#104 Dr. Ben Bikman: How To Reverse Insulin Resistance Through Diet, Exercise, & Sleep

0:00Insulin resistance is increasingly recognized as a key contributor to chronic diseases such as obesity, diabetes, cardiovascular disease, and even cognitive decline, often developing silently years before conventional tests detect a problem. Yet most people don't realize they're insulin resistant until blood glucose tests finally flash a warning sign, often decades too late. The reality is, is that millions of people are unknowingly walking around with persistently elevated insulin levels, what we might call pre-pre-diabetes, and this silent dysfunction

0:31has profound implications for their long-term metabolic health, disease risk, and longevity. Today, I'm joined by Dr. Ben Bickman, an expert in insulin metabolism and one of the most insightful voices in unraveling the complexities behind insulin resistance. Dr. Bickman is a professor of physiology and developmental biology at Brigham Young University, whose research has reshaped our understanding of insulin's broader roles far beyond glucose regulation. His work highlights how insulin resistance differentially impacts muscle, liver, and

1:01fat tissue, the critical roles environmental toxins play, and the practical interventions that can significantly restore insulin sensitivity. In this episode, Ben and I dive deep into crucial topics, including why insulin resistance remains hidden until advanced stages, how to detect it early through simple tests, and actionable first steps to reverse insulin resistance immediately. What insulin's broader physiological roles are beyond just blood glucose, its profound influence on fat storage, appetite regulation, inflammation, and chronic disease.

1:34We also discuss macronutrients and insulin sensitivity, discussing how different dietary compounds like refined carbohydrates, sugars, even certain types of fats like saturated fats and polyunsaturated fats uniquely impact insulin signaling, inflammation, and metabolic health, as well as their relative roles in driving insulin resistance. We discuss how meal timing, frequency, and caloric restriction independently influence insulin sensitivity, including practical insights into intermittent fasting and time-restricted eating protocols. We also discuss why not all fat cells are equal, including the metabolic dangers of visceral fat

2:09versus subcutaneous fat, the concept of personalized fat threshold, and what actually happens to fat cells during weight loss. We discuss lifestyle and environmental factors beyond diet, including stress, sleep deprivation, nicotine exposure, and endocrine-disrupting chemicals, including those found in microplastics. We also discuss lifestyle and environmental factors beyond diet, including stress, sleep deprivation, nicotine exposure, and microplastics, and how they may significantly influence insulin sensitivity and overall metabolic health. We discuss the emerging use and potential pitfalls of GLP-1 agonist

2:44medications, including Ozembic and Wegovi, including their effects on fat versus muscle loss, long-term metabolic health, and whether microdosing offers a safer path to longevity benefits. And finally, we discuss practical evidence-based strategies you can start today, including dietary modifications, exercise protocols, targeted supplementation to rapidly improve insulin sensitivity, and invest in your long-term metabolic health span. By the end of this conversation, you'll have a deeper understanding of insulin resistance as a significant contributor to chronic diseases and

3:15aging. And you'll also gain practical tools to meaningfully improve your metabolic resilience starting immediately. Before we dive into this episode, I want to take a moment to remind you that I publish a weekly research newsletter, and if you're not signed up for it, you're missing out. Each week, my team and I pick a recent groundbreaking study, often one the media has misinterpreted or incorrectly summarized, and we do a deep dive into its results and what they mean for you. No topic is off limits, but we generally keep coverage to studies that are in the realm of nutrition, longevity, exercise, and brain

3:48health, topics we know our audience loves. A few examples of recent newsletters we've sent out include a fascinating study that linked living close to a golf course linked to a higher risk of Parkinson's disease. The widely circulated study showing that glass bottles might contain higher levels of microplastic than plastic bottles, and the first ever randomized controlled trial on creatine for Alzheimer's disease. We believe that you won't find this information anywhere else, and I encourage you to subscribe today so you can receive the very next email newsletter. You can find that at

4:18foundmyfitness.com forward slash newsletter. Once again, that's foundmyfitness.com forward slash newsletter. Welcome back to the podcast. I'm very excited to be sitting here with Dr. Ben Bickman, who is a professor of cell biology at Brigham Young University, and he specializes in all things metabolic disorders and metabolism, so I'm pretty excited to have a very well-rounded discussion today. Ben, this has been a while. I've been following your research for some time now, so I'm excited to have this conversation with you. I'm too. Yeah, thanks. This will be great.

4:51I kind of wanted to start out with something a little provocative, and I don't want to say surprising. This question for you is, a lot of people that have normal blood glucose levels, quote unquote, can actually be insulin resistant. Why is that? And what is this state of like pre-pre-diabetes, why is it something that is not caught sooner? Yeah, and yet so common. Right. I mean, that adds

5:23an extra layer of reason to talk about this, because it's become the most common problem. People, much of modern clinical care has what I call a glucose-centric paradigm when it comes to monitoring metabolic health, or even cardiometabolic health, given how relevant diabetes and metabolic problems are to cardiovascular disease. But the consequence of the glucose-centric paradigm, and there's reasons for it. So I don't mean to state this in any kind of incriminating way.

5:53They have their own justification for the glucose-centric paradigm, but it's increasingly harder to overlook because of what we know with regards to insulin. So insulin resistance is the state where insulin levels are higher. The body's having to use more and more insulin in order to keep glucose in check. But because it is able to keep glucose at that normal range, it flies under the clinical radar because of our glucose-centric paradigm. The conventional clinician is only measuring glucose every time

6:27the patient's coming in for an annual visit, with no regard to the patient's insulin levels. If we were able to broaden the paradigm a little bit and include insulin, then all of a sudden we are measuring the earliest signs of insulin resistance because it is insulin itself that ought to be measured when we're trying to get that view of the patient's not only metabolic health, but insulin resistance. So to stay all that another way, type 2 diabetes is when both insulin is high, but it's

6:59starting to really lose the war. And now glucose rises as well. Then the conventionally trained clinician says, ah, the glucose is elevated, so you have diabetes or pre-diabetes. But in its earliest stages, the glucose is still normal, but there's this cold war happening in the body where the insulin levels are still two or three or four times higher than they used to be. It needs to be that high, and it's working well enough to keep the glucose in check. And so the glucose-centric paradigm has us

7:31miss the earliest metabolic canary in the coal mine, which is insulin. So the sooner our paradigm with modern medicine includes insulin, then the earlier we can detect these metabolic problems in a person who's progressing towards type 2 diabetes. But also it changes the treatment protocol too, because not to go off on a tangent too soon off the very first question here, but if the longer we ignore the insulin, the more the clinician may be tempted to push the insulin up even higher by giving,

8:05say, a type 2 diabetic an insulin therapy. Now they're pushing the insulin from high to super physiological, all in an effort to control the glucose, little realizing that in the process you're actually killing them faster. Because so much of what kills the type 2 diabetic is not the hyperglycemia, it's the hyperinsulinemia and the insulin resistance. Oh, I definitely want to get into that. Well, just sort of as a follow-up question, in this world we live in now where continuous glucose monitors are so becoming very popular,

8:39many people have them without a prescription, you can get them. Is there any signs or tests using those that people can do to kind of look for this potential problem with, you know, having perhaps high insulin? In fact, they're not measuring insulin but glucose. Yeah, right. Yeah. So to answer the first, the question very directly, I'm an enormous advocate of CGM use. The more we democratize access to CGMs, I think the better we put individuals in a

9:10position to be their own coach. You know, they don't need to have someone like me or you berating them and telling them to change their habits and eat a little better. When you see how your body's responding to what you're eating and the CGM enables that, you end up making your own lifestyle changes. So with the use of the CGM, fasting glucose isn't going to be the best indicator. It's going to be the dynamic glucose. So if you've eaten a carbohydrate heavy meal or a simple carbohydrate, I shouldn't call it a big meal, but a simple carbohydrate like two pieces of bread.

9:43If your glucose levels aren't back down to normal by about two hours, that suggests a problem. So in my mind, the greatest utility of the CGM is to monitor the dynamic changes rather than the static where am I at every morning. That has less value. The dynamic changes are what has value. But beyond the use of the CGM, if a person's curious about their insulin resistance, in many instances, you don't even need to get a blood test. The skin is a window to the metabolic soul where if there are two things you

10:15can observe just on your skin, and they're both generally going to be right around the neck. One of them is a condition called acanthosis nigricans, which is when around the little skin fold that most people have around their neck, the skin will get darker pigmented, which can be harder to tell depending on the pigment of the person's skin. But what is obvious regardless of pigment is the kind of crinkled tissue paper texture of the skin. So the skin will be very sort of roughed,

10:46like crinkled tissue paper. So that's acanthosis nigricans around the neck. And then the other one people know is called skin tags. And that is those little, it's not like a rounded little mole, but rather a distinct little kind of mushroom stock column of skin. People probably know what I'm talking about. You can see them around the neck. Sometimes you can see them around the armpits. But again, it's just a teeny little, like a little mushroom stock almost of skin, skin tags. Both of those are very, very strong evidence of insulin resistance. And the nice thing is, as the insulin

11:20sensitivity improves, those problems go away, just like everything else will. So many researchers, including yourself, do view insulin resistance as a sort of root of causing many different types of chronic diseases, age-related diseases, obviously type 2 diabetes, obesity is in there, cardiovascular disease. Alzheimer's, fatty liver disease, infertility. So why is that something that people think is the root cause of so many chronic diseases? And again,

