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Ep. 383 Exploring Metabolic Medicine: Insights to Optimize Health with Nick Norwitz


I am thrilled to have Dr. Nick Norwitz, a researcher-educator on a mission to mainstream metabolic health, joining me today. Dr. Norwitz is a Dartmouth College graduate who completed his Ph.D in metabolism at Oxford University before attending Harvard Medical School to complete his MD. 


Dr. Norwitz is passionate about teaching and encourages everyone to join the growing camp of metabolic health enthusiasts who will be instrumental in changing the world. In today's conversation, we explore the complex and controversial world of non-nutritive sweeteners, covering several topics, including the effects of allulose on PCOS, metabolic medicine, and the research on how gut sensor cells impact our preference for sugar over sweeteners. We look into studies on sucralose, commonly known as Splenda, and Dr. Norowitz shares insights from his Oreo LDL reduction experiment. We also touch on our human tendency toward simplicity and confirmation bias, the importance of bio-individuality, and the concept of N=1 medicine.

Dr. Norwitz is committed to remaining curious. He will return to the podcast later this year to share more about the research on metabolic health, muscle, and metabolism. I know you will love this discussion, so stay tuned for more.


IN THIS EPISODE YOU WILL LEARN:

  • How the different molecules that exist within various types of non-nutritive sweeteners impact our biology

  • Dr. Norwitz explains how his view on non-nutritive sweeteners has shifted over time.

  • Why is allulose such a unique non-nutritive sweetener?

  • How the brain can distinguish between different sweetener molecules, and why that can drive changes in behavior  

  • Dr. Norwitz explains how the hypothesis that sucralose may cause insulin resistance, was proven incorrect.

  • Why some non-nutritive sweeteners may be more problematic than others

  • Dr. Norwitz shares his approach to creating engaging social media content and discusses his famous Oreo versus statin experiments.

  • Why Dr. Norwitz believes that there should be more studies on lean mass hyper-responders

  • How dietary changes affect LDL cholesterol levels

  • What is N=1 medicine?


Bio:

Dr Nicholas Norwitz is a researcher-educator whose mission is to “Make Metabolic Health Mainstream.” He graduated Valedictorian from Dartmouth College, majoring in Cell Biology and Biochemistry. He then completed his PhD in Metabolism at the University of Oxford before attending Harvard Medical School to complete his MD. 

Nick’s enthusiasm for the field of Metabolism derives from a personal struggle with severe Inflammatory Bowel Disease. In desperation, he found a ketogenic diet put his disease into complete remission where conventional approaches failed. And he became curious…


Fast forward, and Nick is now completing the last months of his dual doctorate, with a distinctive determination to upset the intellectual and social environment with respect to metabolic health. His mantra is “Stay Curious,” he has a passion for teaching and wants to invite everyone to join the growing camp of Metabolic Health Enthusiasts who are going to change the world.

 

“Even beyond the mouth, your brain can figure out differences in taste because you have receptors throughout your gut and other places in your body.”

-Nick Norwitz

 

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Transcript:

Cynthia Thurlow: [00:00:02] Welcome to Everyday Wellness podcast. I'm your host, Nurse Practitioner Cynthia Thurlow. This podcast is designed to educate, empower and inspire you to achieve your health and wellness goals. My goal and intent is to provide you with the best content and conversations from leaders in the health and wellness industry each week and impact over a million lives.


[00:00:29] Today, I had the honor of connecting with Dr. Nick Norwitz. He's a researcher, educator whose mission is to make metabolic health mainstream. He is a graduate of Dartmouth College, completed his PhD in metabolism at the University of Oxford before attending Harvard Medical School to complete his MD. His mantra is stay curious. He has a passion for teaching, which will become very evident, and he wants to invite everyone to join the growing camp of metabolic health enthusiasts who are going to change the world.


[00:00:57] Today, we spoke at great length about non-nutritive sweeteners, how they are both controversial, complicated and nuanced, the impact of allulose on PCOS, the role of metabolic medicine, research surrounding the preference for sugar over sweeteners depends on gut sensor cells, as well as research specific to the use of sucralose, aka Splenda, is Oreo LDL reduction experiment, why humans are wired for simplicity and have a degree of confirmation bias and lastly, the role of bio-individuality the N of 1 medicine. 


[00:01:34] I know you will love this conversation. Dr. Nick will be back for a round two later this year where we will dive deeper into some key pieces of research that are relevant to listeners that are specific to metabolic health, muscle and metabolism. 


[00:1:54] It is such a pleasure to have you on the podcast. I know we've been working hard to make this come to fruition, and I'm glad were able to make it happen right now. 


Nick Norwitz: [00:02:02] Thanks for having me. Excited to be here. 


Cynthia Thurlow: [00:02:04] Yes. I would love to start the conversation around non-nutritive sweeteners. I think that there's a lot of good information/misinformation that's ongoing. I know that one of your recent YouTube videos, you were talking about allulose and why this is such a unique non-nutritive sweetener. Talk to us about how it works mechanistically, and what the research is suggesting, and mouse models, how it is impacting our health or potentially our health as a human. 


Nick Norwitz: [00:02:35] Yeah. If you don't mind, I want to take a step back and take a 50,000-foot view on how I used to think about non- nutritive sweeteners and how I think about them now. That is I think there's the one bucket of thought, which is they don't have calories, they're not a problem. There's the other bucket of thought, which is that there's no such thing as a free lunch, so they must be doing something bad. I think both are a little bit extreme and misrepresentations. 


[00:03:02] The first thing to recognize is that the universe of non-nutritive sweeteners is diverse molecules, just like there are diverse fatty acids, and myristic acid and linoleic acid aren't going to have the same effects on our biology. It's a whole heterogeneous class of molecules. Some natural, some unnatural. Good versus bad doesn't even necessarily partition with natural versus unnatural. 


[00:03:24] So, this is a very complicated topic that I think one deserves nuance and two deserves an appreciation of the fact that there are a lot of unknowns. And so, I could cite some really interesting studies, for example, with respect to say, aspartame, which is in Diet Coke, and anxiety and transgenerational inheritance of anxiety traits, which we can get to, I think is pretty cool. And then somebody could push back and say, “Well, that's not in humans.” And I'm like, “Well, you're not going to have an RCT looking at transgenerational effects as a sweetener in humans.” 


[00:03:52] So, you have to take the literature for what it is at present and what can actually be collected in terms of actual human data, and then, like any tool, make a logical evaluation, “Is this something I want to use for myself?” So, at a high level, I just want to say, I don't think they're good non-nutritive sweeteners. I don't think they're bad, per se. They're a tool, and all I want to do is provide data for people to make informed choices and start there. 


[00:04:18] So, we can now answer your question about allulose. Of all the non-nutritive sweeteners, I find allulose the most fascinating and most likely, potentially beneficial. At a high level, it's a kind of cousin molecule or twin molecule of fructose. So, it's called an epimer, the C3 epimer. So, it doesn't get processed by the body like fructose, because enzymes in the body are like gloves. They're like right-handed or left-handed. And so, you can think of like, the body's enzymes are a right-handed glove that fits on fructose, which is right-handed, and then allulose is the left hand. At a high level, you can think, “Oh, it displaces fructose from the diet.” Fructose has unique harmful properties. We can talk about those. 


[00:04:59] So, on the one hand, it's like, “Oh, cool, you're getting fructose out of the diet.” But that's only the tip of the iceberg. Allulose has really interesting metabolic properties like that it induces the production of GLP-1, which is the hormone that drugs like Ozempic and Wegovy try to mimic. Now, those are mouse data, but they're still pretty interesting that it would even do that. And the mechanisms by which it would do that, it was via a Nature Communications paper. But I think that there are some potential benefits of allulose. 


[00:05:27] So, for example, in let's go to the human trials. Human randomized controlled trials has been shown to not only not increase insulin and not increase glucose, but attenuate, reduce the effects of sucrose on humans. So, if you take 50 gm of sucrose with allulose, the net effect will be lower on your insulin and your glucose versus just having the sucrose. So, I think that it's a tool that you could use displacing sucrose or fructose. Beyond that, there are some interesting metabolic properties that we're only beginning to explore. One can speculate based on the physiology, but in terms of the human data, they're still outstanding, but something that I'm interested in pursuing. 


