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

Starting point is 00:00:00 Insulin 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 has profound implications for their long-term metabolic health,

Starting point is 00:00:34 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 fat 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

Starting point is 00:01:18 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. We 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

Starting point is 00:01:59 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 versus subcutaneous fat, the concept of personalized fat threshold, and what actually happens to fat cells during weight loss. We discuss lifestyle environmental factors beyond diet, including stress, sleep deprivation, nicotine exposure, and endocrine disrupting chemicals, including those found in microplastics.

Starting point is 00:02:27 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 GLP1 agonist medications, including Ozembic and Wigovi, 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

Starting point is 00:03:05 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 aging. 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

Starting point is 00:03:45 nutrition, longevity, exercise, and brain health. 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 studies 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

Starting point is 00:04:14 subscribe today so you can receive the. the very next email newsletter. You can find that at foundmyfitness.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, 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.

Starting point is 00:04:51 I 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. Right. Why is that? And what is this state of like pre, pre. diabetes and why is it something that is not caught sooner? Yeah, yeah, and yet so common. Right. I mean, that adds an extra layer of reason to talk about this because it is, 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

Starting point is 00:05:39 and metabolic problems are to cardiovascular disease. But the consequence of the glucose-centric And there's reasons for it. So I don't mean to state this in any kind of incriminating way. They have their own justification for the glucosecentric 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 the 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 patients, 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 starting to really lose the war. And now

Starting point is 00:07:02 glucose rises as well. Then the conventionally trained clinician says, oh, 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 miss the earliest metabolic canary in the coal mine, which is insulin. So the sooner our paradigm with modern medicine includes insulin than the earlier we can detect, these metabolic problems and a person who's progressing towards type 2 diabetes, but also it changes

Starting point is 00:07:49 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, say, a type 2 diabetic and insulin therapy. Now they're pushing the insulin from high to super physiological, all in an analysis. 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.

Starting point is 00:08:30 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, many people have them without a prescription you can get them. Yep. Is there any signs or test using those that people can do to kind of look for this potential problem with, you know, having perhaps high insulin? Yeah. 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 position to be their own coach. You know, they don't need to have someone

Starting point is 00:09:14 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. If 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

Starting point is 00:09:59 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 can 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 skinfold 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, like crinkled tissue paper. So that's

Starting point is 00:10:48 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 stalk 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 sensitivity 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

Starting point is 00:11:34 many different types of chronic diseases, age-related diseases, obviously type-to-diabetes, obesity's 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, you know, why do you, you're talking about insulin resistance being common and certainly like this 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.

Starting point is 00:12:16 So I'm not claiming that it's the singular cause. For example, the connection between insulin resistance and breast and prostate cancers, the 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 is the question I asked myself as an academic at my university. when I got tenure, I thought, I looked 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?

Starting point is 00:13:11 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 attributed 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,

Starting point is 00:13:43 we're giving them 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 is a reflection of just how powerful the hormone insulin is. Most individuals only think about insulin as being a hormone that controls blood sugar,

Starting point is 00:14:15 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, in 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 of erectile dysfunction.

Starting point is 00:14:45 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 over-stimulated because insulin resistance is insulin not working the same at all cells of the body,

Starting point is 00:15:10 and blood insulin levels are higher. So there's too much insulin. Some 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

Starting point is 00:15:40 resistance. And to me, it 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 fat 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 origins, where you have what I call fast insulin resistance and then slow insulin resistance.

Starting point is 00:16:27 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 in 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 stress. 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

Starting point is 00:17:12 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 changed. 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 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.

Starting point is 00:17:59 So too much insulin can cause insulin resistance. Now, none of those touch 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

Starting point is 00:18:36 point, 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, 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 insulin-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

Starting point is 00:19:24 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 seramides. And those do not track the same across the, say, the lean marathon runner and the obese type 2 diabetic, when you start measuring levels of tissue seramides or its precursor dihydrocerer, There's still some debate as which is the two matters most. I'm very strongly just saying it's one of them. And so I'll just say seramides as a family. You can, in any biological model, cause very strong, robust insulin resistance just by increasing the seramides.

Starting point is 00:20:06 Because seramides will block the insulin signal. When insulin binds to its receptor, then you have a series of phosphorylation events. Ceremides block that very well. it's a very well-defined pathway, and if you can just do one thing and just resolve the seramides, 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 seramides in various tissues throughout the body? Interestingly, all of those primary stimuli, the quick insulin resistance, all induced seramide biosynthesis and accrual, but with the slow insulin

Starting point is 00:20:46 resistance, I still think it'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 We've got a lot to dive into here. I mean, it's funny. I remember one of my first projects as a budding young scientist was to look at insulin

Starting point is 00:21:27 resistance, like free fatty acids, and can you make like a little nematode worm insulin resistant? Yeah, yeah. And, you know, it, from my understanding, had to do with the adipocyte cell and this sort of spillover of seramides that are then attack. It all had to do with the AKT signaling pathway. where, you know, stopping basically the insulin receptor. Yeah, like that's exactly. And that's where seramides acts.

Starting point is 00:21:51 Right. 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.