11:52you know, why do you, you're talking about insulin resistance being common and certainly like this pre-pre-diabetic state being pretty common. What do you think the reason for that is? Yeah. Yeah. So the first part of the question, I unapologetically embrace the view that to some degree, that's italicized wording there, to some degree, insulin resistance is a common root cause for most chronic diseases. So I'm not claiming that it's the singular cause. For example, the connection between insulin resistance and breast and prostate cancers,

12:25the two most common cancers in women and men respectively. I'm not saying insulin resistance is the singular contributor, not at all, but it is absolutely a contributor. With regards to Alzheimer's disease, insulin is not probably the singular contributor, but it is one, undeniably. And the same goes for polycystic ovary syndrome, the most common infertility in women or erectile dysfunction in men and fatty liver disease and hypertension. So when I, in fact, this question

12:55is the question I asked myself as an academic in, at my university, when I got tenure, I thought, I looked at the rest at my future career. And I thought, do I want my career to be defined by the number of peer reviewed papers I publish in science journals? And I thought, no, that's not enough because most people will never read those articles. No one will ever get a direct benefit from them. And I thought, what would be the one message as a biomedical metabolic scientist that I would want to convey to people? And it was this one. It was that to some degree, most of chronic disease can be

13:31attributed to one common origin. And so rather than trimming at the branches of this sick tree, where we're giving the patient a drug for their Alzheimer's disease, we're giving them a patient for a drug for their hypertension, we're giving them a drug for their infertility. What if all of those were actually just branches coming off of one tree, let's just cut down the tree. So when we can acknowledge a sort of common soil hypothesis, it starts to simplify the clinical approach. So all of this, in my mind,

14:07is a reflection of just how powerful the hormone insulin is. Most individuals only think about insulin as being a hormone that controls blood sugar, which is fantastically unfair. Insulin is one of the few peptide hormones that will literally affect every single cell of the body, from brain cells to bone cells, lung cells to liver cells, and every cell in between. There's no exception. Insulin will have an effect at every cell of the body. And the particular pathology with insulin resistance is unique because you have some cells that aren't responding very well to insulin, like in the case

14:43of erectile dysfunction. Insulin is less capable at producing nitric oxide in the endothelium of the blood vessels, so there's less vasodilation. Less vasodilation means compromised erectile function. So on one hand, you have some cells that suffer because they're not responding. But on the other hand, you have some cells that are overstimulated because insulin resistance is insulin not working the same at all cells of the body, and blood insulin levels are higher. So there's too much insulin.

15:15Some cells are responding too much to that insulin. So with polycystic ovary syndrome, for example, that's not a problem of the insulin signal not working well. That's a problem of there being too much insulin, stimulating the ovary to inhibit the conversion of testosterone into estrogens, and thus she manifests with polycystic ovaries. So to some degree, most chronic diseases can be connected back to insulin resistance. And to me, that has a tremendous power. That's a reason to focus on that disorder. So some researchers think that the high insulin is more of a response to ectopic

15:53fat accumulation, obesity sort of being the underlying cause of the high insulin. So how do you kind of differentiate between this cause and effect? What role does ectopic fat accumulation have in insulin resistance causing high insulin? Yeah, that's a great question. In fact, that's a big question. And I already am too long winded with my answers. So I'm going to try to be concise here. I look at the origins of insulin resistance as being one of two, one of two origins, where you

16:24have what I call fast insulin resistance, and then slow insulin resistance. And what you're touching on is the slow insulin resistance, which I'll come to in just a second. Within the fast insulin resistance side, there are three what I call primary stimuli that in humans have been confirmed and in rodents and isolated cell cultures that can cause insulin resistance quickly, like within hours. But at the same time, if the stimulus is removed, the insulin resistance is resolved in short order. And that is

16:54stress. So elevated stress hormones, whether it's cortisol or epinephrine, adrenaline will cause acute insulin resistance in humans. As that stimulus goes away, the problem resolves. Next is inflammation. If you increase the levels of inflammatory cytokines in cells or rodents or humans, they will be insulin resistant very quickly. In fact, people wearing CGMs may notice this, that the CGM may reveal that they're starting to get a cold or a flu, because they notice that their glucose levels, they're having a much harder time controlling them, even though their habits haven't

17:28changed. That's often a sign of inflammation. But even with autoimmune diseases, where you have people where the autoimmune disease will ebb and flow, so too will the insulin resistance, it will track very well with the how active the disease is. And then lastly, of the primary fast causes of insulin resistance is too much insulin itself. So we know in humans, rodents and cells, I've published my own work on this topic, that too much insulin will result in a resistance to the stimulus. So too much insulin can cause insulin resistance. Now, none of those

18:04touch on what you had mentioned, which is the ectopic idea. That idea is very important. And there's a lot of nuance to it, where we have to define the fat, first of all. And by that, I mean, what of the many of the hundreds of thousands of types of molecules that we call a lipid or a fat within a cell, which are the ones that actually matter to insulin resistance. Some people will think of just triglycerides, which is the main form of storing fat. And yet triglycerides are totally inert metabolically. There was a case in

18:36point, Brett Goodpastor and David Kelly, 30 years ago, described this phenomenon of the athlete's paradox, where they noted that in obesity, with type 2 diabetes and insulin resistance, if you pull a muscle biopsy, there's really high levels of fat in the muscle of triglycerides. And they're very insulin resistant. And so some people would say and did at the time, well, high muscle triglycerides causes insulin resistance. And yet, when they did muscle biopsies from very lean, exceptionally

19:07insulin sensitive marathon runners, they had just as much fat in their muscle in the form of triglycerides as the obese type 2 diabetics did. And again, they were very insulin sensitive. So it couldn't be the fat that was being stored in the muscle. The same could be said of the liver. If the liver has triglycerides, it's not the triglycerides that are causing insulin resistance. So what is it? If there is any lipid that's to blame, it's going to be a lipid called ceramides. And those do not

19:38track the same across these, say, the lean marathon runner and the obese type 2 diabetic. When you start measuring levels of tissue ceramides or its precursor dihydroceramides, there's still some debate as which of the two matters most. I'm very strongly just saying it's one of them. And so I'll just say ceramides as a family. You can, in any biological model, cause very strong, robust insulin resistance just by increasing the ceramides because ceramides will block the insulin signal. When insulin binds to its receptor, then you have a series of phosphorylation events.

20:15Ceramides block that very well. It's a very well-defined pathway. And if you can just do one thing and just resolve the ceramides, you correct the insulin signaling. So when it comes to ectopic fat, it's not a matter of how much triglycerides you're storing, but rather what is the entire metabolic milieu to be promoting ceramides in various tissues throughout the body. Interestingly, all of those primary stimuli, the quick insulin resistance, all induce ceramide biosynthesis and accrual. But with the slow insulin resistance, I still think

20:48it's appropriate to invoke fat. But by that, it's the fat tissue. And I don't want to get ahead of us. But my view is that among, if you look at tissue level insulin resistance, is it starting in the muscle or the liver or the fat? I'm very much an advocate of the fat first focus when it comes to insulin resistance from that slow, progressive, it settles in over years. And it may take, you know, weeks to months in order to reverse. Yeah, well, this is, we've got a lot to dive into here. I mean, it's funny, I remember my one of my first

21:20projects as a budding young scientist was to look at insulin resistance, like, like free fatty acids. And can you make like a little nematode worm insulin resistant? And, you know, it, it, from my understanding, had to do with the adipocyte cell and this sort of spillover of ceramides that are then attacking. It all had to do with the AKT signaling pathway, which, you know, stopping basically the insulin receptor. Yeah, I think that's exactly, and that's where, that's where ceramides act.

21:51Right. You mentioned AKT. That's what we would measure. And you must have too. We would measure a particular protein in AKT for, or an amino acid residue for phosphorylation, and then look at one other downstream signal. And then we can do some other more complicated metrics, but that was always the absolute baseline. I, in fact, I've run so many Western blots measuring phospho-AKT that next time I, if I have to have, if I ever have to run another, I'm going to like shove the pipette in my eyeball. I'm so tired of it. Well, it's just one of those things that, you know, when you do experiments and especially when it's like something, one of your first projects, you kind of remember it. And so, you know, as I became

22:26interested in nutrition, you know, later on down the line, and it's like, well, it always stuck with me. Like there's, there's a role for fatty acids in causing insulin resistance. Oh, there is. So, so that was something that kind of stuck in my head, but, and I think we're going to get, we're going to get into some of the dietary causes in just a minute, but like beyond, you know, we're talking about, you kind of hinted at this earlier, insulin has many roles. And oftentimes the general public thinks about its role in just regulating blood glucose levels, but maybe you

22:57could just talk about some of the other roles insulin plays, for example, in fat accumulation. Oh yeah, for sure. Yeah. In fact, we've, I've already touched on a few, like, for example, who would have imagined that insulin regulates the enzyme that's responsible for the conversion of testosterone to estrogens, for goodness sake. And yet it does. Insulin has a direct inhibitory role on aromatase, that enzyme that mediates the conversion and the synthesis of estrogens in men and women. It also regulates nitric oxide production, regulating dilation of blood vessels

23:28and other hormones throughout the body that affect water retention, salt signaling, neuron conductance of signals and, and more. But when the, at the fat cell, insulin probably has its most powerful effect where the, you cannot under, now we're touching on a broader topic of why do we get fat here. And I welcome that topic. In fact, of all the human tissue I've studied the most in my lab, it's fat tissue that we've, when we, we started doing fat biopsies in