[00:06:07] So, this morning's video was on PCOS. It was actually about a new mechanism that was discovered about how a microbiome bug, a microbiota, produces a metabolite that acts on an axis to reduce GLP-1 levels, and that that might contribute to PCOS. So, even in this mouse model, if they took a GLP-1 receptor agonist, like an Ozempic class drug and gave it to mice, secure their PCOS, which is really interesting. And so, you have to start thinking at the base physiology, at what different points can we attack this new understanding of a causal pathway, a contributing pathway, it's not the only one, I would say, PCOS, to potentially help patients. 


[00:06:44] Yes, we can always wait for RCT's, but you can also experiment with, I think dietary interventions beforehand on N equals 1 basis provided they're safe. So, that was a lot. I'm going to pause. I have a tendency to ramble. So, if I do, just cut me off and say, “I have a question or you rambling. My audience is going to like this.” 


Cynthia Thurlow: [00:06:59] No, no, no, this is very, very important. I love that you led with talking about how non-nutritive sweeteners can be nuanced and complicated, because I think there has a tendency, whether it's on social media or when mainstream media picks up information, they want things to be very rigidly dogmatic and polarizing. Really what I'm hearing from you is there's some interesting information and research that's coming out around this particular non-nutritive sweetener, and then making it relevant, because PCOS is the number one endocrine disorder in women. It's not hypothyroidism. It is actually PCOS, and so many women are under diagnosed. The thought processes that you have to be obese or overweight to have PCOS. 25% of women with PCOS, myself included, are thin. It's this thin phenotype. 


Nick Norwitz: [00:07:48] Yeah.


Cynthia Thurlow: [00:07:50] And so, I love that you tied in that piece of understanding that this deficit in PCOS and animal models can mechanistically be improved upon by utilizing this non-nutritive sweetener. 


Nick Norwitz: [00:08:05] I just want to clarify, because I think I was doing a poor job of communicating the point I was trying to make, which was in this paper, they weren't looking at allulose. They were just dissecting this axis. Now, trying to be a scientific communicator in media spaces, you always try to draw a takeaway, so what for someone, especially, I'm not going to prescribe GLP-1 receptor agonist, nor can I over YouTube. That's silly. So, you're like, “All right, here's the physiology. How can we apply it?” 


[00:08:32] In my tweet this morning, I was reflecting on that, because I used the term nature's Ozempic in the thumbnail, at least the original thumbnail. I'm talking about GLP-1 And a podcast recently came out. I was listening to, it was Dr. Zachary Knight on Huberman Lab, and he made a good point, which is that could potentially be misleading, because the GLP-1 receptor agonist class of medications, Ozempic, etc., they work because they induce supraphysiologic doses in very, very high, much more than any food product could induce in you. And so, could it potentially be misleading? 


[00:09:02] I wasn't talking about the data. I was very clear. Don't show allulose treats PCOS. But I was speculating based on the physiology and what I've seen in other trials, including mouse trials, where, say, allulose actually does both induce GLP-1 levels to go up and protects against Western diet induced obesity with stevia as a control. So, it's like you have this-- I had somebody that was not in a scientific space try to explain it to me as they saw it as the transitive property. You have this thing. It induces GLP-1. And then you have a clinical effect that is consistent with the clinical effects of GLP-1 reduced obesity. He's like, “Via the transitive property, it must be that X, Y, Z.” 


[00:09:45] That's actually not accurate scientific logic. I think this is a good moment to pause and have that teaching point, which is you can have a true, true unrelated phenomenon. Just the fact that say allulose induces GLP-1 and might have metabolic benefits doesn't mean it's working through GLP-1. There are ways to dissect that. But I think it's just an important point to raise, because the last thing I want to do is make people think that you can just take an RxSugar bar, which is an allulose company, and treat your PCOS, because it might not be that simple. It's more a matter of here's the physiology of what we understand, here's what we don't understand and here's an interesting potential application. But I don't really know the limits of this knowledge. I also don't think it's fair to conclude that you couldn't have benefits from lower doses because you're acting via a different mechanism. 


[00:10:32] For example, it could be truly unrelated. It could be also that endogenous production of GLP-1. So, you change your lifestyle, for example, you reduce inflammation in your gut, you have something that's a GLP-1 inducer, you're then promoting more of your own body's production of GLP-1, which is going through a different system, the portal vein to the liver, which is the hub of metabolism and you might have more GLP-1 of bioavailability in the gut. 


[00:10:56] There's some interesting data from 2019 showing that in obesity, GLP-1 production is reduced, but also GLP-1 bioavailability, because there are these immune cells in the gut with their own GLP-1 receptors that'll gobble up the GLP-1 before it gets to the body. And then you compare something like endogenous production of GLP-1, it's going to deliver versus injecting yourself with semaglutide or Ozempic. Now, those are two very different things. They could have different physiologic outcomes. I think we are afraid often to say in medicine, I don't know. And right now, as a communicator, I'm waffling between this space of, I want to give you an actual takeaway, but I don't want to oversell it. I want you to have the nuance there. So, I don't know if I'm doing a good job unpacking all that, but I think it's a fun thing to struggle with and start to have a conversation about. I invite everyone listening to give me feedback on my communication, if I'm being utterly confusing or if something I'm saying is landing to you. 


Cynthia Thurlow: [00:11:48] No, no. One of your gifts of many is that you have the ability to take complicated information and make it accessible for the masses. And so, this is one of many reasons why I wanted to have you as a guest. 


[00:12:03] Before we move forward, what I would love for you to do is just to give listeners a bit about your background, because it is quite unique and it will provide some context into the research aspects, the medical aspects, kind of marrying themselves together, because you're in a very unique position. 


Nick Norwitz: [00:12:22] Thanks. Yeah, I'll try to be concise in my story, which is, I grew up always wanting to be a physician. My parents are physicians, also scientists. And so, that was always the career trajectory I was set on be a physician scientist. The pinnacle of that for me was like, “Oh, go to the best college, the best med school, do the whole MD-PhD thing, which I ended up doing, but in a unconventional way, because while I had the most respect for Western medicine at the time came in my life, where it wasn't working for me, despite access to the best healthcare systems in the world. 


[00:12:55] Well, I had a couple things go on with me, some weird case of osteoporosis, which ended up being a rare genetic mutation. But then at the end of college, I developed inflammatory bowel disease. It got really bad to the point that after graduating college and going to grad school at Oxford for my PhD, I ended up in and out of ICU palliative care like 100 pounds, bleeding bloody diarrhea 20 times a day. I guess I could describe it as frustrated state, where there was this possibility that the world was my oyster. So, at that point, not to give you a true sense of where my mind was at although it's going to sound a little bit like braggadocious, but I just graduated Ivy League College Valedictorian. I had a position at Harvard Medical School and a fully funded scholarship at Oxford, like the world could be my oyster if only I could get out of this damn hospital bed. 


[00:13:48] At the time, I couldn't do my work. Getting up and walking to lab was like a marathon for me. I say like a marathon, because a few years before, I was running sub-3 marathons. Every Sunday I get up, I'd run 20 miles like nothing. To go from that and being a high performing academic to being like I can barely roll over in bed, barely walk to lab, my brain is complete fog. No matter what drug I try, I can knock it better and I feel terrible. And then beyond that, social life, dating, you got to be kidding me. Imagine asking a girl over where there's a chance that you're just going to have blood and diarrhea all night. It's not a very romantic setting. So, my life was, pardon the pun, in the toilet. 


[00:14:31] I was quite desperate. So, I started just trying things, because there was nothing to lose. Eventually, I tried a ketogenic diet, and it worked for me, really well. I started feeling better, and my inflammatory markers dropped. And then I ended up getting a biopsy years later, and I've been in remission, biopsy proven remission, for five years now. So, that's what drew me into the metabolic health space. Just to be clear, I don't consider myself in any given camp. A ketogenic diet worked for me. That doesn't mean it's the silver bullet for everything. But it did show me the power of what I call metabolic medicine, targeting root cause physiology to address the chronic diseases that plague society today, and just the true power of that. And so, that's what drew me into the space. 


[00:15:13] Ever since then, I've been engaged in the research, engaged in a little bit of clinical outreach while I'm studying medicine via a very conventional path, may I add. And now I'm on the cusp of figuring out what I want to do with my life. So, obviously, I finished my PhD in metabolism at Oxford in 2021, and now I'm about to finish my MD at Harvard and then I'm going to graduate and go off into the world. I will not tell you listeners exactly what I'm doing, because I don't know yet, but part of it will definitely involve scientific education. 