Starting point is 00:22:07 In fact, I've run so many Western blots measuring phosphoakT 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 interested 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

Starting point is 00:22:42 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 could 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,

Starting point is 00:23:26 regulating dilation of blood vessels, and other hormones throughout the body that affect water retention, salt signaling, neuron conductant of signals, and more. But at the fat cell, insulin probably has its most powerful effect where 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 my 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,

Starting point is 00:24:13 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 put a fine point on that, if you have all the calories in the world, so I grow fat cells in petri dishes in my lab right now back at biu i got students growing fat cells in the incubator um 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

Starting point is 00:25:01 to get big if we check 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 when we go out on a jog outside, our fat cells are breaking down triglycerides as free fatty acids

Starting point is 00:25:39 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.

Starting point is 00:25:55 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, 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, well, Ben, that's just in fat cells. What about humans?

Starting point is 00:26:14 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 diabolemia, 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. So 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.

Starting point is 00:26:56 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, I'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 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.

Starting point is 00:27:33 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 they 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. Faty acids go to zero because you're inhibiting lipolysis, you're inhibiting ketogenesis, you're stimulating glucose uptake.

Starting point is 00:28:08 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. So 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,

Starting point is 00:28:39 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, where it's burning so much fat, it has such an abundance of acetyl co-A that it can no longer feed the acetyl co-A into the citrate cycle because it's too full. It cannot divert it to lipogenesis because insulin's low, so that pathway's inhibited or not activated. Then the only other option of all that acetyl-CoA is ketogenic. 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

Starting point is 00:29:24 reconcile 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 that 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 goes down. So the body's just burning a little hotter. The engine is revving higher.

Starting point is 00:30:04 So the overall energy expenditures 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. Okay. 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. Yeah. And then ultimately, obesity is in the... in that mixture as well. And I think, you know, refined carbohydrates is something that you've mentioned,

Starting point is 00:30:52 and I think a lot of people think that refined carbohydrates definitely play a role in insulin resistance, perhaps a primary role. But aside from the obesity, 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 seramide, 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, you know, being in a deficit? Does that matter as well? The mixture of the two sort of like, because there's nuance here. Oh, yeah, there is. I'd love to get into it. In fact, a big nuance is

Starting point is 00:31:45 the calories. And this is where I need to be careful because 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 hypercalorie, 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, which of the balance of saturated fats to refined carbs. Now, then someone would 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 if you're in a calorie deficit and you're eating, you know, some refined carbs, then it's not necessarily going to,

Starting point is 00:32:27 you have more wiggle room. I think you do. Yeah, yeah. I'm, I'm comfortable saying that. And then again, I just have to counter that by saying, that's not really feasible long term. You know, people get hungry. For hungry. Hunger always wins. Yeah. You got to, you got to eat. You got to eat. You got to fuel the body. So 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 seramides. And I'm going to upset some people. but in cell cultures, if you treat cells with saturated fat, palmitate, which is the main saturated

Starting point is 00:33:19 fat in the body, you get insulin resistance very quickly. Now, if you block seramides, you resolve that insulin resistance. If you treat those cells with mono-unsaturated 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 approve of that focus. I think they're pathogenic, but I grimace when 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.

Starting point is 00:34:15 I think they're highly pathogenic, but not within... Well, 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.

Starting point is 00:34:34 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 assumptions when I saw the work of Dr. Jeff Volick, a friend and a legend in the realm of low-carbohydry 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, they can eat two or three or four times more saturated

Starting point is 00:35:27 fat than a high carb group. And then they're circulating levels of saturated fat. So the saturated fat in some 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's making, not from what we're eating. And he showed this very, very well. But that's only in the background of low carbs. Exactly.

Starting point is 00:36:04 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... No problem with insulin resistance. Yeah.

Starting point is 00:36:18 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 with the higher metabolic rate and then the ketone wasting. So it starts to get a little cloudy. 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

Starting point is 00:36:51 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 carb, are getting, the less the dietary saturated fat matters. Now, in the context of a higher carb diet, 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,

Starting point is 00:37:34 then as much as it pains me to admit, because I'm such a defender of saturated fats from natural sources, which is where they 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 a, you know, 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 rough food? Yeah, no. Of course, the easy answer would be no,

Starting point is 00:38:19 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, 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 of what are the carbs, I think think if you're talking about the low glycemic load carbs like cruciferous vegetables and berries and citrus fruits for example now there's almost nothing and then you've chased that down with a

Starting point is 00:39:05 tablespoon of coconut oil the most sat 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 its mcc which doesn't follow which is not a substrate for seramides 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 villain. 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 of 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

Starting point is 00:39:51 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 barcodes, more whole foods, you're fine. 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... 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 hypochrocer. glycemic 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 isn't the same but

Starting point is 00:40:33 even still depending on the person you know you and i were too 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 a 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. So with respect to insulin resistance and weight loss and obesity and what's causing, like the cause of these things, right?

Starting point is 00:41:13 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 were on a ketogenic diet. They were isocalloric, so the same calories.

Starting point is 00:41:40 But if I recall the... No, in fact, they were able, it was ad libidim. And then 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 rejoiced in the fact that it challenged the carbohydrate insulin theory of obesity, which I can articulate in a moment because they found that the higher carb group spontaneously achesely. about 700 calories a day less. Does that sound right?

