true that the primary cause of elevated blood sugar levels is actually from gluconeogenesis in the liver and not from carbs in the diet?

Casey Means: Yeah. Gluconeogenesis is certainly one of the pathways through which we're getting glucose into the bloodstream, it's how we make glucose from other pathways. But I think that certainly my understanding of it is that it's a lot to do with how our body is processing exogenous glucose that comes in the body, and the underlying insulin resistance that causes us to poorly respond to it. But in terms of causes, it's so, so, so multifactorial. There are so many different aspects that go into why someone would become insulin resistant. It's anywhere from eating high carbohydrates over the course of years and decades, and that subsequent-- the constant insulin spikes, insulin resistance that develops. There's lots of information now about more of an intracellular lipid accumulation theory of diabetes, whereby we're accumulating things like ceramides and diacylglycerol, DAG, and other things inside the cell, which are actually causing the insulin receptor to be less responsive to the signal of glucose. There's things like micronutrient status. There are our metabolic pathways, like what happens in the mitochondria to actually process glucose require lots of different nutrient cofactors for those processes, like zinc and manganese, magnesium, B vitamins, and so chronic deficiency of these critical micronutrient cofactors can be involved in the pathogenesis. There's, of course, genetic factors as well.

Then, there's so many other things that can change glucose levels, the medications that we're on, underlying illnesses that may raise glucose levels, chronic stress, and the chronic cortisol associated with stress that keeps glucose levels high, sleep deprivation, and that is the impact of sleep deprivation on insulin sensitivity. You can imagine over the course of decades, how much that can compound. There are just so many elements that are both intrinsic to our biology, but also environmental and our behavior base that are contributing to the development and the pathogenesis of this disease. Actually, last one that's underrecognized but very well established at this point is environmental chemicals and their impact on our metabolic health and our endocrine system. Things like persistent organic pollutants, POPs, and nitrogen dioxide in the environment, these things can actually block our metabolic pathways. Everything from food, insulin, intercellular lipids, liver function, and micronutrients, genetics, environmental, sleep, exercise, stress over the years, all those things feed into the pathogenesis of this disease. There's a lot. It's just amazing and it's just really a testament to how our current world and the world we live in right now, it's really an uphill battle.

Yes, certainly my mission as a physician is to help people understand these different factors and build as many of those into our product and our software. How can we educate people about sleep, stress, exercise, food pairing, food timing, even micronutrients, environmental exposures, all into one app that just helps people understand the comprehensive nature of metabolic health? Well, food is a key driver in our metabolic outcomes. It is necessary but not sufficient for metabolic health. You have to have these other ducks in a row as well. That's really my mission in trying to build a software product that cues people into all these different aspects that ultimately feed into our metabolic health.

Melanie Avalon: Yeah, I could not agree more. I think it's so huge. I've recently become really obsessed with endocrine disruptors and obesogens in particular, and all the messages, the signals that they send in our body that I think people don't quite realize the potency of it, because, “Oh, we're not eating it. We're not putting it in our mouth, and we can't see it.” It's hard to really understand the vast impact that it can have. The gluconeogenesis thing, I heard that-- I was listening to a Peter Attia podcast on metformin. That's where I heard that idea that with type 2 diabetes, the main issue was with the liver producing excess sugar all the time. Actually, speaking of metformin, I did not get metformin, but I did just order berberine, which has been shown to be comparable to metformin. I'm really excited to try it with my CGM and see what happens.

Casey Means: I'm really curious to hear that. That one's been well studied clinically in the diabetic population, and I'll be fascinated to hear what you learn with that. Then, I guess I would say one other plug in terms of testing out supplements, there's a really interesting supplement now on the market by Pendulum Therapeutics, which is a probiotic company that's now approved for type 2 diabetics for lowering A1c and glucose levels, and has not been studied in nondiabetics, but first probiotic that I'm aware of on the market that's actually clinically validated for lowering glucose levels. That list that I gave earlier of all the things that contribute to the pathogenesis of diabetes, another huge one, of course, is microbiome. So, when you were talking about environmental chemicals, not only can they be in endocrine disrupting in their own right and directly impact enzymatic pathways, critical and metabolic health and hormones, but they're also have such an impact on the microbiome, what we're putting in our body, on our food, and our water, this is going to directly impact our microbial biodiversity in the gut, which make these critical metabolic cofactors. Yeah, totally with you on that, endocrine-disrupting chemical train, I think it's way under talked about, and really something we’ve got to address at the societal level.