[00:15:44] So, in terms of my narrative, more my story before we get back into the science, I want to talk about some sucralose studies that came out that are really cool. But what I would say is I'm not here pretending to be a guru or an expert, someone who runs an esteemed lab or someone with 30 years clinical experience. A lot of the people I collaborate with have more clinical experience in a particular field than I've been alive. But what I will say is I think I come with a lot of youthful exuberance, and willingness to evolve and desire to be here and teach, but also to learn, because I'm at the beginning of this journey, and so, I want to invite everybody listening to give me feedback and be my data, because I'm looking for data to iterate and evolve. So, that's what I can offer that. 


[00:16:29] I think together, you, me, everybody in the space, we're really building a metabolic army, that's a grassroots movement. And to be part of building that community together I think is something I'm pretty excited about. 


Cynthia Thurlow: [00:16:40] Well, thank you so much. 


Nick Norwitz: [00:16:41] Silver lining, I have some passion and purpose. 


Cynthia Thurlow: [00:16:44] Thank you so much for sharing your story, because I know giving listeners context as to what your background is, you have literally walked through fire, going from debilitating inflammatory bowel disease and osteoporosis to now having healed your body with nutritional changes. I think certainly for myself, I trained at the other big research institution on the East Coast that begins with an H. 


[00:17:10] Nutrition was never something that we talked about. It was never a focus. It was back in the days of the food guide pyramid, not even my plate. I mean, it tells you how long ago I trained. And so, I always very refreshingly remind people that it all starts with food. Like, the food choices we make really do have a profound net impact on our health. And certainly, you're walking example of that as well. 


Nick Norwitz: [00:17:33] Yeah. I think it's something that's given a lot of lip service. More lip service today, I would say, in formal education, but not something that is actually internalized by most people. I think a struggle that we all have is how to show people that, “This isn't something we should just lip service to. It's more powerful than you can possibly imagine.” I don't want to believe that people actually have to, as you say, go through fire to realize that. So, part of my mission, part of what I'm trying to figure out is how to get people excited about their own metabolic health journey and observe the benefits and live the life of, what I call, a citizen scientist, or what people call a citizen scientist, decided to make up the term. 


[00:18:09] Because I think your metabolic health journey shouldn't be a chore. It should be something incredibly exciting where you get to enjoy the learning process about metabolic health and then apply it to yourself with what tools you have access to. Be it that just observations or continuous monitors of various sorts. There's some controversy around that we can speak about, and then become more and more informed, so that you can make informed decisions with respect to your everyday choices, be that, whether or not to have sucralose or allulose or ice cream. There's no good or bad choices. It's just about making informed choices and adult and enjoying the process and hopefully improving your metabolic health along the way. 


Cynthia Thurlow: [00:18:45] Absolutely. You've alluded to this research done around sucralose. So, sucralose is one of these-- Again, I say this non pejoratively, non-nutritive sweeteners, but you are especially excited about the cell metabolism research that had been done. Can we speak to this? Because I do think this ties in nicely to the trajectory of where our conversation is going. 


Nick Norwitz: [00:19:08] Yeah. There were two studies that came up recently that I wanted to talk about. The one more recent I'll give a very quick overview on, and then I'll go to the cell metabolism one. But the first question is like, “Does our body distinguish between different sweet molecules?” As I've already alluded to, the answer is yes. We're only starting to unpack how it does this. So, there was some really interesting research done in 2023, published by the Bohórquez Lab in Nature Neuroscience. It came to my attention-- 


[00:19:34] Yeah, Diego Bohórquez is the [unintelligible [00:19:35] was on the Huberman podcast but ended up reading some of the papers. They were studying these intestinal cells called neuropod cells, which are named neuropod, neuro, because they have a nerve like property. So, you can think of them as a middleman between the intestines and then the vagus nerve, which goes to the brain. 


[00:19:53] Basically, long story short, is a way to think about it, this is the analogy I used in a video review I did, is these cells have different receptors. I'll get to the analogy in a minute. The different receptors bind different sweet molecules. So, sucralose versus sucrose. And then downstream, they release different transmitters onto the vagus nerve. So, basically, these molecules are placing a phone call to the brain. But the brain knows, we can't talk right now, knows who's calling. So, the analogy is like, the sweet molecule receptor pair is like a phone number. And then there's a caller ID, which is the transmitter released into the vagus nerve. So, bottom line is, first thing to acknowledge is the brain really can distinguish the difference. These are post oral signals. So, after you taste them, the brain can figure out, “Is this sucralose or is this a sucrose?” This can impact behavior change. 


[00:20:38] So, we know this because you can manipulate the systems, even independent of the sweet molecules. You can do this via techniques like optogenetics, where you can turn on and off cell circuits with light. It's a whole cool technique. You can watch the video for a breakdown. But the first thing to observe is, even beyond the mouth, your brain can figure out the difference. You have taste receptors throughout your gut and actually other places in your body. So, your brain can distinguish the difference. But then there's, you know, so what? What is the impact on physiology? What does your brain do with this information? 


[00:21:06] Now, a separate paper. I want to be clear. These two research projects are separate. But came out of Yale from Dana Small's lab in 2020. I had read the paper, but this new research stimulated me to go back and read it again and then just talk about it, which was, it was looking at the impact of sucralose. That's this non-nutritive sweetener. It's popular, means Splenda is the brand name. They wanted to ask, “How does it impact metabolism? In particular, how does it impact say, insulin resistance?” 


[00:21:37] They were going into the study with the hypothesis that it had to do with sweet nutrient uncoupling. So, the idea that is, if your body tastes sweet, but then it doesn't get the calories that it's expecting, it's like, “Oh, crap, there's a mismatch here.” That can cause metabolic dysfunction. At a high level, that makes sense. So, what they ended up doing is a really brilliant randomized control trial where they took 45 healthy adults and they randomized them to have sucralose, or sucrose, or a mixture of sucralose and maltodextrin. 


[00:22:13] The brilliance of that design is the sucralose post-maltodextrin provides the sucralose and the sugar calories. But maltodextrin isn’t actually that sweet, so you can match it, so the people don’t know if they’re having whatever drink. So, the hypothesis should be, or the basis the uncoupling hypothesis would predict, you get the metabolic dysfunction where and which of those three groups, the sucralose only, the sucrose only or the sugar plus sucralose, which of those three should produce the metabolic dysfunction, according to the uncoupling. 


Cynthia Thurlow: [00:22:42] You would imagine that the third one would.


Nick Norwitz: [00:22:45] The sucralose only, because you're getting the sweet without the calories. That's the prediction of the uncoupling hypothesis. It was wrong. The interesting thing was that the combo group, the sucralose, plus the carbs, is the one that produced insulin resistance. To a quite profound extent, which is not consistent with the uncoupling hypothesis, just to be clear. People can pause and think about it, but you have these three groups, sucralose only, zero calories. Sugar only. Or, sucralose, plus another source of sugar that isn't that sweet. It's the combo group, not the sucralose only group that causes the insulin resistance. 


[00:23:18] Just to emphasize how profound the effect was, there was a pretty impressive effect in human adults. I should have said the dosing was just over two weeks and seven drinks. Seven drinks total. So, it was not like they were having these absurd doses. People have these doses all the time. They did another study in adolescents, ages 13 to 17. The reason they sectored out adolescents is because teenagers, as you probably know from having teenagers, they grow, and part of growing is actually developing adaptive insulin resistance. You get hyperinsulinemic, it's part of the growth process. And so, at this stage in development, the brain can be wired in such a way that people crave more sweet, and they also just have a different insulin profile. 


[00:23:59] I actually should have added before going on to the adolescent’s sub study, was that in conjunction with the insulin resistance that was induced, there was changes in brain activity. So, they're measuring brain activity by fMRI. There were changes in activity in the dopamine reward pathway, areas of the mesolimbic system. So, basically, they were seeing insulin resistance induced and decreases in brain activity in this dopaminergic circuit, which is really interesting. But then they did the sub study in adolescence. It was actually prematurely terminated on ethical grounds, because two of the three participants had such profound jumps in their insulin resistance driven by high levels of insulin. I'm just trying to remember the numbers here, but less than 3.5 to greater than 12.9 in a short period of time that they just said, “We're terminating the study at this point.” 