23:59my lab a few years ago, and that's the tissue we study the most. So I'm very comfortable talking about adipose tissue physiology. There is, as much as there is the debate in two camps of what makes fat cells grow. It's just purely a matter of thermodynamics or no, it's purely a matter of endocrinology. The truth is, of course, you actually have to have both. You cannot under any circumstance make a fat cell get big unless you have both. Just to make a, put a fine point on that, if you have

24:30all the calories in the world, so I grow fat cells in, in petri dishes in my lab right now, back at BYU, I got students growing fat cells in the incubator. They are swimming in a culture medium filled with calories. Everything the fat cell needs is all the calories that fat cell could ever want are around it right now. And yet they're teeny little cells. They're not getting big at all until we add one thing. And the moment we add insulin into that culture, now the fat cells start to get big. If we

25:01check them six hours later, there's a big lipid droplet. Six hours still later, it's even bigger. So in other words, the fat cell knows what to do with the energy that it has access to. A cell doesn't have any kind of intuitive intellect to think, okay, there's calories here, or more accurately, carbons that I can turn into triglycerides, and I'm going to take them in and store them. But in the context of the body, the fat cell needs to know, am I playing nice with the rest of the body? How stupid would it be if we got up and we go out on a jog outside? Our fat cells are breaking down

25:37triglycerides as free fatty acids by activating lipolysis. And yet at the same time, they're pulling them right back in to store them. That would be stupid. The fat cell wants to cooperate well and be part of the orchestra of the body. And so it will be releasing its fat so that the muscle can take it up. But if insulin were elevated, so insulin acts as the signal, basically telling the fat cell when it's time to eat and when it's time to share. So to, and then let's, if we flip it, in fact, actually, I'll stay there for one more second. We even see this, someone could say,

26:11well, Ben, that's just in fat cells. What about humans? In fact, humans provide the most convincing evidence of all that you cannot get fat unless insulin is elevated. Because one of the more common eating disorders among young people with type 1 diabetes is a condition called diabulimia, which is this terrible, tragic scenario where the person feels such pressure to be lean. And they have learned that that little syringe of insulin is the absolute gatekeeper of the fat cell.

26:41So they will deliberately underdose their insulin in order to stay as thin as they want. They can eat as much as they want. And as long as they underdose their insulin, and it's not even at zero, they're just doing a deliberately lower dose, they will be as skinny as they want. Now there's metabolic hell to pay, right? They're hyperglycemic, they're getting into ketoacidosis. So they're dying, but they'll be as thin as they want. So as much as people want to say, no, it's just calories, we have a human case study that absolutely proves that wrong, that it's not just calories. Now, having said all that,

27:13I'm not claiming calories don't matter. Because on the other hand, if you just have high insulin in the absence of sufficient calories coming in, that's also incompatible with life and the person will die. Because if you, if you and I were fasting, in fact, Dr. George Cahill did these studies about 40 years ago, you could never get IRB approval to do it now. He would fast men for days and then give them an insulin dose and drive their glucose levels down to about 20 milligrams per deciliter, just to see how low could the glucose get and the person maintains consciousness. And

27:47they did. But suffice it to say, if you spike insulin, which is telling the body to store energy, but there's not energy coming in, then the total energy available in the blood drops to essentially zero. Glucose goes down to zero, ketones go to zero, fatty acids go to zero because you're inhibiting lipolysis, you're inhibiting ketogenesis, you're stimulating glucose uptake. Now the brain has no energy because it doesn't have a reserve of energy like the liver or the fat cells or the muscle. And so as blood energy goes to essentially zero, the brain shuts off.

28:18So coming back to the fat cell, you have to have both. You have to have elevated insulin sufficient to tell the fat cell to store that energy, but then you have to have the energy to store. So calories matter, but so too does the insulin stimulus, because in the absence of the insulin stimulus, there is no such thing as fat storage. And indeed, the body can't stop breaking down the fat. And in fact, that's what ketones are. Ketones are nothing more than a sign of the liver burning a lot of fat,

28:51where it's burning so much fat, it has such an abundance of acetyl-CoA that it can no longer feed the acetyl-CoA into the citrate cycle because it's too full. It cannot divert it to lipogenesis because insulin is low. So that pathway is inhibited or not activated. And then the only other option of all that acetyl-CoA is ketogenesis. So ketones are simply sort of this overflow, this metabolic release valve of fat burning. But they go one step further, if you'll allow me, where how do we then

29:24reconcile it? What is it about insulin? Like if I'm not saying calories don't matter, I'm not trying to break the laws of thermodynamics. In fact, my PhD is bioenergetics. I have a unique appreciation for energy in organisms. So those carbons need to be accounted for. But the more insulin is low, you have two adaptations that allow the body to stay lean or to not store that excess that they're eating as fat, which is one, a higher metabolic rate by several hundred calories a day when insulin

29:58goes down. So the body's just burning a little hotter. The engine is revving higher. So the overall energy expenditure is up again by two to 500 calories a day. And when you're in ketosis, you're eliminating ketones through the breath and the urine. And every ketone that a person's breathing out or urinating out has a caloric value roughly similar to glucose. So you're just excreting calories from the body. So the net effect of all of that can be up to 800 or so calories a day that the person's just wasting.

30:30Okay. Well, we're really getting into this sort of underlying cause of what, you know, what's causing the insulin resistance, what, I mean, obviously the, what's causing the high insulin as well. And then ultimately obesity is in that mixture as well. And I think, you know, refined carbohydrates is something that you've mentioned. And I think a lot of people think that refined carbohydrates definitely play a role in insulin resistance, perhaps the primary role, but aside from the

31:02obesity, as you're talking about obesity being that slow forming insulin resistance. What role can we talk a little bit deeper about carbohydrates, refined carbohydrates, saturated fats is also something you touched on the ceramide, you know, as well, we know, palmitate kind of plays into that pathway. And so what role do dietary carbs refined versus maybe complex saturated fats play? And then is this all in the background of caloric excess or, or, you know, being in a deficit? Does that matter

31:37as well? The mixture of the two sort of like, cause there's nuance here. Oh yeah, there is kind of get into it. In fact, the big, a big nuance is the calories. And this is where I need to be careful because the, the degree of studies that have looked at these interventions that you're alluding to, and I'll touch on more now in low calorie or hyper calorie, it's not been fully fleshed out, but I would think it's safe to say if there is a caloric deficit, then it becomes less relevant. Um, which of the, the balance of saturated fats to refined carbs. Now then someone

32:11would say, well, then let's just always live in a caloric deficit. Yeah. Good luck with that. I mean, if it were, if it were that easy, then people would just shrug their shoulders and say, okay, I'm just going to be on a low calorie diet for the rest of my life. So, so if you're on a, if you're in a caloric deficit and you're eating, you know, some refined carbs, then it's not necessarily. I think you have more wiggle room. You have more wiggle room. I think you do. Yeah. Yeah. Um, I, I'm, I'm comfortable saying that. And then again, I just have to counter that by saying that's not really feasible longterm. You know, people get hungry, hunger, always wins. Yeah. Yeah. You got it. You got to eat. Yeah. You got to eat. You got to fuel the body.

32:43So you can't be in that kind of chronic low calorie state. So my view on, so saturated fats is one of the more polarizing topics. And I'm very comfortable talking about it because my entire postdoctoral fellowship was looking at, I shouldn't say entire, my biggest paper ever published was looking at the degree to which different fatty acids are capable of causing insulin resistance through the conversion into ceramides. And I'm going to upset some people, but in cell cultures, if you treat cells with

33:16saturated fat, palmitate, which is the main saturated fat in the body, you get insulin resistance very quickly. Now, if you block ceramides, you resolve that insulin resistance. If you treat those cells with monounsaturated fatty acid, no insulin resistance. If you treat those cells with polyunsaturated fatty acid, no insulin resistance. So as much as there is, and I believe it's justified, a very heavy focus on seed oils, I, I approve of that focus. I think they're pathogenic, but I grimace

33:48when people invoke them as a primary cause of insulin resistance, because the data do not support it. Again, I think they're very harmful, but not when it comes to insulin resistance, because you can, in fact, we would treat cells with palmitate, cause insulin resistance, co-treat them, co-incubate the cells with either oleic acid or linoleic acid, and we would reverse the insulin resistance. Now, I do not mean to give seed oils a pass. I think they're highly pathogenic, but not within-

34:18Well, there's other dietary sources of linoleic acid. There are, and you can't even avoid them, really. Yeah, yeah, and meat. I mean, literally any animal source of fat, any animal food has some linoleic acid in it. It's ubiquitous. You would just, you know, want to control it, I guess. So with regards to saturated fat, that my own work, when I published that paper in 2010, maybe, I left that project with this idea that saturated fats are thus a cause of insulin resistance. And I had to challenge my own

34:53assumptions when I saw the work of Dr. Jeff Volick, a friend and a legend in the realm of low carbohydrate studies, because he published some incredibly compelling papers. Over a few papers, he found that I had to sort of challenge the model where I thought, all right, I was treating cells with saturated fat. Is that the same as a human eating it? And of course it's not. And now to touch on his work, you can have humans that if the carbohydrate levels are going down,

35:24they can eat two or three or four times more saturated fat than a high carb group. And then they're circulating levels of saturated fat. So the saturated fat in sum in the plasma, is significantly lower. That's because most of the saturated fat that's flowing through our veins is coming from the liver. When the liver is told to make fat through de novo lipogenesis, the fat that it makes is palmitate. So most of the fat, most of the saturated fat we have flowing through our blood that's going to get to a cell is going to be coming from what the liver is making,