Starting point is 00:42:24 I think that's right. So they just spontaneously were eating less because they could eat freely. They just ate. And 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. Yeah, they did. They did.

Starting point is 00:42:44 Yeah. But it was, this is modest. I mean, 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 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 found that they spontaneously ate 700 calories a day less. That challenged

Starting point is 00:43:16 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 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 coming from leafy greens and berries and, you know, citrus fruits.

Starting point is 00:43:50 It's coming from bags and boxes with barcodes. But nevertheless, that's an interesting finding. 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 be 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.

Starting point is 00:44:40 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 more 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,

Starting point is 00:45:18 they were able to eat 700 calories more per day and only had one more pound of fat than the other group 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, 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 of energy expenditure, he collaborated with Elliot P. Jocelyn, who the most famous endocrinology clinic in the world, the Jocelyn Diabetes Center is named after him.

Starting point is 00:46:09 So you had these two legends in their own realm who tried to do that. understand the metabolism of people in what they called severe diabetes, which we would call type 1. 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 author is NER, Sri Nair, N-A-I-R, they not only confirmed the findings from 60 or 70 years earlier that in type 1 diabetes, the metabolic rate is too high. Like something's broken, they're burning too hot.

Starting point is 00:46:41 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. We're energy expenditures up by several hundred calories a day. And we found in human work that part of 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 was 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.

Starting point is 00:47:36 Well, 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 a caloric deficit, gives you a little more wicker room. Yep. Being in a ketogenic or, you know, close to a ketogenic state seems to give you more wiggle room. But what about being, like, 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 wonderful way to do it. I 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.

Starting point is 00:48:34 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 health. However, 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 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

Starting point is 00:49:20 course is the great glucose consumer when if someone's wearing their 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 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 glucose curve come up and down, and it'll be back down to normal in an hour, maybe 90 minutes. The

Starting point is 00:50:02 person who has less muscle, even more fat, so same body mass, 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. So the more muscle mass the 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 carbs 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, normally a ketogenic diet's no more than 50 grams,

Starting point is 00:50:48 well, unless you're just burning that glucose. Right. And also you mentioned this study that was comparing strength training to the, you know, low arc. Right. Well, I think also high intensity needable training. When you're doing, you 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 glute four 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. Yeah. And so at that point, you know, you're becoming insulin sensitive too, right? You are. You're really kind of changing the scenario in some ways. It doesn't, I don't personally think it should give people the, um, justification to go and eat tons of pizzas and, you know, ice cream and all that stuff. Um, all, you know, cheating once in a while is fine. But like, I, I think that people, you can't, you can't, you can't out, you can out eat exercise in other words. So. But you can't out exercise bed. Right. Exactly. You can't out exercise bed. Yeah. But I do think exercise is.

Starting point is 00:51:57 extremely important, especially like there's different types of exercise. And that was kind of another question, you know, the strength training versus like really going hard or, or 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. Maybe 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

Starting point is 00:52:38 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 show 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.

Starting point is 00:53:17 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, higher 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

Starting point is 00:53:38 there's a spectrum, right? Like, well, what were they doing? Were they able to talk? You know, if they're really going hard. 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

Starting point is 00:53:54 and them sort of translocating up to the muscle and opening the floodgates. And so, yeah, it's nice to know, in other words, there's, there's many roads to Rome. 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,

Starting point is 00:54:31 they're not 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, Mario, where you're combining the two. Yeah, well, anytime, yeah, to me, high fat, high carb is the worst combination for every outcome. You'd mention 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 giving it a stimulus of insulin,

Starting point is 00:55:06 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's 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 of what shrinks the fat cell, well, you look at those two levers, the high insulin and the high calorie, you have to pick one. My only worry is, as much as people are so ardently defending the caloric view, which they have

Starting point is 00:55:40 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. So 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

Starting point is 00:56:24 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 using ketones now, and you're more accustomed to 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,

Starting point is 00:57:01 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 want to get more into 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.

Starting point is 00:57:25 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.

Starting point is 00:57:45 So with regards to meal frequency, I 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 lunch, then you need an afternoon snack, and then dinner, then an evening snack. We can see the consequences, which is insulin resistance and obesity are the most common problems.

Starting point is 00:58:25 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 what 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

Starting point is 00:59:09 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 humans 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

Starting point is 00:59:57 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 scientist 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 we pity the shift workers

Starting point is 01:00:38 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 level spike, you activate your sympathetic nervous system.

Starting point is 01:01:08 And 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?

Starting point is 01:01:39 Well, it's not because you have anxiety. It's because you went to 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 can't, 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

Starting point is 01:02:12 point of the day, not only metabolically and in maintaining good 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 you, 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, shy at all in New England Journal of Medicine in 2012, where there are so many decades worth of evidence showing that as much as we had that one study

Starting point is 01:02:54 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 end up creating this roller coaster 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 literally have food in your stomach. And yet your brain is starting to sense, well, I'm hungry.

Starting point is 01:03:23 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 roller coaster 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,

Starting point is 01:03:46 either a soda or a sugary fruit juice. Right. And the difference between, you know, this sugary type of breakfast you're talking about and perhaps like something that's more of a complex carbohydrate would be the fiber is slowing that glucose response and causing some satiety as well. So that would be something that you would contrast. Not to mention even. Perhaps in that study in 2021, they probably were doing more complex carbohydrates and not.