[00:24:42] You can look at the graphs. People say, “Oh, it's a small N value.” I'm like, “But look at the graphs.” Some people don't overvalue the number of participants in a trial. Really good data you should just be able to look at and be like, “Wow, there is something there.” That was the case here where it's like, “Yeah, it was small, but you can just see profound effect.” So, they prematurely terminated the adolescent sub study. But what this presents is some useful takeaways, I think, in terms of how to use sucralose, if you're going to, practically speaking, and then raises some interesting questions. 


[00:25:12] So first, with the useful takeaways. Based on these data, what I would say is, interestingly, sucralose alone doesn't appear to induce or be sufficient to induce insulin resistance at least in the short timeframe. There are other data that suggests it could be problematic. But if we take these data in isolation, do these data suggest that it would be bad to put some Splenda in your black coffee in the morning? The answer is not based on these data, no. But based on these data, what might be problematic is if you have sucralose in combination with a mixed carb meal, so say, a sucralose sweetened beverage when you're eating a bowl of pasta, or if you have it mixed in with something with carbs. So, say, the Light and Fit yogurt, I think, is one brand with sucralose. 


[00:25:54] And so, it's really interesting, because it presents the idea that, again, to this isn't good or bad, but it's complicated. It could be that having sucralose is actually pretty benign if you have a black in your black coffee, but maybe not in a Light and Fit yogurt. Even though it's the same molecule, the food context you have it in could actually make a big difference, which I think is really cool. And then it presents more questions like, “Well, what is the mechanism? Does it have to do with affecting the brain first and then top-down processes or bottom-up processes by which peripheral insulin resistance induces the brain? Or, is there a common underlying phenomenon?” 


[00:26:28] Provocatively, if you have this in teenagers, say you feed teenagers a lot of sucralose, and it is a top down process, and you're affecting the dopaminergic reward circuitry in the brain that can affect peripheral instrumental distance here speculating. But if that's the mechanism and you're doing it at a critical period in neurodevelopment, could you rewire the brain chronically to maladaptive effect? These are open questions, but I think it's the questions we need to be asking, because again, making informed decision like you have teenagers, is that something that should be on their radar, so they can think, “How important is having this Light and Fit yogurt to me, or is there another option? Can I take some just Greek yogurt and actually enjoy that without the sweet?” You put a little allulose in it or whatever. You know what I mean? So, I find that the literature just on a mechanistic basis, very fascinating. So, those were the two studies. Realized I talked a lot.


Cynthia Thurlow: [00:27:16] No, this is really interesting. I think a great deal about, you know, years ago, before I knew better, there's Splenda for baking. So, this is a perfect example. You take Splenda or sucralose, and you’re using it in conjunction with baking cookies or cake or what have you, and then understanding that magnification of what comes from that. It would make sense to me. Thats why when you asked me what of the three would you assume would cause the most issues, I was like, “Oh, the combination of the sucralose and some type of carbohydrate at the same time.” That was what I was thinking- 


Nick Norwitz: [00:27:51] Mm-hmm


Cynthia Thurlow: [00:27:52] -in the context of Splenda for baking. Because when you're making baked goods in most circumstances, they tend to be hyper palatable, they drive that high reward mechanism, they drive the desire to consume more and more and more, they just regulate your blood sugar, etc. So, to me, I find this all fascinating. What I want listeners to take away from this, is what Nick is saying based on what he's reading, it's in the context of the dose is the poison. Or, if you're having some non-nutritive sweetener in coffee, that is very different than having it in conjunction with a bowl of rice, pasta, baked goods, etc., can really have a profound different effect in the body. 


Nick Norwitz: [00:28:33] Yeah. It's difficult I realize, because understanding these nuances for every sweetener, because there's probably different effects, it's like, you can't assume people will know that. And so, provokes a lot of confusion. At the same time, I feel it's disingenuous to try to boil it down to hear the rules. So, I feel like, as a communicator, I'm caught between a rock and the hard place, at a very high level based on the evidence I've seen, like, allulose and stevia and monk fruit all seem to be pretty benign, with allulose potentially having a little bit of a metabolic edge. 


[00:29:11] There was a recent study in mice, a 12-week study, whereby allulose protected against Western diet induced obesity versus stevia. So, it was the first head-to-head allulose versus stevia I saw. And then other molecules, or in particular, sucralose, aspartame, saccharine, I think, are a little bit more potentially problematic. So, it's one of those things where all things being equal. If you have access to these different tools, would I preference allulose over sucralose? Yeah. So, if that's an easy swap for you to make, then go for it. If you don't need sweet at all, some people don't, then there's no reason to have it. Again, tools for people to use as they see fit. There might be little hacks by which you can exploit metabolic loopholes, like if you're going to have Splenda, having it in black coffee rather than in a sweetened yogurt. 


Cynthia Thurlow: [00:30:00] So, interesting. Why do you think that we, as a culture, and I just say we, I'm not picking on any one individual, that we like to distill information down to saying, “Here are the food rules. This is what you should do. This is what you should not do”? On Twitter as a good example, we see there's a lot of polarization, there's a lot of rigid dogmatism, what works for one person may not work for another. Is it just human nature that we're trying to understand the information and apply it to real life? What do you think, from your perspective, really drives that thought process? 


Nick Norwitz: [00:30:36] I think there's two elements, both having to do with human nature. One is that we're heuristic building machines. We take in so much data every day that we can't possibly process properly and fully logically, so we build these heuristics. They help us organize the world. And so, at one level, people are always driven to find the heuristic that'll best, on average, serve them well. So, we're wired for wanting this simplicity. I also think, compounded on that, there's a lot of frustration by just confusion. People want someone who will cut through the BS for them and say something that serves their confirmation bias. I think that's part of it. 


[00:31:14] I think another part of it is just the nature of social media and what drives engagement, which is polarizing extreme positions on either side. So, there are certain influencers that will be defend to the hilt sweeteners and shout about it, and that gets good engagement. I'm not saying that necessarily in-- Well, I'm saying it in a critical way, but what I want to acknowledge is that that is the currency of the space. It's necessary to engage in some degree of, let's say, packaging. One could say clickbait, but I would say packaging, because clickbait in the vernacular, it's considered to be, this is completely disingenuous. Whereas I think clickbait can be legit bait. Like, you can package something in a way that is provocative, but within the package, there are actually nuanced lessons. So, that's what I try to do. But at the same time, I won’t-- Well, I'll acknowledge that I've played around—


[00:32:20] YouTube right now is a social experiment for me, and seeing what lands and what doesn't. My most engaged with videos-- I actually went to my YouTube, went into my analytics, and if you click order by most views, the top three videos I have on views-- I don't put junk food in my videos a lot or on the thumbnail. The first one is my famous Oreo versus statin experiment. So, that's got Oreos on it. The second one is a deep dive into allulose. To be clear, I literally go into the intracellular biology of fructose metabolism. Nox4 translocation, whatever. But the thumbnail is World's Healthiest Sugar, and I'm staring at a Giant Brownie Sundae. 


[00:33:01] And the third one is fructose is metabolical or something, four Far-Fetched Facts about fructose again. I'm going into the cell biology of it, but the thumbnail was-- There's this shop called Bagel Nook. If you google the Instagram for Bagel Nook, it's insane. These multicolored bagels, these massive purple rainbow cream cheeses, it's crazy. I put that in the thumbnail. I'm making a face that is so extreme that people actually comment to me, “Is this AI?” because my face [Cynthia laughs] doesn't even look human. That's how extreme I went with the facial expression. 


[00:33:33] It's something I play with because it's just like-- I'm trying to figure out what lands, what doesn't. But think about that incentive structure. Each of those videos are getting 160,000, over 200,000, 500,000 views. So, I know how to get views, but I don't want to be misleading at the same time. So, how do you balance that packaging with the story you want to tell? You can see how the incentives could push somebody down one pathway. And so, I acknowledge that, because I want you to-- For those listening, if you're willing, you can go to my YouTube page, you can see those videos, then juxtapose that to how you hear me talking now, which is maybe a little bit vague, waffly, not taking a stance, but trying to express some degree of nuance genuinely and authentically. 


[00:34:13] Nevertheless, every communicator in the space trying to have their voice heard to some degree needs to engage in a little bit of this packaging with a few exceptions of people that are very, very big and well established already who have names that precede them. They're the kind of people that if you put these people-- If you put their face on a thumbnail, this is how you know these people. Other people, including me, will put their face on a thumbnail, because that in itself will be a tactic to drive engagement. 