35:58not from what we're eating. And he showed this very, very well. But that's only in the background of low carb. Exactly. Yeah. So in fact, I won't even elaborate more on that if that point's clear. So the lower carbs are getting, the more you can eat saturated fat and appear to have no deficit. I'm very comfortable with that. No deficit in insulin resistance. Okay. And indeed- But calories aren't an issue in that context, really. I don't recall whether they had it in a low calorie context or not. I would suspect, because insulin is low, once again, you probably have a little more of that metabolic wiggle room

36:31with the higher metabolic rate and then the ketone wasting. So it starts to get a little cloudy. Okay. So the saturated fat scenario is that there is definitely a pathway to insulin resistance. However, it seems as though if you're more of a ketogenic type of eater, low carb ketogenic type of eater, that pathway doesn't seem to be relevant. I'm very comfortable with that. Yeah. In fact, that's a great way of stating it. The lower the carbs are getting, the less the dietary saturated fat matters. Now, in the context of a higher carb

37:05diet, as much as it pains me to admit, because I'm such a defender of saturated fats, there are a couple studies that are very well done. If I recall, it was some groups in Europe, in the European Journal of Clinical Nutrition, where they had in the context of a high carb diet, and then manipulating the saturation of fats, the high carb and high saturated fat was the worst for insulin resistance and insulin signaling. And so when it comes to, again, the background of high carb, then I, as much as it pains me to admit, because I'm such a defender of saturated fats from natural sources, which is where

37:42they come from, that begins to be problematic. I think it's problematic and not just, you know, for metabolic health, but cardiometabolic health. I mean, that's where you get small dense LDL particles. Again, it's the combination of the saturated fat and the refined carbohydrates. Now, are we talking about when you're having, you know, a high saturated fat diet in combination with what you call carbohydrate, high carb? I mean, is this, what if you're eating, you know, fruits and vegetables and, you know, maybe some oats? Is that the same as eating cookies and processed foods?

38:17Yeah, no, of course, the easy answer would be no, but I can't recall the specifics of that study. And anytime I can't cite a study, I want to be careful in the answer. But my view would be, what is the underlying insulin effect of those carbs? So if these are low glycemic load type carbs, where the insulin response is going to be very modest, right? Insulin itself causes insulin resistance, and again, rapidly. And so what I think is, if you take the context of an insulin spike with a saturated fat load, that's uniquely harmful with regards to insulin resistance. So back to the idea

38:53of what are the carbs? I think if you're talking about the low glycemic load carbs, like cruciferous vegetables and berries and citrus fruits, for example, no, there's almost nothing. And then you chase that down with a tablespoon of coconut oil, the most concentrated form of saturated fat on the planet, I think you're fine. Well, coconut oil is a bit of an outlier, because so much of it's MCT, which doesn't follow, which is not a substrate for ceramides, so it doesn't quite fit. But in that case, no, I think that would be perfectly fine. But you are touching on what is, to me, the obvious

39:28villain, as much as we have increasingly two camps of people saying, no, it's the seed oils. And I'm generally more just because I'm an insulin resistance guy in the notes, refined starches and sugars. The fact is, they always come together. And so the more a person has a dietary ideology, that's just simply based on the idea of don't get your carbs, or don't get your food from bags and boxes with barcodes, you're getting rid of both the refined starches and sugars and the refined oils. Anything else is going to be fine for the average for most people, just less bags and boxes with

40:01barcodes, more whole foods, you're fine. And but what about like fructose versus glucose? If you're having more fructose in the fruit, is that really causing the same insulin response as a refined sugar? No, it's not. No, it absolutely is not. No, fructose itself will not elicit an insulin response whatsoever. Now, the body will convert some of that fructose to glucose, which is why the diabetic who's gone hypoglycemic can just drink a cup of orange juice. And within minutes, it'll start to you know, that's such a concentrated load of fructose that they will see a glycemic excursion. But no, fructose

40:32isn't the same. But even still, depending on the person, you know, you and I were two lean, healthy people, we could get away with it. If I'm talking to an overweight type two diabetic, then I say, all right, well, the most sugary of the fruits, just be more careful with like say, mango or banana. Um, then I would say, all right, you maybe want to be a little more careful because your disorder is you don't burn glucose, you don't burn sugar very well. And so you just be careful with the most sugary of the fruits, but then everything else enjoy liberally. Um, so with respect to insulin

41:06resistance and weight loss and obesity and what's causing like the cause of these things, right? I mean, this is where we get into, there's also this sort of war between saturated fat versus sort of a high carb diet. And can you lose weight on one or the other better? And that's where Kevin Hall's study was kind of interesting. I'd love to get your thoughts because, so he's published a study back in 2021, NIH did a pretty well-controlled study where people were on a higher carb diet or they

41:36were on a ketogenic diet. They were isocaloric, so same calories. But if I recall the- No, in fact, they were, they were able, it was ad libitum. And then they found, they found that the plant-based group just spontaneously ate less. So yeah. So the 2021 study, they, one of the powers of that study, and it's not a perfect one, which I can articulate, was that they allowed them to just eat freely, but you got to follow these kinds of balance and you follow this pattern, you follow that pattern. And if I recall the plant-based, he, he, um, rejoiced in the fact that it challenged the

42:12carbohydrate insulin theory of obesity, which I can articulate in a moment because they found that the higher carb group spontaneously ate about 700 calories a day less. Does that sound right? I think that's right. So they, they just spontaneously were eating less because they could eat freely. They just ate in 700 calories a day is a meaningful amount to just spontaneously eat less of. That did challenge the idea because one view I actually don't like- But did they lose more fat as well?

42:42Yeah, they did. They did. Yeah. But it was, this is modest. I mean, to, to, to, to be fair to the study, they did a good job controlling it. To be a little critical of the study, the findings were exceptionally modest. This is the kind of thing where it was like one pound versus two pounds and it was two weeks and it was a very small study. And, and a lot of what Kevin has done is a lot of these kind of mathematical modeling outcomes where they sort of speculate or extrapolate beyond the data that they get. So they, they found that they spontaneously ate 700 calories a day less. That

43:15challenged one of the central ideas of the carbohydrate insulin model, which is if you spike insulin, you get hungry. And he was saying, well, they ate all these carbs. Mind you, it was mostly plant-based. Complex carbs. Exactly. So that's right. And so it's almost, it's a little unfair because that's not how most people are getting their carbs these days. And, and just to put a fine point on that point, 70% of all calories consumed globally, it's about 60% in the U S are carbohydrates and they're not

43:46coming from leafy greens and berries and, and, you know, citrus fruits. It's coming from bags and boxes with barcodes, but nevertheless, that's an interesting finding. My, my criticism of that is, one, it's an extremely short-term study. And there are longer studies that we ought to highlight just to offset this very short study. But at the same time, when you're eating so much fruits and vegetables, you're putting a lot of bulk in your stomach. And it didn't surprise me that these may

44:16be people who within just two weeks on this diet were just probably having a lot of bloating and gas from eating a lot of plants when they probably weren't eating that many plants before they started the diet. So it didn't entirely surprise me that they were spontaneously eating less. I would personally enjoy eating more meat than I would big leafy greens and other fruits and vegetables. So I would probably eat more calories. The fact at the end of the two weeks, in fact, what's funny is I looked at the outcome and thought, okay, the low carb group was eating 700 calories

44:49more per day. And you're telling me they only gained like one more. They only had one more pound of fat. If anything, you could have looked at all that data and said, wow, there is a metabolic advantage to a low carb diet. And in fact, some of the studies, Kevin Hall, of his own work that he's trying to distance himself from is finding that in a ketogenic state, people have a significantly higher metabolic rate. And so perhaps one outcome of that study is that when a person gets to ketosis, they were able to eat 700 calories more per day and only had one more pound of fat than the other

45:25group did, that to me is a pretty big win. And that touches on something that's become a theme for my lab, where if you'll allow me very briefly, and we'll try to be brief, I'm not very good at that. But over 100 years ago, two famous legendary scientists, Francis Benedict, who you and I may recall created what's called the Benedict equation, which is an equation that is still used to this day to try to assess metabolic rate based on someone's body size. So the Benedict equation, this legend

45:56of energy expenditure, he collaborated with Elliot P. Joslin, who the most famous endocrinology clinic in the world, the Joslin Diabetes Center is named after him. So you had these two legends in their own realm, who tried to understand the metabolism of people in what they called severe diabetes, which we would call type one, they found that their metabolic rate was about 20% too high. And then years later, when insulin began to be a therapy, a group at Minnesota, the first authors

46:28Nair, Sri Nair, N-A-I-R, they not only confirmed the findings from 60 or 70 years earlier, that in type one diabetes, the metabolic rate is too high, like something's broken, they're burning too hot. But when you gave them insulin within minutes, the metabolic rate began to slow down. And so all of this back to that study from 2021. The reason I even brought all of this up is to me, that's further evidence of the lower insulin gets, like with a low carb diet, the more metabolic wiggle room a person has, where energy expenditures up by several hundred calories a day. And we found in human work, that part

47:07of it is because the fat tissue starts having a much higher metabolic rate when insulin comes down, there's much more mitochondrial uncoupling. So the engine is just revving and revving and burning energy just to create heat. But at the same time, the more you're making ketones, the more you're expelling those ketones, and ketones are calories. And so maybe those 700 calories a day that the low carb group is eating in excess, the fact that they only had one other pound of fat could be that they were just burning the rest off because of these metabolic advantages.