Melanie Avalon: Yeah. I particularly think our skincare makeup is one of the worst exposures to it every single day. Is that probiotic? Is it a strain I never heard of, or is it a specific blend of lacto or bifidobacteria strains?

Casey Means: When I first thought about, I thought I was going to be like bacteroides, or bifidobacterium, or something like that. I'm forgetting the exact strain. I believe it's just one strain. I's been clinically studied. I'm really curious to try it even, certainly, it's not what it's indicated for, because it's for people with type 2 diabetes, and it hasn't been studied in non-diabetics, but it'd be interesting to see if it can even move the needle in someone who's fairly healthy.

Melanie Avalon: That's fascinating. I have to look into that. I'll put more information in the show notes. Quick question, because I ask listeners for questions for this show. One of the questions I thought was really good was, she wanted to know, is a two-week monitoring period, although you said it is a month, because you get two sensors, but is that enough time to learn about yourself? During that period, that two week or that month period, do you suggest following your normal diet for a certain amount of time, making changes? How should people best approach that two week or that one-month trial period?

Casey Means: Yeah. One month is really the perfect amount of time to do it. I certainly think doing it longer is excellent. You can even learn more. Then shift into maybe you've learned a ton, and then you're using it more for accountability, which is I think where I'm at, where I'm really using it as my accountability tool.

Melanie Avalon: You said, you've been using it how long?

Casey Means: Almost a year and a half. I can't even imagine taking it off.

Melanie Avalon: Like not having it would be-- you feel naked.

Casey Means: Yeah, I feel super weird without it. I do find myself making different decisions without it. My team, we all of course, share our glucose data, write each other a little bit if we're going off course. That accountability is super fun. Yeah, I think a month is a really great amount of time for developing metabolic awareness and starting to build out your metabolic toolbox of what are these levers you can pull to keep your glucose more stable. I think the best way to approach the program which we lay out in the app and in our program guide is the first week is really exploration. Your normal foods, eat what you love, and see what happens. What is what you've been eating been doing to your glucose? I think that's pretty fascinating, the first week is just try not to modify the diet and just eat what you normally eat and make some observations there.

Then moving into the second and third week, it's really about experimentation. What happens when you've had a good night of sleep versus a bad night of sleep? What happens when you do yoga versus high-intensity interval training? What happens if you add a lot of fat to your carbohydrates versus no fat? What happens if you take berberine? What happens if you take an apple cider vinegar shot before your meal, which in many studies has been shown to lower glycemic responses? What happens if you add cinnamon to your oatmeal instead of no cinnamon, which cinnamon is shown to be an insulin synthesizer? Try these different things. Also really suggest try walking after meals and see what that does. That's really just exploratory. We have some challenges that we can guide people with to help them, create these experiments for themselves, and really just start to see like how these other factors are impacting the response.

Then, fourth week, I would really move into optimization phase. Take what you've learned from your experiences, and just try and keep it flat and stable. That's really the time to see how much you can move the needle with everything that you've learned.

Melanie Avalon: If listeners do it for the month, how does it work, if they want to keep getting more sensors, is it starting over again? You still have the account, is the price the same? How does that work if they do want to use it indefinitely?

Casey Means: Yeah. Right now, we're really set up mostly for this one-month program, but people can subscribe if they want to. We do have a very large number of people who want to subscribe. The main issue there is really is price point. The hardware right now is still quite expensive. The thing is, is that that is going to change, I think, rapidly in the next 6 months to 18 months. There's a lot of hardware companies coming down the pipeline, and people really innovating for new hardware. I think we're going to see a huge drop in the prices as this technology becomes more and more widely adopted, especially by a wider market. As those prices change for hardware, it's going to be much more amenable to a subscription-type product where people can use it long term. That's the main barrier now. But if people do want to subscribe, we can do that for people for essentially, it's half the cost of the first month, because they don't have to go to the physician consultation again. We will just essentially ship them to new sensors for the month to continue working with the app and with the program. But I think over time, we're going to see-- it could be people being able to use this more for six months, a year, as long as they want, as long as it's valuable for them as the prices come down.