Starting point is 01:04:11 They were, yeah, and it was plant-based. And that's, again, another reason why I thought we need to be careful. 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, which 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, they looked at breakfast, and the name of the article was something like a more rapid return of hunger. It was something like Return to Hunger was in the title.

Starting point is 01:04:41 And if the breakfast, isocholaric 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 want 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 in my view, for me personally, I don't eat breakfast as much as I said.

Starting point is 01:05:16 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 evening. 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

Starting point is 01:05:48 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 want cereal in the home. Because if there's cereal in the home, Daddy is a meth addict when it comes to cereal.

Starting point is 01:06:08 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 bowl? And then yet there's this little shoulder angel telling me, oh, but you know you're not going to stop. put 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.

Starting point is 01:06:44 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 lot 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, if you're late night eating, it can disrupt your sleep. Yeah. And, you know, for many reasons, you're also, you talked about some very interesting stuff that I hadn't really thought about before.

Starting point is 01:07:38 But also you're digesting, you know, when your systems are all activated. Yeah, that's thermic-effective food. Yeah, you're hot. Yeah. So, I mean, it makes perfect sense. And in fact, I remember a friend of mine, I'm 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 time stamped and they're putting comments. And, like, one of the most common comments he was getting was disrupting sleep. Eating later was disrupting sleep. And finally it was like, like he's like got to look into this. I mean, there's like, you know, dozens of people talking about this. And it's kind of funny when you kind of get that reversed 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

Starting point is 01:08:35 more of it isn't blue light, it isn't evening light exposure or evening activities, it's you're going to bed hyperglycemic and full and you're full. And so like you said, 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 does lack of sleep come into that? Because I have seen,

Starting point is 01:09:16 I've read studies, and we were talking a little bit about this before we, you know, started the podcast. And that is, first of all, when I became a new parent, and my sleep was entirely wrecked. I mean, just entirely wrecked. I mean, I aged like 10 years. But for a good cause. But for a good cause. I would do it all over again in a heartbeat. my post-pranthial 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, I was pre-diabetic. It was unreal. And so I started looking into literature. And this was the most surprising thing. When I wanted to wear a CGM, I was more like, how is watermelon going to affect my glucose? And I was more eating in the fruit and the, oh, look what a grape did. This is insane. 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. And I started looking to 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?

Starting point is 01:10:19 Oh, yeah. So I'd love to hear about that and how that's contributing to this, you know, fact cause of insulin. Yes. Yes. Well, everything you just said, I am nodding to because I can relate. 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,

Starting point is 01:10:48 so it fits under the stress category to make it 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 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 with regards to sleep deprivation. And even epinephrine, even adrenaline can cause insulin resistance in humans.

Starting point is 01:11:26 If you do a steady little drip in a human of adrenaline, they're going to be insulin resistant, demonstrably insulin resistant within just an hour or two. to make so that's how sleep deprivation causes 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 inadvertently compounding the metabolic consequences of the sleep deprivation. Now, that's not to say epinephrine, 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,

Starting point is 01:12:12 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. What about, so we're talking about other causes of insulin resistance. You've also kind of looked into some of this other stuff that's very interesting with respect to environmental toxins. Yeah. 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. Are these other talk about it and whether or not they're pretty meaningful in the context? Super, yeah, super question. And really fair of you to state it that way,

Starting point is 01:12:58 because as much as I found that work and still do really, really cool, and we're doing more of it. So to articulate what we've done so far, we've published reports looking at PM2.5 diesel exhaust particles, and we published another report looking at cigarette smoke. With the cigarette smoke particles, that was purely in the context of seramides, 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 clamped these, we pear 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 fat or fat cells. So they had much more adipocyte hypertrophy, which accounted for a higher body fat mass, even though they were eating the exact same amount of calories.

Starting point is 01:13:58 Again, we pear-fed them. We only let them eat as much calories as the other group is eating, and they still had more fat. So it does suggest that there are non-nutrative stimuli. You'd mention some others. We've not done work on microplastics or the plasticizers, those like diethylostobestrol 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 the last part of your question, which is to what degree should the average person be worried about that?

Starting point is 01:14:41 It pains me to say this because it's my own work. I think 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 in-home air filter more frequently and get one. 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.

Starting point is 01:15:11 But I guess other than that would be the only thing you could do. If you could have a better in-home purifier, great. But for the vast majority of people who couldn't even quantify 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 some more affordable hepa filters now that do seem to kind of make a dent and reducing particulate matter. and but it's interesting that this air pollution is really, it seems like pretty pervasive. Like it's not just metabolic health, but it's Alzheimer's disease. I mean, it seems like it's a cardiovascular disease. I mean, it's really affecting lungs, of course, you know, respiratory health.

Starting point is 01:15:56 It's affecting so many different chronic diseases as well. And so it is important to keep the context in perspective, right? I mean, obviously diet, you know, exercise. These things are the most important when it comes to metabolic health. 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.

Starting point is 01:16:17 I'm witting smoking or vaping, vaping, right? In fact, that's the new project that we're starting. We have just what's preliminary data now. When we look at the superheated particles, which is what you're inhaling, we have finding, we haven't published this yet. So this is unpublished. My master's student, this is her thesis project right now. So the data is forthcoming.