47:37Well, speaking of wiggle room, I mean, we're talking about a variety of scenarios here where people can have wiggle room. We talked about, you know, being in caloric deficit, gives you a little more wiggle room. Being in a ketogenic or, you know, close to a ketogenic state seems to give you more wiggle room. But what about being highly physically active? Absolutely. Yeah, good. I love how you're framing that with this context, these themes of wiggle room, where do you have a little bit of margin to work with? Yeah, absolutely. Exercise is one of those other outlet, if you will, where if you have energy that you need to account for, exercise is going to be a

48:16I often don't focus so much on exercise because I don't want to convey to people that it can outdo the diet. There was a paper published in Women where they looked at a very structured and intense exercise program with just, it was, I think it was just low carb diet. And the low carb diet had better metabolic improvements than the strength training did. And so diet is going to generally smart, smartly done diet. So changing nutrition is going to yield better long-term benefits with metabolic

48:48health. However, the exercise, I'm an enormous advocate of exercise. And to me, you are not going to go, it's one thing to be metabolically healthy and lean, but then it's something else to be lean and sick or, or, or, or weak or frail. And that's where to me, the exercise comes in. So my, my view is you eat smart to be lean and metabolically sound. You exercise to be strong and capable and metabolically sound. So muscle of course is the great glucose consumer. When, if someone's wearing

49:23their CGM and they see the glucose come up and down, 80% of that coming down is what's going in to fuel the muscle. The muscle is just by mass so big and so hungry that the more muscle you have, the more you're going to have this big buffer or what we're calling wiggle room, where you're going to clear, you're going to clear that glucose much, much faster. So if you had two people of equal body mass, but one having more fat, one having more muscle, but otherwise the same. And that's a big difference though. I know they eat the same amount of carbs. The guy with more muscle is going to have his

49:56glucose curve come up and down and it'll be back down to normal in an hour, maybe 90 minutes. The person who has less muscle, even more fat. So same body mass there, it's going to take much, much longer for that glucose to come down and thus take longer for the insulin to come down because muscle is the main place where insulin is going to escort the glucose to. And it does so very well if, so the more muscle mass a person has, the more sort of metabolic wiggle room they have to clear that glucose. And then the more carbs they can eat, as much as I really point the finger at

50:30carbs as a primary problem, the more they can eat. And even to the point where if a person's very active, I knew a guy who was training for a marathon, he would eat over 200 grams of carbs per day and still be in deep ketosis the next morning. You'd think, well, no, normally a ketogenic diet is no more than 50 grams. Well, unless you're just burning that glucose. Right. And also you mentioned this study that was comparing strength training to the low carb. Right. Well, I think also high intensity interval training, when you're doing,

51:02you know, there's a lot of work on, so we're talking about how exercise can improve metabolic health. And I think it is a really important lever to pull here because you're activating these GLUT4 transporters and it does that. Like that activation happens through lactate, the generation of lactate, which is happening when you're really pushing yourself hard. And so at that point, you know, you're becoming insulin sensitive too, right? You are. So you're really kind of changing the scenario in some ways. It doesn't, I don't personally

51:32think it should give people the justification to go and eat tons of pizzas and, you know, ice cream and all that stuff. You know, cheating once in a while is fine. But like, I think that you can't, you definitely can, you can't out, you can out eat exercise in other words. But you can't out exercise bed. Right. Exactly. You can't out exercise bed. But I do think exercise is extremely important, especially like there's different types of exercises. That was kind of another question, you know, the strength training versus like really going hard or,

52:05or the long endurance training, right? So high intensity interval training, you can kind of get away with doing less time, but you're going really hard, right? You're pushing that. And I am unapologetically an advocate of that. As much as people may look at their day and say, I have one hour, I would say everyone, man, woman, old, young, strength train, strength train.

52:24Maybe someone, I sometimes question my own motivations where I just think if I were in a crisis situation, would my ability to run away from the challenge be better than my ability to face the challenge? No, I don't think so. Because I'm going to be with my wife and kids. And the fact that I can outrun them isn't going to solve the problem. And so I want to be ready to do something if I need to. But even beyond that silly, dramatic scenario, the bigger the muscle, the hungrier the muscle. And given the time constraints that most people have, but even then there are studies to

52:55show that minute for minute at that shorter end, if a person spending, I think it was like 30 minutes a day, the strength training group had better improvements in insulin sensitivity than the aerobic training group. So if you have constrained time, and let's face it, everybody does default to strength training, whatever degree of strength training you can get. And just to touch on your point about intensity, just try to go to failure, at least at some point during that overall muscle or that movement. It doesn't have to be a high weight, low rep. Even if you're doing a lower weight,

53:29higher rep, just get to failure. Fatigue yourself. Yeah, fatigue yourself. Yeah. Yeah. And that's where, like, if you're in the context of aerobic training, I think that's also like there's a spectrum, right? Like, well, what were they doing? Were they able to talk? You know, if they're really going hard, again... Which zone are they in? Right. You know, it really, it does make a difference with respect to your, how you're pushing that lever for, you know, insulin sensitivity and your glute transporters and them sort of translocating up to the muscle and opening the floodgates. And so, yeah, it's nice to know,

54:00in other words, there's many roads to roam. And so, I do, I'm just trying to, you know, there's definitely a lot of diet wars out there. And I do think it's important to keep in mind that biology is complicated. There's a lot of things going on here. And yes, having a low carb diet can be very beneficial for insulin sensitivity, for staving off insulin resistance. But there's also people that are not going to eat a low carb diet. And they can still be very metabolically healthy, particularly if they're avoiding refined carbohydrates, they're exercising, they're

54:32not overeating, they're not in a caloric surplus. And then there's people that hear saturated fats okay, and they don't quite understand the whole context of it. And they'll eat a lot of carbs with it. And that's the worst case scenario, where you're combining the two. Yeah. Well, to me, high fat, high carb is the worst combination for every outcome. You'd mentioned cardiometabolic with regards to adverse changes in lipoprotein profile. Absolutely. I agree with that. But high carb and high fat, just bringing it back to the fat cell, you are now

55:04giving it a stimulus of insulin, which is telling the fat cell to get big. And the fat cell wants to get big most easily just by pulling in fat, which if you're eating fat, it's going to pull in very happily, but it won't if insulin is low. And so, you know, that's why you can sort of pick which variable you're going to play around with. Not that you've asked this, but then having touched on what causes the growth of the fat cell, naturally, it begs the question, what shrinks the fat cell? Well, you look at those two levers, the high insulin and the high calorie,

55:34you have to pick one. My only worry is as much as people are so ardently defending the caloric view, which they have for a century now, if you just cut calories without addressing someone's underlying high insulin, you're going to make them hungry very quickly. And that's one of the reasons why I speak to the insulin side, as much as I acknowledge the calorie side, I think that is a step to take. It just shouldn't be the first step. What I like to see is the first step is control your insulin. Okay, how do I do that? Well, reduce your consumption of refined carbs.

56:06So make sure you're getting a lot of good protein and fat, and then fruits and vegetables, that's going to help your insulin come down. Don't worry about your calories yet. We'll get there later. And just by focusing on the lowering insulin aspect, you have the metabolic advantages come into place, which is metabolic rate goes up, calorie wasting through ketone excretion goes up. And so you're going to start to lose weight. And then when you get to that next sort of plateau, all right, now we can look at that calorie side. Because with lower insulin, your brain is more accustomed to

56:38using ketones now. And you're more accustomed to you mobilizing fat, you have more mitochondria, because you've been burning more fat with low insulin. Now you can start cutting calories and not have to worry about hunger, kicking you out. The most obvious example of the problem with just going after calories without addressing a high insulin would be perhaps like the biggest loser, hunger, where you never see a reunion tour with those poor contestants, because they gain everything back. Right. Hunger always wins. It's true. I definitely we're going to I want to get more

57:14into some of what you touched on. But I kind of want to just complete this, you know, talk about a little bit more about what's the underlying cause of insulin resistance. We've talked about diet composition. That's a big one. What about meal frequency? So how often you're eating if you're a snacker, if you're when you're eating, if you're late night eating, or if you're a shift worker? Yeah, how does that play a role? Yeah, well, we pity the shift workers and bless them for everything they're doing for community. But that's the worst way to do it. So with regards to meal frequency,

57:48I think that our the advice that we've been giving since the 19 unofficially since the 1960s, officially since the late 1970s of high carb diet, and then what transitioned into with the food guy pyramid, and then what transitioned into eating multiple small meals per day, I think the proof is in the pudding, which is that's how most people eat. They eat a starchy, sugary, terrible breakfast, and they need a mid morning snack, and then they need a lunch, then they need an afternoon snack, and then dinner than an evening snack. We can see the consequences, which is insulin resistance and

58:23obesity are the most common problems. Even where obesity is not common, insulin resistance is still common. Not to go on a tangent too much, but even countries like Japan or Singapore, my second home, one of my kids was born there, I did my fellowship in Singapore. Why would the beautiful little island of Singapore care so much about diabetes when the average Singaporean is incredibly lean? Because their rates of diabetes are higher than ours by a lot. We're not even close to the most diabetic country, and that actually comes back to how we store fat. So with regards to meal frequency and

58:56what we eat, I think high carb diet with abundant calories and eating multiple times a day is the worst way to do it. So I would think it'd be better to have fewer meals, two to three meals a day, where you're controlling carbs. So whole fruits and vegetables, enjoy them. And then good proteins and fats, enjoy them liberally. But this isn't convenient in social or family situations. But the more you can stack your meals to be earlier in the day, the better. So studies that have looked at

59:29humans finding where they do the kind of intermittent fasting or time-restricted eating of you have one group eat breakfast and lunch, one group eat lunch and supper. The lunch and supper group has worse outcomes. Not that they're not better. I mean, any one of those is better than the standard. But when you compare the two, the outcomes are better for the meals being earlier in the day. Now, you and I are parents. How awkward would it be for me to come home and just sit around the dinner table and look at my darling wife and kids eat dinner while I'm not? I'm not going to do that. And so as much as me as a

1:00:03scientist knowing that it would be better for me to have breakfast and lunch and fast through later part of the day, including supper, I'm not going to do that. Because I care more about being a husband and father than I do about having a six pack or whatever. So I'm going to, my own way of doing it is, well, maybe without, I don't need to explain my own situation, but I think that intermittent, finding one meal of the day or at a minimum, just have three meals a day and try to have about four hours between those meals. And then the most important thing I would say, and this is where

1:00:36we pity the shift workers and thank them, it would be evening. Do not snack in the evening. Especially one of the things I think that people don't appreciate is as much as they're monitoring their sleep and they're wondering why they have night after night, terrible sleep habits. The most common cause of insomnia is elevated body temperature. So they're too hot. And one of the most common causes of being too hot is hyperglycemia. Most people don't appreciate that when your blood glucose levels spike, you activate your sympathetic nervous system.