[00:34:45] So, there are a few exceptions, like Attia or Huberman or Rogan or something. But for the most part, people engage in packaging. It's a practicality. That's the thing. You can be ideological about it, and I know people who are and I could be that person. But then you're also going to be the person that's like, your post reaches five people. So, it's a balancing act. I think the important thing is always to be self-auditing and accepting feedback on like, how well are you walking this line? Because it's not easy, but it's fun. 


Cynthia Thurlow: [00:35:13] No. You do a really good job with it. Obviously, I've been following you for a while. I subscribe to your channel. For anyone that's listening, you do such a good job of translating the science into actionable information, or at least being able to understand. When I went down the rabbit hole about that, that one allulose study that you were talking about, the neuropods and the optogenetics,- 


Nick Norwitz: [00:35:35] Yeah.


Cynthia Thurlow: [00:35:36] -my kids were like, “What are you listening to?” And I said, “This is the gentleman I'm interviewing tomorrow. Just to make sure that I was properly understanding your interpretation of some of this research.” Now, you talked about the Oreos experiment. 


Nick Norwitz: [00:35:47] Yeah.


Cynthia Thurlow: [00:35:47] This is something that I definitively want to make sure that we cover in this first podcast. How did this opportunity avail itself to you? Because this has been something that, as someone who prescribed statin agents for over 16 years and someone that used to bow at the almighty of evidence-based medicine vis à vis atherosclerotic cardiovascular disease, MI, etc., statins were a large part of what I worked around. 


Nick Norwitz: [00:36:15] Yeah. 


Cynthia Thurlow: [00:36:16] So, let's talk about this experiment. How did it come about? Because it's incredibly clever, but it's also very thought provoking. 


Nick Norwitz: [00:36:23] Yeah. So, what I'm going to do now is I'm going to present what the study was and the results, and I would encourage those listening to pause and then audit your own emotional reaction and then we'll talk about why I did it, which was I did a study where in a particular metabolic context, phenotype I'm studying lean mass hyper responders. You can assume you don't know what that is, because a lot of people didn't. Based on the models we were working with, we predicted that carbohydrates can lower LDL cholesterol. 


[00:36:54] So, I designed a study where in myself as a publicity stunt, but also a true study. I went into Harvard and said, “I want to do this study. Will you give me an IRB exemption?” And they said, “Yes.” I had my PCP on board, and I had a very senior lipidologist, actually, the guy who trained Thomas Dayspring, who trained Peter Attia in lipids. So, very well-respected guy. He was the senior author. So, I know how to dot my Ts and cross my eyes, nevertheless. [Cynthia laughs] 


[00:37:18] The study was I was going to have a run-in period on my standard ketogenic diet lock in that as the baseline diet. Then for about two weeks, eat a sleeve of Oreo cookies, 12 cookies on top of my baseline diet, then do a washout period and then do high dose, high-intensity statin therapy. So, I did rosuvastatin, which I think Thomas Dayspring refers to as one of the gorilla statins, I think is the term he used. The highest starting dose you can have which is 20 milligrams. This was all informed for six weeks by Professor William Cromwell, who has over 30 years of lipidology experience. So, that was the protocol. 


[00:37:58] Of note, not only did I go and get IRB exemption at my PCP on board, I have a lipidologist on board, but I announced this a priori. So, as I was starting the experiment, I said, “I don't have the results yet, but I'm telling the world I'm doing this.” I announced it on Chris MacAskill at Plant Chompers YouTube. I was like, “I don't know what the results are going to be, but let's find out.” So, the results were the Oreo cookies kick statins butt in terms of LDL lowering with a 71% reduction using the Oreos in about two weeks, 16 days. 


[00:38:31] The reason it was a 16-day protocol instead of the original two weeks with the Oreos is, in the first two weeks, the drop was so crazy large that we decided we needed to continue it to actually show it wasn't just a fluke on that lab. So, we did a triple kit, days 14, 15,16. Over those three days, it was still dropping. So, I had a 71% reduction in about two weeks, 16 days with Oreo cookie supplementation. Not a swap out of fats, adding the Oreo cookies. So, saturated fat went up. Even fiber, I guess. Oreo cookies have sub fiber went up a little bit. It was just adding some Oreo cookies 12 a day and I had a 71% drop in LDL, which-- 


[00:39:07] Just to put that in perspective, that's bigger than a PCSK9 inhibitor is expected to produce bigger than a statin is expected to produce, which I listened to your most recent episode with Thomas Dayspring. He was saying about 30% expected for the statin. The statin arm indeed did produce a 32.5% reduction. So, it wasn't negligible. It produced the expected results. The fact was though, the Oreo was double the effect of the statin in one third the time. So, I threw a social media or a media grenade out there, which was, Harvard Medical student lowers his cholesterol with Oreo cookies/Oreo cookies are twice as potent as high-intensity statin therapy for lowering LDL in a lean mass hyper-responder, subtitle yada yada. The things that might go over people's head if they're not looking. 


[00:39:55] But my interest was not in the people that would skirt over the initial headline, but was in provoking people to turn their heads and say, “What is going on here?” Because at the one level you think, “Okay, just another crazy media headline, somebody pulling your leg.” But for those who delve a little deeper, it's a really interesting metabolic demonstration. It was legitimate. It was predictable enough that I felt confident predicting it. It's consistent with other literature we have including, yes, this is an N equals 1, but we have like a meta-analysis of 41 human randomized controlled trials published in the top nutrition journal in the country, the American Journal of Clinical Nutrition, consistent with the underlying hypothesis, lipid energy model, and other case series data and interventional data showing that, say, carbohydrate reintroduction can reverse a lipid phenotype, lower the LDL in this particular metabolic context. 


[00:40:47] So, the purpose was to provoke a conversation about a fascinating new phenotype that we've been studying that I don't think has been getting enough attention and enough discussion around it that I think provides a natural experiment, this lean mass hyper responder phenotype, that really deserves further study because it has lots teach us. So, for me, it was one of these moments of, “Dang it, this thing we're studying that I really, really want to talk about, but nobody is investing serious resources in it and nobody else is talking about it seriously.” 


[00:41:19] So, I don't have multi-million-dollar grants to do the studies I want to do. I'm a 28-year-old PhD, at the time third year med student. How can I use the resources available to me, which include social media, to provoke enforce a conversation that I think really needs to happen? So, I came up with Oreo versus statin, and it had the intended effect. It has garnered attention, forced conversations, some of which have been recorded and not released, some of which are going to happen. But let's just say, I think it's really forced the conversation in a productive manner too. To be clear, Oreos are not a health food. I hope I couldn't persuade any logical adult that they are. But understanding the physiology that explains this phenomenon does provide people with useful tools to apply potentially in a clinical setting. 


[00:42:16] Now, I'm not your doctor, but I have been contacted by doctors, including cardiologists, who say, “I wasn't aware of this. But I went down the rabbit hole associated with your Oreo versus statin study, and now I have lean mass hyper responder patients who were freaking out but statin intolerant, and now they're having a sweet potato per day because they weren't using a ketogenic diet therapeutically, and their LDL and ApoB have gone to basement, and we're all happy because they don't mind having sweet potato per day.” So, it actually does give clinically actionable takeaways based on understanding of the physiology. So, that was the study. Yeah, it's created a stir as intended. 


Cynthia Thurlow: [00:42:50] Yeah. I love that you did so creatively. For the benefit of listeners, obviously, I've had Dave Feldman on twice. We talked about lean mass hyper-responders. But for maybe people who missed that episode, could we give a quick overview? I am myself, a lean mass hyper responder. So, this is particularly relevant, something that I try to make sure listeners are attuned to if they themselves fall into the same parameters. 


Nick Norwitz: [00:43:15] Yeah. So, lean mass hyper-responders was a term coined by Dave Feldman, a friend of mine, a software engineer in 2017, where he observed, as a lot of people do, he went low carb in his LDL cholesterol in an association ApoB, although he wasn't measuring that at the time, went through the roof. I mean through the roof, to levels so high that most doctors think it's either a joke or if you don't start pharmacotherapy, you should go shopping for your headstone. 