Starting point is 01:16:35 but the early data suggests that it's it actually 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 tumoragenesis effects. Like maybe the person's going to have slightly better outcomes with cancer. But 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 vaping? I don't know.

Starting point is 01:17:18 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 culprit is more to blame with regards to the ESIG exposure versus the cigarette smoke? Because it is different chemicals. Yeah, right. No, I'm going to, you have to let me know. 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 also looked at with respect to other causes of insulin resistance and metabolic health. And that is, you know, commonly prescribed medication. Mm-hmm. And this is something, you know, that I've witnessed firsthand and friends where they're, you know, metabolically healthy.

Starting point is 01:18:02 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 not a weight, you know, 30 to 40 pounds and are no longer metabolically healthy. So 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 concerned about? Oh, for sure. Yeah, it absolutely 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 of statins that I'm aware of are going to create weight gain, but there are metabolic consequences to

Starting point is 01:18:46 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 when 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 stentz. Now, I'm not intending to sound like I don't think there's ever a place for statins, but I do think they're over-prescribed. Now,

Starting point is 01:19:27 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 disease 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 AP-I-N-E, is generally going to promote weight gain. That's probably through 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 some sensitivity, 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, you know, on their way to insulin resistance or already insulin resistant and not even really know it. What are some of the best strategies people can do now to really make a difference? And, you know,

Starting point is 01:20:52 know, dietary strategies, you know, stress reduction, physical activity, but also 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 start with that last part of your question, which is how quickly 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 2 diabetes. And their A1C was 8.9.8.9.000. 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 a nutritionist and go through this lifestyle nutrition counseling.

Starting point is 01:21:43 And in just 90 days, their 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 our own evidence. Now, what did we tell them?

Starting point is 01:22:23 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 my mind. mindful of the most sugary fruits and vegetables. So the tropical fruits, we said,

Starting point is 01:22:54 please be careful with, like bananas, 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, we 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 that's, 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 enzymes more active better. They work better.

Starting point is 01:24:05 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 earlier 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

Starting point is 01:24:43 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 just do something if you can do the sort of higher intensity 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.

Starting point is 01:25:29 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 physical 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 and a commensurate insulin dose as well, you're going to cut that down substantially 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,

Starting point is 01:26:08 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 university, 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 body weight squats. That's something that I'll, you know, try to do after a meal,

Starting point is 01:26:49 particularly when I'm on vacation and get the gelato that I never, 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, you know, you hear everything from magnesium to alpha lipoc acid to berberine, apple cider vinegar. And if there's any merit to that or taking it before a meal or is this just like dropping like a drop of water in the pool to like try to fill the pool up. Yeah. In fact, everyone you just mentioned works, frankly, the one I like to talk about the most because

Starting point is 01:27:27 the evidence is so compelling and it's so easy to get. So berberine is undoubtedly effective. No doubt it works. Burbrine absolutely works. I love apple cider vinegar as a personal favorite. Maybe it's because of my old man palette 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's the shortest of all short chain fats, that acetic acid.

Starting point is 01:27:54 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 soybean oil. But we lose out on the full spectrum of fats because we don't really eat a lot of, 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, that's a small little molecule that punches well above its weight where the acetic acid will reduce hepatic gluconeogenesis to help control glucose, which is very relevant in a person with diabetes, especially type 2. There's so much glucagon always in their bloodstream.

Starting point is 01:28:39 It's constantly pushing the liver to make more glucose. Applesite of vinegar will inhibit that. And so it helps the blood glucose by just having the liver dump less glucose into the blood. But it also stimulates AMPK. And you'd mention glute 4 at the muscle. The reason exercise is able to open glute 4 or translocate it and get the glucose in without insulin is because of AMPK. So it's that interesting paradox of exercise where insulin 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 backdoor of the muscle exercising.

Starting point is 01:29:17 A&PK gets turned on through a series of events that moves glute for. 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 the 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.

Starting point is 01:29:51 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 that 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 A&P kinase, it's very much, you know, and then I'm thinking, well, is this like a short chain fatty acid? Sort of like, is there signaling molecules, right? They are. And is there something that would be so interesting to look at to see if there's something going on with lactate, acetate, malate, right?

Starting point is 01:30:27 Like that's in like a granny Smith apple or something, like the more sour apple, right? I mean, all these different short chain fatty acids, well, the short chain fatty acids that you're getting from foods. And then there's another mallet's also in like blueberries, malic acid. Yeah. Malic acids in them. And then so, so I just, my, my sort of wheels are turning here when you're mentioning that because it would be so fascinating to see if there's a common mechanism. Like, why is the acetic acid working? We know lactate works too.

Starting point is 01:30:52 Yeah. And so. I think acetic acid, I know beta hydroxybuterate, one of the one of the ways that main ketone, not that we've talked about ketone, but some of my work is on ketones. 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.

Starting point is 01:31:18 Part of it is through changes elicited because of a 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-hydroxybutyate, 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 markers 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.