1:01:08And of all the times of the day when your sympathetic nervous system is activated, you don't want it to be turned on when you're trying to go to bed. That's when you want the parasympathetic to dominate. So when someone eats that evening snack of spiking their blood sugar, then they go to bed in a hyperglycemic state, they're going to have all of the signs and symptoms of anxiety. They're going to be laying there hot. Their heart is going to be beating hard and fast. And they're going to feel that pulse pounding and wonder, what am I anxious about? Why can't I just sleep? Well, it's not because you have anxiety. It's because you went

1:01:42to bed hyperglycemic. But unfortunately, that is the one time of day where people are at their weakest. And I'm very sympathetic to that because I feel the same thing. People can walk past treats and junk food all day and deny themselves that, knowing that it's not good for them. But the moment six o'clock comes around or seven o'clock, then all of a sudden the temptation starts to take on a new form and they indulge. And that is the worst time. It would be better for them to indulge in that at lunch, for example, than it would be at that point of the day. Not only metabolically and in maintaining

1:02:15good insulin sensitivity, but not to mention sleep. And then the compounding consequences of poor sleep just creates this vicious cycle. Yeah. Okay. So the meal frequency, it sounds like, you know, the more you're each time you're elevating, each time you're having an insulin response, that insulin is then you're getting into the fat storage. Yeah. And you will get hungry. And yeah. So as much as we highlighted that 2021 study, what I ought to have done is highlight the work of Dr. David Ludwig, Kara Ebeling, and others, and Shai et al in New England Journal

1:02:48of Medicine in 2012, where there are, there's so many decades worth of evidence showing that as much as we had that one study suggesting, well, the insulin, higher insulin group didn't have less hunger. Yeah. There's a lot of evidence showing the opposite. So where you, you, you end up creating this rollercoaster of glycemia and hunger where the person eats a starchy, sugary breakfast, which let's face it, most breakfasts are these days. They have this big spike. And then when you go high, you inevitably go low. And then when you go low, hunger comes again, even though you may still

1:03:18literally have food in your stomach. And yet your brain is starting to sense, well, I'm hungry because the overall amount of energy in the blood has gone down, even though there's plenty of stuff still in the stomach, but it stimulates hunger. That's David Ludwig's main contributions. So anyway, it puts the person on this rollercoaster of glycemia. And every time it comes down, hunger wants to push it back up again. And so, yeah, I cut you off though, but that puts them in a position to eat six or seven times a day. And if they're not eating, they're drinking something sugary, either a soda or sugary

1:03:48fruit juice. Right. And, and the difference between, you know, this sugary type of like breakfast you're talking about, and perhaps like something that's more of a complex carbohydrate would be the fiber slowing that glucose response and causing some satiety as well. So that would be something that you would contrast. Not to mention even in that study in 2021, they probably were doing more complex carbohydrates and not. They were. Yeah. And it was, it was plant-based. And that, that's again, another reason why I thought we need to be careful. Not, I don't mean to sound overly critical of the study. I appreciate it. But at the same time, I think we need to elaborate on the limitations,

1:04:23which is most people aren't starting with a breakfast of a big leafy green salad. But there is a group that found that when you have a breakfast and they looked at breakfast and the name of the article was something like a more rapid return of hunger. They said it was something like return to hunger was in the title. And if the breakfast, isocaloric breakfast, so same number of calories, protein was clamped and it just differed in the ratio of fats to carbs. The high carb group was hungrier much sooner and then ate more for their next meal than the low carb group. And so I would say as much as we

1:04:59want to be sort of fair with whole plants, if that breakfast is a mix of whole plants with good proteins and fats, that's going to be a winning combination of satiety and then have a nice lunch. And then my view for me personally, I don't eat breakfast as much as I said, I wouldn't elaborate on my own approach. I eat a big lunch. That's my main meal of the day because I want, and then I find if I have a big filling lunch, it's easy for me to taper through dinner and then easy to not snack in the

1:05:31evening. But as much as I know, one of the great ironies of being a metabolic scientist and yet a fallible human with bad habits sometimes is that evening time is still my weakest time of the day. And my kids think that I'm the best dad in the world and I want them to be healthy. And I don't really bring a lot of cereal into the home. I make breakfast for the kids every morning for the most part. And it's a mix of various meals that I make. And they think, wow, my dad just loves me so much. Yes, I do. I love you all, my little darling babies. But I do it because I don't

1:06:02want cereal in the home. Because if there's cereal in the home, daddy is a meth addict when it comes to cereal. And if it's there, as much as I know, I will go through this. I can almost script it out where I'll help get the kids to bed. I'll clean the house, straighten things up, and then everything's quiet. And then I think, I need six bowls of cereal right now. And so then I will eat myself sick. And like a true addict, I will tell myself, I'll just have one bowl. What's the problem with one

1:06:33bowl? And then yet there's this little shoulder angel telling me, oh, but you know, you're not going to stop at one bowl. But then there's the addiction side of me saying, yeah, I am. I want this. I'm just going to have one bowl. I never. My wife can, though. My wife has this uncanny, alien-like ability to eat something like this, something sweet, like an ice cream or a cereal, and just have a little bit of it and be done. I can't do that. She is a moderator and I am an addict when it comes to these kinds of things, which is one of the reasons why I don't love a

1:07:05lot of the modern, the most popular modern mantra when it comes to nutrition is moderation and all things. What if you can't moderate? Then it would be better not to even start. Right. I want to talk about, you talked, you sort of alluded to this, and this has to do with the other contributing factors to insulin resistance. And you're talking about this in the context of if you're late night eating, it can disrupt your sleep. And, you know, for many reasons, you're also, you talked about some very interesting stuff that I hadn't really thought about before,

1:07:38but also you're digesting, you know, when your systems are all activated. Yeah, that's thermic effective food. Yeah, you're hot. Exactly. Yeah. So, I mean, it makes perfect sense. And in fact, I remember a friend of mine, Dr. Sachin Panda, he's done a lot of research on time-restricted eating, and he's got this app, My Circadian Clock, where people were, you know, uploading pictures of their meals and it was timestamped and they're putting comments. And like the most, one of the most common comments he was getting was disrupting sleep. Eating later was disrupting sleep. And finally, it was like,

1:08:08he's like, got to look into this. I mean, there's like, you know, dozens of people talking about this. And, and it's kind of funny when you kind of get that reverse thing that you're looking at when you're, when you get the data and then something else kind of pops. Yeah. Yeah. Wow. So eating late at night seems to be disrupting people's sleep. And that's, that's, that's a real thing. I'm convinced. I'm convinced that given that the natural temptation and inclination people have to indulge before bed, I'm in the sleep epidemic, the poor sleep epidemic, I'm convinced that more of it isn't blue light. It isn't evening light exposure or evening activities. It's you're going to bed

1:08:40hyperglycemic and, and full and you're full. And so, like you said, your, your stomach, you're bubbling, you're digesting when no, you ought to have, give yourself at least a few hours before from your last meal. Yep. Before you go to bed. Yeah, exactly. I mean, it takes like what, five, how many hours of digestion that's going on while you're asleep? That's the one thing sleep. So you were talking about these fast causes of insulin resistance, inflammation, the chronic stress, high cortisol. And then the last one, insulin, right. Too much insulin. Where, where does lack

1:09:14of sleep come into that? Because I have seen, I've read studies and we were talking a little bit about this before, before we, you know, started the podcast. And that is, first of all, when I became a new parent and I was, my, my sleep was entirely wrecked. I mean, just entirely wrecked. I mean, I aged like 10 years and like, but for a good cause, but a good cause. I would do it all over again in a heartbeat. My, my postprandial glucose, which is what I was monitoring at the time with my continuous glucose monitor was, I mean, it was not my normal. I mean,

1:09:45I was pre-diabetic. It was unreal. And so I started looking into literature and this was the most surprising thing. When I, when I wanted to wear a CGM, I was more like, how is watermelon going to affect my glucose? And I was more into the fruit and the, Oh, look what a grape did. This is insane. And, and then, and then it was like the disrupted sleep and everything else, nothing mattered anymore. I was like, this is real. Like, this is the real deal here. Um, and I started looking into the literature where sleep, you know, sleep deprivation after one night, like half, you're getting four hours of sleep instead of eight, you can be insulin resistant the next day. And I'm like, what?