[00:43:41] But he also noticed a couple other interesting things. One was the increase in LDL also happened in conjunction with increases in HDL. Two, very high levels not just like in the normal distribution high levels, but the threshold is above 80 milligrams per deciliter, which is high, but sometimes as high as like-- Mine runs as high as 125, like crazy high. On a mixed diet, it's quite normal and also very low triglycerides. 


[00:44:05] So, the first thing I observed was there was a lipid triad that the LDL wasn't increasing in isolation. It was high LDL, high HDL, low triglycerides, which the threshold cut points are 200 for LDL, 80 for HDL, both of those 280 above, and 70 or below for triglycerides. So, that's lipid triad. It's extremely rare in somebody on a mixed diet. Typically, it happens in people who are low carb and who are lean. Hence, lean mass hyper-responders.


[00:44:33]. So, the lean part comes from the empiric observation. He was just noticing, “Huh, this profile tends to occur in people who are on the leaner side. That's interesting.” So, he coined the term. I can talk about the term, and its benefits and drawbacks in a moment, but the definition, just to be clear, is these three cut points. HDL above 80, LDL above 200, triglycerides below 70. It tends to happen in people who are lean, but there is no BMI cut point. So, that was the initial observation in 2017. 


[00:44:59] Now, it took a little while for the balls to get rolling in terms of research on this. But together, the brainchild of Dave Feldman is a Lipid Energy Model, which I've helped to evolve a little bit. We wrote a paper on that, explaining that what we think is going on is that when you're low carb and insulin sensitive, particularly in lean people with very small fat cells, then you release a ton of free fatty acids. When you're low carb, you really go into full fat burning mode. The free fatty acids are, they're released, they're burned by muscle. But a lot of them go back to the liver, where they're picked up by the liver and resynthesized onto the storage form of fat triglycerides, which are put on these VLDL particles, these big spheres, which are shipped out of the liver and then at peripheral tissue, including fat cells, to replenish the fat cells and muscle tissue, the VLDL are depleted of their triglyceride cargo via a lipoprotein lipase. So, the triglycerides are sucked out very, very quickly. 


[00:45:57] So, the important thing to recognize is there's a coupling between increased triglyceride synthesis and export on VLDLs, and then VLDL turnover peripherally. So, the VLDL will shrink, the triglycerides go down, the core is pulled out, so triglycerides are low. That's part of the triad. When the VLDL shrink, they become LDL. So, now you have two parts of the triad. The triglycerides sucked very quickly out of the VLDL. The VLDL turned into LDL, and LDL of a longer residence time. So, you have low triglycerides, high LDL. 


[00:46:23] The third part of the triad, the HDL, comes from the fact that when you shrink the VLDL down, you lose surface area. If you take a big balloon, shrink it down to be a small balloon, the surface area is decreased. Where do the surface components go including the cholesterol components, they get picked up by HDL acceptor particles. So, you end up with this triad of the high LDL, the high HDL and the low triglycerides that tends to occur in lean people. The lipid energy model makes certain predictions. 


[00:46:48] One very simple one is if you cut off the driving force, which is demand on fat fuel, so really, liver glycogen stores is thought to be the origin point. So, if you put carbs back into the liver, the driving force goes away, the flywheel of the cycle slows down and your LDL drops. So, that's why adding back carbs is so effective. Even Oreo cookies. Although we've had people do it with fruits and starches, whatever, will tend to work in a lean mass hyper-responder, that tends to be the most effective approach. 


[00:47:18] That said, there are other predictions of the lipid energy model, like the fact that, all things being equal if you increase energy demands. Increase the flywheel, LDL goes up. We see this too. As the last week of my Oreo versus statin experiment actually, what happened is weeks three, four and five, my LDL in the statin had plateaued. It had stayed within a few milligrams per deciliter. You can see this on the graph. So, I’m like, “All right, I’m going to make the most out of the last week and change one thing, which was add 10,000 steps a day to my routine.” By doing just that, my LDL increased 50 points. 50 milligrams per deciliter.


Cynthia Thurlow: No way. 


Nick Norwitz: Yeah. [Cynthia laughs] And other people have done similar experiments. So, the bottom line is, there are a lot of things, a lot of levers by understanding this physiology that you can pull to manipulate your LDL levels. To be clear, and this is where I think the conversation gets really contentious, is this is really cool physiology. It's scientifically fascinating. To explain the physiology underlying the fact that Oreo cookies really lower LDL more than a statin assuming this is reproducible and we have every reason to believe it is, since again, we have these other data that are very consistent with this model, that's the physiology. And it's interesting. But it's a separate discussion from what one should do in terms of clinical management, and whether or not those levels are safe in this context, which is a whole separate conversation and really has to do with unknowns. 


[00:48:44] So, one thing I could say is that etiology cause does inform consequence. This has been published in other trials, like JAMA cardiology. There was a study showing high LDL levels at the same level had different risk profiles depending on if it was monogenetic FH, polygenic FH or no known genetic cause even for the same LDL levels. 


[00:49:06] That particular study I covered has some limitations and caveats, but nevertheless, just the idea basically that, like, what's causing a change in a specific marker can affect outcomes, I think is pretty intuitive. It's like, if you're 6’5” because you have tall parents-- Okay, you're 6’5” because you have tall parent. If you're 6’5” because a pituitary adenoma creating a growth hormone, same 6’5” but the outcome might be different. So, bottom line, cause can impact outcome. But just because something is a metabolic response and may be adaptive acutely, does not mean it's safe chronically. 


[00:49:42] So, one thing I really push people to do and this is where I think the rubber hits the road with respect to scientific communication, is let's partition these discussions. Say, this is a really interesting scientific thing that we want to study as community, a scientific community, which includes I think engaging with the general public and giving them the confidence that they can understand that, “Yes, this is an area of unknown,” at the same time saying, “Look, on a one a one level, we shouldn't assume this is safe.” The conversation with respect to risk should still be had with appropriate caution, caveats, nuances and appreciation of individual clinical circumstances, including you're on a ketogenic diet, what morbid condition you might be treating, what's your family history of heart disease, do you have preexisting plaque? 


[00:50:28] So, two separate discussions. But what I would say is, if you don't think this phenomenon is interesting-- We have double digit papers on it now. So, it's not like a nothingburger, including published with some pretty esteemed lipidologists. If you don't think it's interesting, you should hide a hand in your scientist card, because this is freaking cool. I think it's a responsibility of everybody engaging in this discussion who has the ability to approach it with nuance. And so, that's the bar I'd hold other people to who are going to comment on lean mass hyper-responders in the lipid energy model. You better believe people have, I think a few of that I'm alluding to and I don't think that they have [Cynthia laughs] hit the level of nuance that I would have held them to. But hopefully, these discussions will evolve. 


Cynthia Thurlow: [00:51:12] So interesting, selfishly, because I am a lean mass hyper-responder, but just understanding how subtle changes to diet have such a large and profound net impact. Out of curiosity, because I don't know this offhand, what is the carbohydrate load for 12 Oreos? 


Nick Norwitz: [00:51:29] 100.


Cynthia Thurlow: [00:51:30] Okay. Which is maybe it's a little more than a sweet potato. But interesting. The sweet potato’s fiber and other things. 


Nick Norwitz: [00:51:37] Yeah. It depends how big a sweet potato. I'm actually probably using as an unfair mental point of reference. I had a sweet potato face as a teenager, but I get those monster sweet potatoes at the grocery store, and admittedly put maple syrup and honey on them. I used to be a marathon runner. So, [crosstalk] a sweet potato with honey and chucking a jar of Nutella after 22 miles run, then hitting the gym in Boston was very routine for me. So, I have a very screwed up perception of serving sizes. My apologies. 


Cynthia Thurlow: [00:52:05] No, no. As a middle-aged female, when I'm talking to patients and I'm talking about root vegetables or sweet potatoes, I usually am like half a cup, three quarters of a cup, because that carbohydrate bolus in a middle-aged person might have a larger metabolic impact. 


[00:52:22] Now, you mentioned metabolic medicine. My interpretation, when we were having conversations prior to connecting today, was the value of bio-individuality, the power of the N of 1. 


Nick Norwitz: [00:52:35] Yes. 


Cynthia Thurlow: [00:52:35] I think it would go without saying that this is a very important concept, and one that I would really relish being able to tie up this conversation, because for listeners, we will have another one, because there are so many different things that Nick and I could have discussed. Let's round it out talking about the N of 1. 