Starting point is 01:32:05 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 ketones. diet, simply knowing that that's not everyone's cup of tea. But 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

Starting point is 01:32:52 uncoupling and help the body burn through that glucose faster? No, it's, it's interesting. Ketone, ketones are definitely signaling molecules. And I also think there's a lot of overlap between lactate and beta-hydroxia butyrate as well. I mean, they're activating a lot of the same like brain drive neurotovic factor. Yeah, agree. And, you know, I've had Dom Degasino on the podcast twice. We talked a lot about ketogenic diets and, you know, Dr. Eric, Dr. Eric Vreden talked about them as well. I do think that, you know, I've had, they're not the easiest diet for people to follow for several reasons, including, you know, social to me.

Starting point is 01:33:29 Yeah, no, no, no, it's restrictive. It's definitely restrictive. But, you know, perhaps cycling them. I'm, I've been interested in cycling it. I've only done it like a couple of times. For me, it's also very hard to do as well. But I'm interested in the brain benefits of ketones. Yep.

Starting point is 01:33:46 And so. Well, this is where exogenous ketones, I think, become so helpful. Where if you have someone who just says, I just don't want to do the ketones, you diet, but I still would like some of the benefits. There are so many good options nowadays that I think it becomes a viable approach for someone to say, I want the ketones, but I don't want ketogenic, so I'm just going to drink them. Do you think the dose matters? So like, not only in respect to wanting the right dose of ketones to activate, you know, these beneficial signaling pathways, but also to make sure that you're not like dipping too low, like your

Starting point is 01:34:20 glucose doesn't go too low where you're kind of like what's going on here a little bit anxious a little bit yeah like you can get i can get you know when i haven't eaten for like many hours i like forget to eat because i'm so busy all of a sudden i'll start to get a little anxious and i'm like what's going on oh i haven't eaten you know so yeah yeah so you what's interesting actually even the earlier in our discussion i mentioned on one of my many tangents dr george kahill's work and he was really one of the more famous prominent, what they called at the time starvation scientists, we would call fasting scientists. But that same study I mentioned where it made you wonder, why was it that these patients who got down to 20 milligrams per deciliter of glucose, many people

Starting point is 01:35:04 will say that's lethal, like it'll kill you. And yet they not only didn't die, they had no cognitive deficit whatsoever. The speculation, I don't know whether it was him or maybe Richard Veach in a sort of follow-up commentary, a ketone scientist, who's also passed away now, where if the brain has adapted to ketones, it may be more resilient to tolerate a low glucose. But most people, one, haven't adapted to ketones and two, don't even have any ketones. That's the problem is because the same intervention, for the most part, that's going to drop the glucose in someone, like someone who eats a really sugary meal or drinks it, their glucose is going to come up and the higher it goes, usually the lower it's going to go at the end, where you have a rebound

Starting point is 01:35:50 hypoglycemia, you would say, well, I should be able to weather that drop because I have ketones. No, because the same thing that's helping you reverse your glucose, the high insulin, is going to inhibit ketogenesis. And so you've deprived your brain in that acute moment of its primary fuels, glucose and ketones, although the brain does use lactate as a fuel as well, albeit to lower levels. But if glucose and ketones have started to go low, that's going to be a panic at the brain. Because that is its two primary fuels. And as I mentioned earlier, the brain doesn't have a reservoir of stored energy at very, very modest amount.

Starting point is 01:36:29 But its metabolic rate is so high that it needs constant supply. Right. Okay. Well, let's talk a little bit more about, you know, fat. And we kind of talked about this a little earlier about, you know, not. all fat being equal and a lot of people are thinking about fat as just stored calories. But, I mean, there's much more to this picture, right? So there's, there's different ways we store fat and there's the subcutaneous way. There's visceral fat. These fats are not the same.

Starting point is 01:36:57 Yeah. I know when you were talking, you were talking about liver biopsies, you kept pointing to the adominium region. I was wondering if you were talking about you were getting visceral fat biopsies or probably not. But can you talk a little bit about these different types of fat? and what determines whether or not you're going to store fat subcutaneously versus viscerally. Yeah. Why visceral fat is so dangerous. Yeah, yeah. So a lot of that conversation, there's so many topics I could take with this.

Starting point is 01:37:25 And perhaps just to try to bring it to one common theme, I would describe the two ways in which a human can gain fat mass. So earlier I'd mentioned, and it's a perfect opportunity to bring in different ethnicities, because different ethnicities will store fat differently. And this all is underlying the earlier conversation of the slow insulin resistance where I said it starts in the fat cell. And I very much advocate that view. So why is it that Singapore 15 years ago was recruiting young scientists to come do diabetes research where you look at the average body weight in Singapore and by American U.S. standards, they're very lean people. And that's reflective of all East Asians and many South Asians as well. so India up through Japan and the Koreas.

Starting point is 01:38:13 Why is it that these are people with such low body weights and even low body fat levels, and yet their diabetes rates are way higher than we have in the U.S. And that is the difference in how people store fat. So if a human body is gaining fat mass, it will gain that fat mass through two different mechanisms. It will either be a function of multiplying the fat cells. So the person will have the ability to make new fat cells. that's called hyperplasia. And when the fat is undergoing hyperplasia, the size of the fat cell is staying very modest.