Melanie Avalon: Awesome. It sounds like the trend with blood glucose strips or testing ketone strips, even though this is a slightly higher price point than that. We'll have to keep our fingers crossed that it keeps dropping. Within the app, because there are different scores that it gives you, because I got a lot of questions about, can the everyday person interpret the data? How will we know what this all means? What are the different scores that the app gives you? What user data can you input because I know you can log your meals and things like that? Within that the world of the app, how does it help users to learn the most that they can from their CGM data?

Casey Means: Yeah. In terms of data that you're inputting, so obviously, you've got the continuous glucose data stream. Then, people are logging their food in the app manually. We try to make this as easy as possible with just a really quick photo of your food and you can go back and annotate it later and put in the ingredients. Then, people can import their data through Apple Health kit or Google Fit to start getting their activity, sleep, heart rate data in there, so they can start correlating that with their glucose. That's the data input. Then, in terms of the interpretation, that's really what we're trying to make easy for people. It's tough to know whether going from 80 to 126 after a meal, what is the impact of that? It's tough to know. We've created two scoring systems to make it easier for people. One is what's called the Zone Score, and one is called the Metabolic Fitness Score.

The Zone Score is a score that's graded from 0 to 10. It basically tells you how good or bad your meal was metabolically for you. A 10 is a perfect score, 0 is a failing grade. This takes into account a lot of different aspects of the response to the meal. Things like how long were you elevated? How high did you go? How far did you rise from baseline? Where did you start out? What was your glucose before you started? Just taking into account a lot of these different factors that we know are important for health and then turning them into one very simple composite metric, with the Zone Score. What's really cool about Zone Score is that it doesn't just take into account the food you ate, but also anything that you did around that meal. Clearly, if you eat a meal and then take a walk, both of those things are going to impact the glucose outcome. It's not just a meal score, it's actually what happened in that zone.

Then, there's some neat comparison features where you can compare zones, so you could do oatmeal followed by a 30-minute walk and that Zone Score may have gotten 7, and then oatmeal followed by no walk, and that Zone Score may have gotten 5. Then you could do like oatmeal followed by gave a really stressful talk to my company, like high stress, and that may have gotten 2. Then, you can graph those really nicely to basically show, okay, so this plus walk was the best, this plus no walk was worse and this plus stress was absolutely the worst. That starts helping people guide them towards that metabolic toolbox and what metabolic awareness.

Then, the Metabolic Fitness Score is a longer-term metric. This is actually looking at your whole day and giving you a percentage out of 100 of where you stand metabolically. This is taking into account the more longer-term metrics about the day, like, how many spikes did you have? Which is a term called glycemic variability. What were your averages throughout the day? How much glucose exposure basically, did you have? How quickly did you recover from your glucose spikes? And that's more of that. That longer-term metric that tells you a little bit more about where you're standing. Not just what a meal did to you, but how you might be standing overall on your metabolic health. Those are the two main scores we use to try and really make it easy for people to understand.

Melanie Avalon: That metabolic score, is it based on what you were saying earlier in the show about the ranges of 70 to 120 in like 92% of the population being a certain amount, what is it based on?

Casey Means: Our optimal range that we tell people in the app is 70 to 110. The more people stay within that range, the closer they're going to be to 100 on their Metabolic Fitness Score. But even within 70 to 110, people can be super stable and low, or they can be super up and down. You still might not be 100% on your Metabolic Fitness Score if you're going up and down all the time, even within the healthiest range, or people might be living in the higher end of that range versus the lower end of that range. All those things are taken into account to give this score. It's a score that's under constant evolution. We are growing our user base, we're in a beta program right now, we've had about thousand people go through the program, but certainly refining the score as we learn more from the data.

Melanie Avalon: That's the amazing thing about apps, that they can constantly be updating and constantly making them-- adjusting from user data and all of that. That's actually one thing. Do you anticipate having an update? Right now, well, I guess it might be different too, if you use the other CGM, is it Dexcom?

Casey Means: Dexcom. Yeah.

Melanie Avalon: Right now, you scan with the FreeStyle Libre app, and then it pulls the information to Levels. Do you anticipate making it a one-stop shop with direct from the Levels app?