Nick Norwitz: [00:52:52] I love it. So, N equals 1 medicine. I was just saying, I have a thumbnail literally on my desktop, provocatively labeled, it's N equals 1 medicine and there's a tombstone with the word RCT on it. I'll unpack what I mean. I was talking with Dominic D'Agostino when the idea arose to me. But I think we're transitioning. Let me say, I think there is going to be a big pivot in medicine towards building individual protocols based on large data sets on individuals addressing the root cause physiology of different diseases, because we're so individual. 


[00:53:32] And so, the reason I juxtaposed this to RCTs is because you alluded to earlier like, you're paying homage to the altar of evidence-based medicine. The funny thing about evidence-based medicine is it's a nice term, and we all want to be like, “We're evidence based.” But there are limitations, including the idea that, in our current system, which is built on addressing in large scale RCTs the efficacies of drug monotherapies. The power of that is you figure out, “Okay, what is the effect of this individual intervention,” which is important at some level, and you're saying, “How reproducible is it in populations?” 


[00:54:08] The problem is there's heterogeneity in the human population. You're necessarily taking a giant group of people who are heterogeneous and putting them into a study, so that specificity and individuality is lost. And so, the results, even if they're “statistically significant” don't necessarily speak to one the effect size, but also the effect in any individual and whether or not you're actually covering up symptoms or addressing root cause physiology in that person. 


[00:54:39] One would think, “What if, rather than trim the branches of the tree of metabolic disease?” The branches being the symptoms or individual diseases we affected the roots, and the roots are going to be different for every single person? So, what I'd love to see in medicine is a shift towards collecting multi-omics datasets. When I say multi-omics, I mean all the -omes, genome, microbiome, transcriptome, proteome, and then assembling that into a picture of the metabolism of every individual, and what might be going wrong there and then addressing the dysfunctional nodes. 


[00:55:12] The really cool thing is we're already starting to see a pivot towards that with certain labs. There's like the Snyder Lab out of Stanford that's doing incredible work on longitudinal multi-omics. Longitudinal being like, not only are you taking all the -omes and assembling them into an individualized picture, but you're taking it at multiple time points to see how these things flux over time, because yeah, your genome is static, but your microbiome, your metabolome, they aren't. So, we can get a video of individual metabolism, and then use that as the basis for personalized interventions, which is what I think of as metabolic N equals 1 medicine. I love it, because it reclaims that N equals 1, which is like a dirty, that's just anecdote idea, and says, “No, this is the most potentially efficacious, and rigorous and futuristic approach to medicine that we could have.” 


[00:56:00] Now, to be clear right now in terms of what's accessible to people, things like a CGM, which are pretty rudimentary by comparison, are accessible, but I think they're a harbinger of what's to come, which is a shift towards N equals 1 bio-individual medicine, and I think that's going to be the future. 


Cynthia Thurlow: [00:56:17] Yeah. It's so interesting to me, because I think about when I'm working with patients and clients and we're talking about the value of-- Most of my community, north of 35, these are women that are dealing with the throes of perimenopause and menopause, so sleep issues, food cravings, suddenly becoming weight loss resistant. This is where dialing in on lifestyle is so, so important. 


[00:56:39] You touched on continuous glucose monitors or glucometers. How do you think that these are going to be used differently as this N of 1 medicine is evolving?


Nick Norwitz: [00:56:48] Yeah. I think that there's a lot of controversy over CGMs. My position is that when used in an informed manner, they're really powerful biofeedback tools. And so, I think it's exciting to talk about providing people with a video of their metabolism and intervening at those nodes. But I think that only works if you invite the individual, call him, the patient, the person, to engage in their metabolic health journey. It needs to be more of a partnership between the data provider, physician, healthcare worker and the patient person. 


[00:57:24] I see CGMs as just one example about how we can now provide people with their own data that is a powerful biofeedback tool. I think all you need to really make the case and then we can go through some of the counterarguments, because there are counterarguments is like, how are people saying they are using this tool? Are they saying it's inspiring them to make behavior change and teaching them about themselves? I listened to your wonderful episode with Glucose Goddess, and she had some interesting thoughts on that, and basically is more or less consistent with what I'm saying, which is, this forces one to consistently engage with their own metabolism. Think about like your glucose curve is a bellwether of what's going on in your body metabolically. It gives you insight, or forces you at least to introspect. That alone is very powerful. 


[00:58:10] That said, of course, you need to educate people on proper tool use, caveats, normal glycemic variations and then not apply the tool in the wrong user. So, by analogy, if somebody's struggling with anorexia nervosa, they probably shouldn't use a bathroom scale every day, which is another tool. So, tools can be misused. I don't want to say they can't and I don't want to say the data can't be misinterpreted, but I think that's more of an opportunity for education and that fundamentally these tools have a lot of benefit as a biofeedback tools provided proper education. 


Cynthia Thurlow: [00:58:43] It's interesting though. I think I have patients that use and utilize CGMs and glucometers, and it doesn't cause them stress. And then I have a minority of women that the added information, whether it's after playing tennis or they've had a sweet potato and nothing else, the anxiety that it produces because they're so mindful. They think any glucose spike is negative. And so, helping people understand you mentioned this glucose distribution. Helping people understand like, what is a normal glycemic response to a meal what is considered to be abnormal?


Nick Norwitz: [00:59:17] Right. To have conversations to people, help them understand the data and then letting them audit, what's the impact on them and is this a tool, like the sweeteners? Do you want to use this or not? Nobody needs to use it. You don't need to use the scale, you don't need to use sweeteners, you don’t need to use the CGM. Providing it as an option in the right people, I think is fair enough. By analogy, I haven't gotten into sleep tracking. I don't have an Oura Ring, because I actually think that would get in my head. And everybody [Cynthia laughs] says, “It's great.” I'm like, “But I know myself and I'll just get competitive.” And then that might cause me to stress. So, that's a tool that might be very useful for some people, and people speak very highly of it. I might try it, but knowing myself, I've just been hesitant. So, it's the same with CGMs. 


[00:59:57] I think it has to do with a novelty and novelty of access, that people are really gun shy about it, because you could say the same thing for almost any tool. You brought up statins earlier. So, if somebody thinks lower glucose is better and just has that simplistic point of view-- And then I've literally heard this argument, “Oh, and then I've had patients just stop eating,” and they're fasting because they think lower glucose is better and they're starving themselves. I'm like, “Well, if you think lower LDL is better and you're prescribed a statin, what if you start hammering 200 mgs of Crestor per day?” That wouldn't be healthy. 


[01:00:28] Hopefully, we don't have patients that do that. But again, it's a tool and you provide patients with the education to use that tool properly. If they're not using that tool properly, then you say, “Maybe this isn't a good idea for you.” I bet you I'm going to get heat for that analogy, but you see where I was coming from with it. 


Cynthia Thurlow: [01:00:44] No, absolutely. I think you bring up some good points, that there are some people, and I refer to them as the outliers, there are people that take things to extremes. Thats their personality. That’s their nature. If a little bit of Crestor is good, more is better. If a little bit of fasting is good, more is better. If a little bit of exercise is good, more is better. And so, finding that happy, healthy middle of the road for each person. 


Nick Norwitz: [01:01:08] Yeah. I actually have a question for you on the topic of CGMs that came to my mind. We were talking, me and Dom, about CGM's and Dom D'Agostino, I should elaborate, and eating disorders and the comment of orthorexia, because you were just-- The reason it came to mind you were talking about extremes. It's an interesting term. So, orthorexia, for those who don't know, it's a term that's used to describe people with an unhealthy relationship to healthy eating. So, who becomes so obsessive about it that it has a negative impact on their health? 


[01:01:38] To be clear, I think this is a true phenomenon, and that there's something to having equanimity and balance, emotional balance, with respect to how you approach food. So, I think people can get too obsessive about it in an unhealthy manner. However, the way I've seen the term be used more and more is it gets used more and more liberally to a point that I think the term is being abused and applied to people who are just enthusiastic about metabolic health because of the social norms we established. 