Starting point is 01:38:45 So the size of each individual fat cell is smaller, there are just a lot more of them. On the other hand, you could have someone who's storing more of their fat through hypertrophy, where the number of fat cells is not changing, but the size is the hypertrophic fat cell is a very sick fat cell for two reasons. And then I'll explain the ethnic predisposition. predispositions because of it. So firstly, the fatter the fat cell gets, the more insulin-resistant it becomes to prevent further fat growth. So to say that all another way, a fat cell can undergo more expansion than any other cell in the body that I'm aware of. It can get 20 times bigger than its original volume. And as it starts to reach this point of maximum dimension, it has to start

Starting point is 01:39:31 limiting its growth. And so it becomes insulin-resistant to stop growing. But at the same time, it starts to become hypoxic, where the fat cell has become so big that they've pushed each other too far from capillaries. And now it can't get the oxygen from the capillaries. And so it starts releasing a bunch of pro-inflammatory cytokines because some of them will work like a trail of breadcrumbs, resulting in one capillary having a little budding capillary grow off and follow the cytokines to the hypoxic or suffocating fat cell. So the hypertrophic fat cell becomes insulin resistant to stop growth, and it becomes pro-inflammatory to try to correct blood flow, all of which results in a very insulin-resistant on the course to cardiometabolic disease body. Now, back to the various ethnicities, some ethnicities, like whites and blacks, have the ability to make new fat cells. So these are ethnicities that can be a little fatter than other ethnicities and yet have lower levels of insulin resistance in type 2 diabetes.

Starting point is 01:40:35 And that's what we see in the U.S. High rates of obesity, but relatively modest rates of type 2 diet. As much as we think the problem is bad here, I think the U.S. ranks somewhere in the 70s. If you look at all the countries in the world and how diabetic they are, we're about number 70. Whereas Singapore, for example, in Japan is not too far back, Singapore is, I think, number nine. And all the countries of the Middle East are actually, numbers one through eight are like Oman, Dubai, Jordan, these countries in the Middle East. And then the other countries sort of round out through Southeast Asia and the Middle East and the Pacific Islands, the most diabetic places.

Starting point is 01:41:13 These ethnicities, especially, so India has among, it is among the highest most diabetic countries on the planet, East Asia, Southeast Asia. Their fat cells, on average, are significant. The one paper I'm recalling where it looked, it took Caucasian men and South Asian men and did an adipose subcutaneous biose. biopsy and have found that the average South Asian man had adipocytes that were about four times larger volumetrically than the fat cells in the Caucasian at the same body size, same body fat percent. They just had much bigger fat cells. So to say all this another way or to start to wrap it all up, what is more problematic about fat storage? It's not the mass of fat that matters most, but the size of each fat cell when it comes to slow insulin resistance and the consequences of too much fat mass. And this explains why, say, an East Asian fellow will just be moderately overweight compared to his obese Caucasian counterpart. And yet he has all of the complications of insulin resistance. And this guy just doesn't look good in his speedo and is otherwise fine metabolically. It's because his fat cells are small because he has so many of them.

Starting point is 01:42:28 His fat cells are so few, but they're much larger. And so he has a lower body fat mass, but it's more harmful because it's more harmful because it's, fat cells are bigger. And that is the problem with visceral fat. There's nothing inherently pathogenic about visceral fat. Those fat cells aren't mystically harmful. It's just that that visceral cavity is so limited in volume that it only allows fat growth through hypertrophy because that is a way to limit the total amount of fat you can grow. If our visceral fat was able to grow through hyperplasia, then it may expand so much that it starts to compress our tissues. It starts to squeeze the liver or squeeze the intestines or squeeze the kidneys.

Starting point is 01:43:13 And so by only allowing visceral fat to grow through hypertrophy, you do limit how much it can grow, but it also becomes much more prone-flammatory because hypertrophic fat cells release a lot more prone-flammatory cytokines than smaller hyperplastic fat cells. So there's very much a genetic, ethnic component, to this that influences how ethnicities are able to stimulate the growth of new fat cells. And then there is, there's absolutely a sex component to it as well, which of course is still

Starting point is 01:43:44 genetic, where women, because of the effects of estrogens, are able to stimulate a higher degree of hyperplasia than her male counterparts are. And so women will have that ability to, and this explains why the average woman both has higher fat than her male counterpart and yet is healthier in every single cardiometabolic metric. If it was just a matter of fat mass, then women should be dying more from all these cardiometabolic diseases, and yet they're not. It's men, because women will have more fat cells, but smaller,

Starting point is 01:44:15 because of estrogens. Men have relatively lower levels of estrogen, so we don't have that hyperplasia as much as the females do. So if we're getting fatter, it's more through hypertrophy relative to the ladies. So with respect to these hyperplasia versus like hypertrophy, fat cells, and I probably should have mentioned the visceral fat, the fat lining the organs. You mentioned the visceral cavity. Yeah. This fat's usually like the lining the organs and I usually find it around the midsection as well. But you mentioned the fact that the the fat in the adipose tissue will become insulin resistant to basically shut down growth like as a response, like adaptation. Like, okay. okay, we got to stop growing. What about spillover of fat?