1:10:19Oh yeah. So I'd love to hear about that and how that's contributing to this, you know, fast cause of insulin. Yes. Well, everything you just said, I am nodding to, because I, I can relate. Um, uh, where I, when I've worn CGMs, I absolutely see that the single most predictive variable of my glycemia in any given day is how did I sleep? Nothing that I've played around with. Nothing has even come close. So when you get one bad night of sleep, the stress home, so it fits under the stress category to put a,

1:10:50to make it a very succinct. So of the three primary causes of quick insulin resistance, it's stress when it comes to sleep deprivation, one bad night of sleep will result in a much higher and disrupted rhythm of cortisol. And, and so cortisol is, will cause insulin resistance in every biological model very quickly. So too will epinephrine and epinephrine is another stress hormone, sort of the faster stress hormone to cortisol being a little more delayed, but both of them are higher, um, with regards to sleep deprivation and even, even epinephrine, even adrenaline can

1:11:25cause insulin resistance in humans. If you do a steady little drip in a human of adrenaline, they're going to be insulin resistant with demonstrably insulin resistant within just an hour or two to make. So that's how sleep deprivation causes, uh, insulin resistance. And to make matters even worse, what is the most common intervention to try to offset the negative consequences of sleep deprivation? Well, it's more caffeine. Well, more caffeine is going to increase epinephrine even more. Epinephrine causes insulin resistance. So even the solution to the sleep deprivation ends up

1:11:58inadvertently compounding the metabolic consequences of the sleep deprivation. Now that's not to say epinephrine, uh, it's not to say caffeine doesn't have some metabolic benefits. It can when used correctly, like I would say when used in the context of performance, but for someone who's trying to offset the consequences of their sleep deprivation, you may have some increased alertness. Yes. But the metabolic consequences of the sleep have now just been added on. Um, what about, so we're talking about, um, other causes of insulin resistance. You've also kind of looked into some of this other stuff

1:12:33that's very interesting with respect to environmental toxins and how air particulate matter from air pollution, perhaps even plastic associated chemicals or microplastics, how those, those can contribute. Is that something that's meaningful? Like the sleep deprivation, the cortisol sounds pretty meaningful. Um, are these other, yeah, talk about it and whether or not they're pretty meaningful in the context. Super. Yeah. Super question. And really fair of you to, to state it that way, because as much as I found that work and still do really, really cool, and we're doing more of it. So, so to

1:13:06articulate what we've done so far, we've published reports looking at PM 2.5 diesel exhaust particles, and we published another report looking at cigarette smoke with the cigarette smoke particles. That was purely in the context of ceramides, forced mitochondrial fission and insulin resistance. And the cigarette smoke did all of those things. The newer paper that we published about a year or two ago was, I think, the first to find that if you just have increased diesel exhaust particles, even when we calorie

1:13:38clamped these, we pair fed these animals and the animals that were inhaling more of the diesel particles at physiological levels, like at a level that a human could be exposed to, they had much fatter fat cells. So they had much more adipocyte hypertrophy, um, which accounted for a higher body fat mass, even though they were eating the exact same amount of calories. Again, we pair fed them. We only let them eat as much calories as the other group was eating, and they still had more fat. So it does suggest that there are non-nutritive stimuli. You'd mentioned some others. We've not

1:14:10done work on microplastics or the plasticizers, those like diethylstilbestrol and BPA, but those also have been shown to promote greater fat expansion in the absence of calorie changes. That's another reason why I think that it's, we don't do ourselves any favors when we only have a calorie centric view of obesity, because there are more variables that come into play here. Now, to answer that last part of your question, which is to what degree should the average person be worried about that? I, it pains me

1:14:43to say this because it's my own work. I think that's a, that's a lower tier concern. It's also one that some people may not literally be able to do anything about, you know, like if you are simply living in an inner city area and there's just pollution, there's nothing you can really do. Maybe you can replace your intern, your in-home air filter more frequently and get one. And, but those aren't cheap either. So I'm very mindful of the financial constraints of the person who we may be fictionally talking about, but I guess other than that'd be the only thing you could do. If you could

1:15:14have a better in-home purifier, great. But for the vast majority of people who couldn't even quantify their, their pollution exposure, let alone afford an intervention to reduce it, the good news is that's going to have a much lower effect than just changing your nutritional and exercise habits. Yeah, there are, there are some more affordable HEPA filters now that do seem to kind of make a dent in reducing particulate matter. And, but it's interesting that this, this air pollution is really it, it seems like pretty pervasive. Like it's not just metabolic health, but it's Alzheimer's

1:15:50disease. I mean, it seems like it's a cardiovascular disease. I mean, it's really affecting lungs, of course, you know, respiratory health. It's affecting so many different chronic diseases as well. And so it is, it is important to keep the context in perspective, right? And obviously diet, you know, exercise, these things are the most important when it comes to metabolic health, but, they are. But, but, but these other things matter. They do. And not just for metabolic health, for a variety, just our overall health, right? And it's interesting of wedding smoking or vaping, vaping, right? Like that's the new project that we're starting. We have just,

1:16:22what's preliminary data now, when we look at the superheated particles, which is what you're inhaling, we've, we've finding, we haven't published this yet. So this is unpublished. My master's student is, this is her thesis project right now. So the data is forthcoming, but the early data suggests that it's, it actually at, at a relatively controlled dose, matching it for the cigarette smoke dose that we used previously, it's worse. So with, now I can't speak to the consequences of the tumorigenesis effects. Like maybe the person's going to have slightly better outcomes with cancer,

1:16:54but when we're looking at forced, the outcome we've measured so far is mitochondrial outcomes, looking at the degree to which the mitochondria can take in oxygen and convert it to ATP rather than the oxygen being converted into superoxide radical. It's worse with the superheated particles from the vaping than from the cigarette smoke. Do you think this is coming down to nicotine or other things in the vape? I don't know. So we have just the whole animal data so far. And then the next step will be isolating individual particles to try to find out, all right, which culprit, if one

1:17:25culprit is more to blame with regards to the e-cig exposure versus the cigarette smoke, because it is different chemicals. Yeah. Right. No, I'd be, I'm going to, you have to let me know. I'm interested in that. Yeah, I will. Yeah. Before we get into some solutions here, I'd also love to touch on one more thing that I, you know, you've, you've also looked at with respect to other causes of insulin resistance and, and metabolic health. And that is, you know, commonly prescribed medication. Mm-hmm. And this is something, you know, that I've, I've witnessed firsthand and friends where

1:17:59they're, you know, metabolically healthy, lean, lean and metabolically healthy. And they get on an antidepressant, for example, and all of a sudden gain a bunch of weight. I mean, unbelievable amount of weight, you know, 30 to 40 pounds and are no longer metabolically healthy. So there's a, there's a whole host of commonly prescribed medications out there from lipid lowering medications like statins to antidepressants and other neuropsychiatric, you know, disorders and medications that help with those disorders. What, what, what, is that something to be concerned about? Oh, for sure. Yeah, it

1:18:35absolutely is. And I'll just mention one that you just mentioned, which is statins, just because of how common they are. So there's no evidence that statins that I'm aware of are going to create weight gain. But there are metabolic consequences to messing with cholesterol. Lest people forget, cholesterol is a precursor to an essential component of the electron transport system. And so it's no surprise that if people are waging war on cholesterol synthesis, the mitochondria may suffer. And in women, middle-aged and older women have a 50% greater risk of developing type 2 diabetes

1:19:07when they get on a statin. That's a meaningful increased risk. Women appear to be much more susceptible to the consequences of statins, metabolic consequences of statins, not to mention the increased risk of Alzheimer's and even certain cancers that come with statins. Now, I'm not intending to sound like I don't think there's a ever a place for statins, but I do think they're over prescribed. Now, more heavily metabolic, any steroid that's been prescribed to control inflammation is going to be deeply problematic for weight gain. So if a person has an autoimmune

1:19:38disease or a chronic inflammatory condition and the clinician has prescribed a corticosteroid, they're going to gain weight very, very quickly because that starts to play on that stress pathway where the more cortisol is, that pathway is being activated, which is what that's doing, the more you're going to make the body insulin resistant, higher insulin promotes fat gain. And then just for the sake of time, perhaps I just mentioned the atypical antipsychotics, any drug that ends with an apine at the end of it, the suffix being A-P-I-N-E,

1:20:09is generally going to promote weight gain. That's probably through a central insulin resistance of the hypothalamus. When the hypothalamus becomes insulin resistant, you have a reduced satiety signal and the person's just going to start eating more. All right. So let's kind of shift gears and talk about some solutions here, protocols to maybe enhance insensitivity, people that are, you know, we talked, we started this conversation talking about people who are a large population of people that are actually pre-pre-diabetic. They might be,

1:20:39you know, on their way to insulin resistance or already insulin resistant and not even really know it. What, what are some of the best strategies people can do now to really make a difference and, you know, dietary strategies, you know, stress reduction, physical activity, but, but also how, how soon can they expect to see changes and what should they look at to see and monitor those changes? Yeah. Well, in fact, I'll, I'll start with that last part of your question, which is how

1:21:10quickly can it turn around? We published a clinical report. So working, collaborating with a local clinic in Utah, we took 11 women with newly diagnosed type two diabetes and their A1C was 8.9%. So very much diabetic range. And the physician who's very much on board had given these patients two options. And he said, you can leave the office with a prescription for an anti-diabetic drug like metformin, or you can meet with the nutritionist and go through this lifestyle nutrition counseling. And in just 90 days,