Casey Means: Yes, that is definitely the goal. We're moving in that direction as rapidly as we can.

Melanie Avalon: I have some other just random rapid-fire questions. I know we're running up on time. One is, do you think there will be a development-- Right now, at least with the FreeStyle Libre, and I don't know how the Dexcom, how often you have to scan it, but it stores data for eight hours. You do have to scan at least every eight hours, if you want to have the full picture. Do you think they'll make updates in the future where it'll store 24 hours?

Casey Means: Actually, what is so exciting is that, both companies Abbott and Dexcom, now made Bluetooth sensors. These are going to actually send the data without having to scan it with your smartphone, which means that eight hours is going to become obsolete, because it's going to be sending the data all the time. The Abbott just released what's called FreeStyle Libre 2. It was just FDA approved and is making its way to pharmacies in the US, and that is Bluetooth and it's going to send every 15 minutes that data to the phone. Then the Dexcom G6, which is the current model that's widely used from Dexcom right now is already Bluetooth enabled, so that sending the data every five minutes to your phone. That's very, very exciting because it can be tough sometimes to remember to scan every eight hours. Usually in the beginning of the program, people are scanning every five minutes, and you don't really want to see that data constantly, but with the Bluetooth capability, it's just coming automatically. No scanning required and you're going to have that higher fidelity data stream as well, because there's going to be no gaps.

Just to clarify where people are listening, with the non-Bluetooth enabled older sensors, you have to hold up your phone to the sensor to transmit the data. It's called NFC, near field communication. You actually have to have it close by. Since the sensor only stores eight hours of data, if you wait nine hours to scan, you might lose an hour of data. That technology has just been advancing rapidly. We're excited about the Dexcom offering coming up very, very soon with us. Meaning that we're going to be able to prescribe and send Dexcoms to individuals, because you've got that Bluetooth capability and you also have a really nice feature on the Dexcom that gets back to the accuracy question, which is a calibration feature, so you can do a finger prick at home and actually calibrate your sensor to make sure they're as accurate as possible.

Melanie Avalon: Oh, that's interesting. Yeah, because right now with the eight hours, because I usually sleep longer than eight hours, so it’s like I wake up in the middle of night and scan, which has been my blue light blocking glasses on in the middle of the night. I know my listeners are going to want to know, is the Bluetooth a problem with EMF? Is there an option still do it the old school way?

Casey Means: That is such a great question. I don't know the answer to that. If you can disable the Bluetooth and [unintelligible [01:20:26] build a communication. I'll look into that.

Melanie Avalon: Or if it's only Bluetooth, can it be put into maybe airplane mode?

Casey Means: I see that, not have it transmitting, and then just downloading all the data every certain-- I don't know. I’ve got to look into that. It's a great question.

Melanie Avalon: I know, they're going to want to know. Then, okay, so there's one larger general question that I meant to ask way earlier, but could you just briefly explain the difference between blood glucose levels, HbA1c, and fructosamine, which I feel like doctors don't usually test fructosamine, but it seems apparently, that might be the perhaps more accurate indicator of your blood sugar load.

Casey Means: Blood glucose value is just like you can imagine like the level of circulating glucose in your circulatory system. When you eat carbohydrates, glucose is, you digest the carbohydrates in it, it enters through your gut lining into the bloodstream, and you get this glucose surge. That glucose level, the body tries to keep it in a very stable range as much as it can, it doesn't want it to get too low, it doesn't want to get too high. We really need it to stay within a fairly narrow range for just optimal functioning of the body. Then, we talked earlier about the different ranges for glucose levels. The ones that you're going to hear about most clinically is under 100 milligrams per deciliter for a fasting glucose being considered “nondiabetic normal.” That's just circulating glucose.