[01:02:07] So, I've heard people be called orthorexic, because they don't want birthday cake, a birthday celebration at an office party. Whereas I'm like, “That's not orthorexic necessarily. That's just maybe caring about your health and you don't want to eat cake and because you feel better.” So, it's just a moment of pause and reflection about what our social norms are, how people react to those. The reason I think that's an important conversation or something to reflect on is, because peer pressure does arise around that, and it really does influence our behavior. For anybody listening here, it’s not going to be an unfamiliar feeling where you're just trying to engage in your healthy lifestyle and you're actually enjoying it. But there's that moment that comes where you're getting pressured by a social circumstance into engaging in unhealthy patterns. The funny thing is, you realize that there are points in time that eating healthy and living a healthy lifestyle isn't hard intrinsically, but it's hard socially. 


[01:03:02] For me, a ketogenic diet, I don't really feel like I could never be pasta for the rest of my life, or soda or sweets, be perfectly happy. But there are obstacles that have arisen with respect to social situations. My situation, 28-year-old male, like dating can be awkward. If you want to go on a date, like, “Oh, you want to get ice cream?” I'm like, “Not really.” [Cynthia laughs] And then you don't want to give your backstory and life stories, like, “I had IBD and I was having lots of diarrhea, yup, yup, yup” [Cynthia laughs] on a first date or something. 


[01:03:28] So, the social obstacles are really real. I raised that, because I think a theme in this conversation has been like, being an adult and making informed choices. These aren't easy things. There aren't easy things for any of us at any stage of life to figure out, is this tool a reasonable one for me? Is this moment in time do I want to make this decision or that decision? But making informed decisions is the most important thing, and then I don't think anybody should judge you for whatever decision you make, including you shouldn't judge yourself provided you make a fully informed decision. 


[01:03:57] I think a lot of people a lot of times we all, I would say, get impulsive and then regret the decisions we make. But if we just paused and though about it, we might have come to the same decision, but at least made it in an informed fashion, which gives us a better relationship to our lifestyles. 


Cynthia Thurlow: [01:04:11] It's interesting to me, because I've been dedicated gluten free for 12 years, dairy free for the last 6 years. It's interesting how in social situations, 95% of the time there are no issues, especially if I’m around other people in the health and wellness space. But it’s incredibly triggering for other people. I’m like live and let live. If you choose to eat X, Y or Z, that’s your choice. This is how I eat. This is what makes me feel good and sometimes means I go out of my way when I’m in certain cities to find certain restaurants that will meet my needs. I don’t see that as orthorexia. I choose to eat the way I do, because it makes me feel good and allows me to have plenty of energy and show up for my family and my community. But there’s nothing more triggering than telling someone that drinks alcohol, you don’t drink. And I’m like, “I don’t pass judgment. I have an alcoholic parent.” 


[01:05:04] Alcohol is so triggering for people. I just use that as one example and I’m like, “Listen, I’m great at a party. I will put a slice of lime in sparkling water and I’m good to go.” It doesn’t bother me. I don’t feel any social pressure, but it's amazing how in our current society that is incredibly triggering for people. I humbly sit back and I'm like, “Listen, I'm totally easy. Just give me water. I'm cool with that.” But that decision in and of itself, people find very polarizing. I think more often than not, when people get triggered by choices that we make that serve our best needs, it's really a reflection of that person's insecurities, discomfort. Maybe they themselves think they have an unhealthy relationship with alcohol or some other sweets, processed carbs, etc. 


Nick Norwitz: [01:05:54] Yeah. I think what you're alluding to is something that I think about a lot, which is like, there comes a point in your health journey, especially if a lot of motivation to live a certain way, where you're just like, “Look at this point. It's a YP. It's a you problem. It's not an MP. It's not a me problem.” I feel bad that you feel bad about it, but at the same time, like you said, live and let live. I'm going to do my thing. I can explain to you that, “Look, I'm not judging you. Do whatever you want to, but I'm not going to change my behavior out of a sense of guilt, because you feel uncomfortable.” 


[01:06:23] We can have an evolved discussion about it, that's great. If we want to use this as a moment to have a conversation, that doesn't necessarily fully alleviate the guilt one necessarily feels about making people feel uncomfortable, because there is so much more to food than just metabolism in terms of culture, in terms of a love language. I honestly still love to bake, because I was a baker throughout my adolescence. And so, I have this weird internal conflict where I actually love to bake and give baked goods, but at the same time, I'm a metabolism PhD and I talk all the time about [Cynthia laughs] metabolic science. So, I have these weird two halves of me. 


[01:06:59] If you want to hear something, your listeners will get a kick out of this. It's pretty freaking pathetic, or it's going to sound pathetic. I actually think it's really nice. But my girlfriend's not low carb. We wanted to have entertain some parties, host people. And so, we thought a cool way to do that would be become really good at making cheesecakes. I don't mean low carb cheesecakes, per se. We can make low carb, we can't use allulose. But I just mean for the sake of cheesecakes, like, being good at making cheesecakes. So, I have actually over there, I can grab it. We bought a cheesecake Bible with 300 recipes. 


Cynthia Thurlow: [01:07:30] I love it. 


Nick Norwitz: [01:07:30] One thing we're doing is a routine is just making cheesecakes. It's funny, because she'll try it. I'm just sitting there having a lot of fun baking cheesecake while being low carb, like, having no intention to try it pathetically like pouring sugar into things and flour, and it's just-- But it's an activity. Like I said, like a love language and something that you can engage in culturally. I bring this up, because I don't know if it's hypocritical. It sounds almost hypocritical, but I think one thing we lack in media is authenticity and the acknowledgement that we all have different parts to ourself. 


[01:08:06] I can have the clinician hat. I can have the scientist hat. I can tell you about cell metabolism studies about sucralose, maltodextrin combos and the effects that has on insulin resistance. At the same time, I can be a 28-year-old guy and bake cheesecake with my girlfriend for the kick of it. That, I think, is okay. I'm not sure if it's okay, but at the very least, I think it's fair to provide everyone getting to know me in this space with an authentic picture of who I am, what I'm doing, and then they can use those data to judge me as they will. 


Cynthia Thurlow: [01:08:39] Honestly, I think it makes you very relatable, and I doubt you probably have shared that on any other podcast, so I'll take that as a win. 


Nick Norwitz: [01:08:47] Let me see if I have the Bible. [Cynthia laughs] Yeah, I brought it back with my apartment. Yeah, proof is in the pudding, the literal pudding. 


Cynthia Thurlow: [01:08:57] I love it. 


Nick Norwitz: [01:08:58] We also have one that we're going to try to make based on an Okinawan sweet potato. There's a secret recipe that was from some guy in Hawaii who recently passed that we were able to get our hands on. And then I even had a patient, I think I'm allowed to say this, who is an organic potato farmer. So, we were down in the [unintelligible [01:09:14] having this whole conversation about potato biology. So, now I'm becoming an expert in potatoes and cheesecake from a non-scientific point of view, more for a cooking point of view. But we all have layers to ourselves. 


Cynthia Thurlow: [01:09:24] Well, I think it makes us much more interesting, to be honest. Obviously, this is the first of hopefully many conversations that we will have. Please let listeners know how to connect with you, how to find you on social media. I would say Twitter and YouTube seem to be the places. It's a great platform for you to be on where you can help educate the lay public and clinicians as well. 


Nick Norwitz: [01:09:45] I would love if everybody, yeah, checks out my YouTube and Twitter. If you just look up Nick Norwitz, N-I-C-K-N-O-R-W-I-T-Z, I think I’m the only Nick Norwitz in existence. On Twitter, I'm @nicknorwitz, Instagram which I'm new to, so I appreciate engagement there as I'm growing is @nicknorwitzphd, and then my YouTube if you just look up Nick Norwitz on YouTube, you'll find me there. 


[01:10:07] I also recently started a newsletter that I'm going to be releasing at least once a week that I'm having a lot of fun with, so you can get more of my ponderings there and sometimes some teases of what's to come. But yeah, I appreciate engagement on all platforms. I think I'm probably most active in combing and replying to YouTube comments on videos that are recently released. Yeah, all engagement is appreciated, all feedback is appreciated, and thank you for this conversation and I apologize for my monologuing I have a tendency something-- [crosstalk] 


Cynthia Thurlow: [01:10:36] No, no, I think it's interesting. To be honest, as an introvert, I enjoy listening to other people, their thought process. So, it's been enjoyable. Thank you, again. 


Nick Norwitz: [01:10:44] Thank you so much. 


Cynthia Thurlow: [01:10:47] If you love this podcast episode, please leave a rating and review, subscribe and tell a friend.



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