1:21:45their A1C went down, the average A1C, the average was 8.9 and it went to 5.6. So no sign of diabetes whatsoever after just 90 days without a pill popped or a needle injected. So I have often taken that 90 day span as a very reasonable amount of time to reverse insulin resistance. Now, depending on the scope of the problem, it may take a little longer to get rid of all of the consequences of the insulin resistance. But I think 90 days is a very reasonable justified timeline. Again, I say justified based on

1:22:20our own evidence. Now, what did we tell them that could sort of segue into the first part of your question? We gave them, in fact, just three pieces of advice based on the three macronutrients. And I've actually kind of already alluded to this, which the first one is control carbs. And that was simply this admonition to eat whole fruits and vegetables. You don't even need to count it, just whole fruits and vegetables. But in the case of these type 2 diabetics, we said, try to be mindful of the most sugary fruits and vegetables or the starchy fruits and vegetables. So the tropical fruits, we said, please be careful with like

1:22:56bananas, pineapples, mangoes. And then the starchy, if the vegetable grows in the ground, eat less of it relatively. But all other fruits and vegetables, and that's still a lot, enjoy liberally. And then prioritize protein and don't fear the fat that comes with that protein. And that was an important caveat because we didn't want them to be drinking fat, but we wanted them to acknowledge that in nature, all protein comes with fat. Don't be afraid of that fat. When humans eat fat with the protein,

1:23:29we digest the protein better, and it's more anabolic. There's studies in humans to show that people work out, give them protein, they'll have a certain degree of muscle protein synthesis. If you give them protein and fat, it's even higher than it was with just the protein alone. Yeah. And most people don't appreciate that bile, when the gallbladder from the liver releases the bile into the intestines, we always just think of that as being relevant to fat digestion. And it's critical for that, but it also enhances proteolytic enzymes. It makes the proteolytic

1:24:01enzymes more active, better. They work better. So we digest the protein better. And that may be the mechanism that explains the enhanced muscle protein synthesis from the combination. So that was the dietary advice we gave them. And I would just say that for people that manage your macros, control carbs, prioritize protein, don't fear fat. And then when it comes to eating time, I mentioned it earlier, the more you can stack your meals earlier in the day, or at least the bulk of the calories coming

1:24:31earlier in the day, the better so that you can taper off through evening. And by all means, or please don't eat within that three to four hour window before bed as much as you can. Don't, don't eat. And then exercise. In my view on exercise, as much as we both are, I am an enormous advocate of exercise. I was a personal trainer back in the day during my master's degree, and I hated every minute of it. But I did it. And I appreciate the role of exercise. And I enjoy exercising every day. If people are wondering what's the best exercise, my somewhat pithy answer is the one you'll do.

1:25:08Just do something. If you can do the sort of higher intense strength training that we were talking about, then please do it. But if this is like some 80 year old grandma who just likes walking around with the girlfriends, just walk around with your girlfriends. Keep doing that habit, whatever exercise you can do, and you're going to do, then just do it. But there is something to be said for timing it, where perhaps you can do your exercise session, if it is a walk around the block a few times with the gals. Do that after your biggest meal. Where if you just do 10 to 15 minutes of

1:25:43physical activity after your biggest glucose spiking meal, you will blunt that glucose excursion by half, if not even better. So what would have been a huge, big, long glucose spike in a commensurate insulin dose as well, you're going to cut that down substantially. If you did, if you do time that little bit of physical activity, and maybe that would be one other comment. If that's not your main exercise, then have that kind of exercise snack, where you had your big meal, maybe hopefully it was lunch, go on a 10 or 15 minute walk. Even those of us that, you know, I'm a professor at a

1:26:17university, I can eat my lunch and still just go on a little walk around the campus. My building is so big that in bad weather, I can walk around my building, even like around the hallways. And so just find a way to get up and do something in little bits, little bits of activity throughout the day, but then still, as much as a person can try to have that concentrated time of, all right, I'm working out right now, and I'm going to sweat and I'm going to get tired from it. Yeah, I love the exercise snacks. I like to do bodyweight squats. That's something that I'll, you know, try to do after a meal, particularly when I'm on vacation and get the gelato that I

1:26:53never, ever, ever eat unless I'm in Rome. Yeah, well, that's the place to do it. But okay, well, that's great. So many people ask about these supplements and, you know, are there these supplements that can improve insulin sensitivity? So they, you know, you hear everything from magnesium to alpha-lipoic acid to berberine, apple cider vinegar. And if there's any merit to that or taking it before a meal or, or is this just like dropping like a drop of water in the pool to like fill the pool up? Yeah. Well, in fact, every one you just mentioned works. Frankly, the one I like to talk about the most,

1:27:26because the evidence is so compelling and it's so easy to get. So berberine is undoubtedly effective. No doubt it works. Berberine absolutely works. I love apple cider vinegar as a personal favorite. Maybe it's because of my old man palate where I like really tart things the older I'm getting. So I just love the taste when I dilute it in water or sparkling water, but apple cider vinegar, that really, that that's the shortest of all short chain fats, that acetic acid and the short chain in the human diet, as much as we eat a lot of fat, most of it is from seed oils and

1:28:00soybean oil, but we lose out on the full spectrum of fats because we don't really eat a lot of fermented foods anymore. So we don't get the medium chain fats. And because we don't eat any much fermentation fermented foods, we don't get any short chain fats for the most part. So short chain fatty acids, which is what apple cider vinegar is, is a really, it, it, that's a small little molecule that punches well above its, its weight where the acetic acid will reduce hepatic gluconeogenesis to help control glucose, which is very relevant in a person with diabetes

1:28:33with especially type two. There's so much glucagon always in their bloodstream. It's constantly pushing the liver to make more glucose. Apple cider vinegar will inhibit that. And so it, it helps the blood glucose by just having the liver dump less glucose into the blood, but it also stimulates AMPK. And you'd mentioned GLUT4 at the muscle. The reason exercise is able to open GLUT4 or translocate it and get the glucose in without insulin is because of AMPK. So it's that interesting paradox of exercise where

1:29:07insulin comes down and yet glucose is taking in more, the muscles taking in more glucose than it ever was. It's because of this kind of back door of the muscle exercising. AMPK gets turned on through a series of events that moves GLUT4. Well, apple cider vinegar will do the same thing in the absence of exercise, albeit to a more modest degree. So that's a couple mechanisms among others, including mitochondrial biogenesis and a little bit of uncoupling where apple cider vinegar is one of my favorites, where if you take a couple tablespoons before your most starchy meal, you absolutely could compare

1:29:43the glucose curve from one day to the next. And you'll see that it's significantly lower with just that tart little bit of drinking. That's fascinating because when you're talking about the short chain fatty acid, you know, and I'm thinking, you know, acetate. Yep. So acetate, acetic acid, we're going from acid base. I'm thinking of lactate, lactic acid, lactate, and that's when you're generating with exercise and lactate signaling is to AMP kinase, it's very much, you know, and then I'm thinking,

1:30:14well, is this like a short chain fatty acid sort of like, is there signaling molecules, right? They are. And is there, is there something that would be so interesting to look at to see if there's something going on with lactate, acetate, malate, right? Like that's in like a Granny Smith apple or something like a more sour apple, right? Yep. I mean, all these different short chain fatty acid, well, the short chain fatty acids that you're getting from foods, and then there's another, malate's also in like blueberries, malic acid, malic acids in them. And then, so, so I was just, my, my sort of wheels are turning here when you're mentioning that, because it'd be so fascinating to see

1:30:47if there's a common mechanism, like why is the acetic acid working? We know lactate works too. Yeah. And so. I think acetic acid, I know beta-hydroxybutyrate, one of the, one of the ways that main ketone, not that we've talked about ketones, but some of my work is on ketones. I've been, I've wondered in the past, the ketone is unique because on one hand, it's a nutrient, it's a calorie to be burned. But at the other hand, it's a signaling molecule and it is known to elicit some of its signaling like anti-inflammatory effects and antioxidant effects. Part of it is through changes elicited because of

1:31:21a G-protein coupled receptor, where it does have a cell surface receptor that it will activate. I don't know the degree to which acetic acid may do the same thing, but with regards to beta-hydroxybutyrate, even exogenous ketones, that wasn't one you mentioned, but there are increasingly, increasing studies showing that you can have, there was just a study in women with PCOS. The only intervention was to give them exogenous ketones and every outcome related to metabolic

1:31:53markers and PCOS got better. And the only change was the supplementation with exogenous ketones. I don't know that that was an effect of the bioenergetics of the ketone. It was probably more of the signaling effect. And so that would be another thing if a person's becoming increasingly curious about ketones. And that's not without justification. The evidence supporting the value of ketones is growing and growing quickly, and it ought to. I have never in the past wanted to be seen as a drum-beating advocate of a ketogenic diet, simply knowing that that's not everyone's cup of tea.

1:32:28But increasingly, I will vigorously defend ketones as very beneficial, viable signaling molecules in the body. So even when it comes to controlling the metabolic response, you're probably going to eat less because ketones have a very satiating effect, more so than, say, glucose does. But then they also will impact mitochondrial uncoupling and help the body burn through that glucose faster. No, it's interesting. Ketones are definitely signaling molecules. And I also think there's

1:33:00a lot of overlap between lactate and beta-hydroxybutyrate as well. I mean, they're activating a lot of the same brain-driven neurotrophic factor. And I've had Dom D'Agostino on the podcast twice. We talked a lot about ketogenic diets, and Dr. Eric Verdin talked about them as well. I do think they're not the easiest diet for people to follow for several reasons, including, you know, social, too. I mean, socially...