Hemoglobin A1c is a longer-term assessment of your average glucose levels. This is actually taking blood and they can test in a lab, this can't be done at home, but can be done in a lab, how much of the hemoglobin and your red blood cells has sugar stuck to it. That's glycated hemoglobin. Hemoglobin is the oxygen-carrying molecule in the red blood cells. Since red blood cells last about 90 days in the bloodstream before they're recycled, this can tell us essentially a 90-day average of our glucose levels, which is in some ways helpful, because you can get a sense of generally where your average glucose levels were. But what it doesn't tell us is how much ups and downs you had, so it totally misses like the whole glycemic variability part of things. Your average glucose might have been 110 throughout the month, 110 milligrams per deciliter, which might lead to a certain A1c level, but is that because you stayed right at 110 the whole time, or is that because you were going up to 150 and crashing to 60 and 70 all throughout the month? And those two things are going to be very different health statuses. You don't want that up and down swing, you want the stability. It's a helpful metric of sort of general long-term averages for your glucose, but missing quite a bit in terms of the granularity of the ups and downs, and, of course, missing the biofeedback element, because it's not going to help you really figure out what in your diet was the thing that was the problem.

Then, serum fructosamine is kind of similar to hemoglobin A1c in the sense that it's a glycated protein that can also enable assessment of long-term glycemic control in patients with diabetes. This is measured in relation to serum albumin levels because reduction in serum albumin will lower fructosamine value. That's a test that's not frequently used, but I have seen very, very few doctors order this test. Hemoglobin A1c is much, much more sort of mainstream, I'd say.

Melanie Avalon: I read it was potentially more beneficial, because hemoglobin A1c, that could be false, I don’t know it can be false positive or false negative. Sometimes people on lower-carb diets, perhaps their red blood cells were living longer, so they were showing higher levels of glycation, but it was because they weren't dying earlier, and so fructosamine me might be more appropriate.

Casey Means: There's a lot of issues with hemoglobin A1c. One is the missing variability component. It's just really telling you more averages, and the other is what you just said, which is that people have a lot of variability in their red blood cell lifetimes. 90 days is about on average, but it could be 90 to 120 days. Hemoglobin A1c tends to pick up more preferentially what the most recent glucose was, so closer to the time of the test. So, it might be skewed higher or lower based on what happened really close to the test and not necessarily be the best snapshot of the full picture. I think we're going to definitely move into a world where dynamic tests like wearing a CGM for a week actually will end up becoming diagnostic tools because you can just get so, so much more information about someone's just baseline metabolic health based on seeing what's happening to the glucose over time. Like, what their one week average is? What their area under the curve is after their meals? This is stuff that's really interesting. Michael Schneider, the Head of Genetics at Stanford, he has published a paper a year or two ago called Gluco Types, which is like different types of people basically, based on their continuous glucose monitoring curve and their risk for future issues. I think we are hopefully going to see a movement towards tests like that, that are more dynamic and more accurate in terms of predicting the future for people.

For now, what we've got is a A1c, fructosamine which is much, much less used, fasting glucose, and then the results of an oral glucose tolerance test, which is, like I mentioned before, chugging the 75 grams of glucose, and then looking at the blood glucose at 30 minutes an hour and two hours after that. Those three things, fasting A1c and oral glucose tolerance tests are the three standardized criteria for diagnosing diabetes in the US.

Melanie Avalon: Yeah, that was actually a question from a listener. She wanted to know if there was the potential that in the future, instead of an oral glucose test, maybe for pregnant women, if they could do CGMs. Do you think there might all be in the future of like the medical system?

Casey Means: I very much hope so. It's something that I'm personally pushing for because, one, I think, especially with gestational diabetes diagnostics, we probably should not be having pregnant woman chug 75 grams of glucose with-- some of them have, artificial dyes in them. It's just yucky. But also, it's just a single snapshot. It could be different on a Monday versus Tuesday versus Wednesday based on hormone levels, and how much sleep they got and how much stress they had in the parking lot before the test. I don't think it's probably capturing all the nuances of someone's current health. I would really love to see us to be able to clinically validate the results you're seeing on a CGM, and how those correlate with these other diagnostic tests, so we can start moving towards like this more nuanced diagnostics with CGM. I think it would be really positive for people.

Melanie Avalon: That's so exciting. She literally said, “Can MDs please petition insurance companies with this rationale?”

Casey Means: I'm on it. For the average person walking around with maybe a normal A1c, like totally normal, their doctor says they're normal, but then they would put on a CGM, and their doctor might see huge variability, and big spikes after meals, but they just haven't gotten to that point where the insulin resistance has tipped over into just really high average glucose levels. That person, you could potentially capture them and find out that they're at risk so much earlier than just waiting for their A1c or their fasting glucose to rise. What I'm most interested in, how can we capture more of the at-risk population through these other aspects of glucose that we know are clinically important, like glycemic variability in AUC that we're just ignoring right now. Maybe we could intervene so much earlier for these people who are certainly on the spectrum of moving in the wrong direction of metabolic health, but their lab tests that we standardly order just aren't showing it yet.

Melanie Avalon: Yeah. This is so incredible. I know all of that is on the doctor petitioning side of things. But I think what you're doing, bringing it into the popular vernacular, making it a thing, I think is so huge for the movement of making for progress, just in general, on the health side of things with patients, as well as the general public, like you're doing so. Thank you so much. I'm so grateful for your company. I'm so grateful this conversation was incredible. Really, really amazing. Right now, Levels is on a waitlist, which is it still around 40,000 or so?

Casey Means: It is, yes. Right now, you can sign up for the waitlist on the website, levelshealth.com. we're in a closed beta program. We're working through the waitlist as quickly as we can. Yeah, we're hoping to just really grow and scale our operations in the next coming months so that we can just get everyone access to this product who wants it.

Melanie Avalon: Well, so the show notes for today's episode will be at melanieavalon.com/levels. But if you are interested in getting on board with us, you can go to melanieavalon.com/levelscgm, that will actually-- I think it'll put you to the front of the waitlist.

Casey Means: Yeah, so it lets you skip the 40,000-person waitlist.

Melanie Avalon: Very exciting.

Casey Means: Yeah. As a person waiting a long time, you can get to the front of the line. So excited to do that for your listeners.

Melanie Avalon: Thank you so much. I really, really appreciate that and I know my listeners will as well. That brings me to the last question that I ask every single guest on this podcast which relates to that. It's just because I'm realizing every single day how important mindset is surrounding everything. What is something that you're grateful for?

Casey Means: I am so grateful that I actually got to spend the last five weeks-- I live in Portland, Oregon, but I got to spend the last five weeks in rural Pennsylvania in Honesdale with my partner's family. We actually left Oregon because of the wildfire smoke last month and flew out there. It was just so wonderful and peaceful that we stayed for five weeks, his poor family. I live really in an urban environment here in Portland, and I was in a cabin looking out over a valley of leaves changing, and it really helped me incorporate health behaviors into my daily life in a way that was, I think, even better than I do here in Portland. I was sleeping on a sleeping porch. I was actually breathing fresh air all night. I woke up to seeing leaves. I woke up to the sunshine, and could not look at my phone for the first half hour of the day because I was just like, “There's so much beauty to see.” I was able to brush my teeth standing outside, looking at the leaves, and just everything on the property. You have to walk a lot more, so I was moving a lot more throughout the day, I was less artificial light, sleeping with this fresh air. I also just read that book, you mentioned this on one of your previous episodes, the James Nestor book, Breath, and I loved it. So, I was doing a lot of the breath stuff while sleeping outside. I think it totally changed my dreams. I was dreaming more.

It just was everything related to stress, sleep, exercise, and food. They're very, very healthy. They have a beautiful organic garden in their house. I was working remotely from there, from this deck, being outside. All aspects of just health behaviors were just easy. I was also just around family, which was wonderful, just people that were just so loving. It just was such a reminder of how much our environment shapes our health and to really just seek out environments that are going to encourage your best self and your best behaviors, for doing those behaviors every day that are going to generate the conditions in the body that are associated with feeling great and doing good work. I'm just so grateful for that time. Sorry, long answer to that, it was really special, and it really made me reflect on how much our lived environment and our surroundings have an impact on the way we live.

Melanie Avalon: I love it so much. That's why I love asking that question at the end. I think it's my favorite question every episode because it's just so wonderful to hear and just puts a smile on my face, it so important. Thank you. This has been so amazing. I can't wait to share it. My listeners are going to love it. Friends, get a CGM, it's going to blow you away what you can learn and I'm really excited to see the updates in the future and where this all goes because-- thank you, you're doing really incredible work. Thank you.

Casey Means: Thank you, Melanie. You are also doing incredible work and it was so great to chat with you. Thank you so much for having me on.

Melanie Avalon: Thanks, Casey.

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