Starting point is 01:45:03 Like, is this feeding into that whole seramide pathway that you started to talk about? Yeah. Is visceral fat and is this, you know, this hypertrophy, like swollen fat cell also causing more seramides to go into your system? Right. I'm so happy you brought that up. I deliberately chose not to because I thought I'm already being too long-winded. But here you are slow pitching the ball to me anyway. So, yeah, the problem with that hypertrophic fat cell.

Starting point is 01:45:28 is that it's becoming, insulin is trying to still force feed it to store more fat. And insulin's main mechanism of promoting fat storage is by inhibiting lipolisis. So insulin will promote the growth of the fat cell. It does enable the feeding to some degree, but its most powerful effect is blocking the breakdown. And so the fat cell is saying insulin, I can't keep, you keep telling me to grow, I can't. If I continue to grow, I mean, it literally gets to the point where the membrane can start to fray. It can't hold itself together. It's like a balloon that's being filled too much. And so it becomes insulin resistant, which is manifested as insulin not being able to inhibit lipolisus. Now we have a

Starting point is 01:46:12 metabolic milieu that's quite odd, where you have high insulin and high free fatty acids. That does not happen unless the fat cells are insulin resistant. So just to make that clear, in a fasted state or a low carb state, insulin is low, and so you have more lipolysis, so free fatty acids will be higher. That's a very common feature. This is the fasted state, low insulin, high free fatty acids. In contrast, the fed state, especially if it has some carbs, now insulin has gone up, it's inhibited lipolisis, and so free fatty acids will be down. This is the normal.

Starting point is 01:46:49 It's one or the other, unless the fat cells are insulin resistant. Now you have high insulin, reflective of insulin resistance, but it can't. inhibit lipolysis, thus we have high free fatty acids. This is a problem back to the ectopic aspect that you'd mentioned earlier, where normally if free fatty acids are high, the muscle will just burn it. And the muscle will happily burn free fatty acids, or any tissue, any cell with the mitochondria would burn it. But if insulin's elevated, you can't burn fat.

Starting point is 01:47:18 Then fat burning beta oxidation has been inhibited at virtually every single step with high insulin. So now we are storing more fat as triglycerides, which is the ectopic fat deposition. So that's where you start to have fatty liver. In fact, the main cause of fatty liver is spillover from fat from fat cells, especially visceral fat. That's the main origin of all that fat. As much as we talk about fructose and other nutritional variables, and those matter, the majority of it is fat that's leaking out from the fat cell. And because insulin's high, it can't burn it. Normally, the liver would take those fatty acids and just say, well, I'm going to burn it into ketones. But if insulin's elevated, it can't happen. The liver has to store it. The pancreas

Starting point is 01:48:01 starts to store it. But as I mentioned earlier, the triglycerides are not the cause of insulin resistance. But now we have the high insulin, which is an acute cause of insulin resistance, and a lot of free fatty acids. And where some of those are going to be palmitate, because palmitate is some of the stored triglycerides, you have palmitate coming out that will directly be activating TLR4, the receptor that's going to then drive seramides to be synthesized. So you have a lot, and not to mention the inflammatory cytokines that are also being released from the hypertrophic fat cell at the same time, also stimulating seramide accrual. Thus, we end up having the perfect metabolic milieu to promote insulin resistance, and it all

Starting point is 01:48:44 started because the fat cells got too big. And not to mention the cytokine signaling, you're talking about now the chronic inflammation Yeah. Yeah. Yeah. There's studies now linking visceral fat to cancer. Yeah, that's right. And so it's the brain, the cancer incidence, it's all... Astrosis. Yeah. C-ractive protein is a better predictor of heart disease than LDL cholesterol is. And the fat cell is the main source of a protein called plasminogen activator 1, P.A.I.1, whose main job is to erode clots as they form. So why is it that bigger fat cells relate so well with stroke and in cardiovascular? disease because you are producing a protein that's inhibiting the breakdown of clots, making it just more likely that someone's going to have a stroke. So you talked about genetics and, you know, someone's sex in terms of like male or female and how that affects whether or not they're going to have this, you know, predisposition to forming more, more fat cells or taking that fat cell

Starting point is 01:49:42 and just expanding. Yeah. What other factors play a role? Because, I mean, you know, is there a dietary? Is there, you know, some other, some other factors that are also contributing to that? There is, yeah, just, I'll just mention one just for the sake of time, which actually is linoleic acid. So my view on seed oils is that they can contribute to insulin resistance through a secondary route by influencing the dynamics of the fat cell, specifically when linoleic acid is taken into the cell, one of its peroxide metabolites that it can turn into is a molecule called 4H&E. And 4H&E has been shown to inhibit the fat cells' potential for hyperplasia, thus forcing the fat cell to only go down hypertrophy. So if there is some nutritional link

Starting point is 01:50:33 that can drive fat cell storage into one versus the other, linoleic acid does have that effect. Linolaic acid being converted to 4H&E will inhibit the adipogenic hyperplastic signaling and only enable the hypertrophic signal of the cats. Is that dose dependent? Like, are you going to get that if you're eating? I don't want people to be scared to eat like walnuts. Yeah, for sure it would be. I don't know.

Starting point is 01:50:58 I can't quantify the dose. But yeah, in general, my view, you and I were chatting earlier, linoleic acid is ubiquitous in nature. You need it. You need your self-rembring. Yes, yes, you have to have it. So as much as I'm talking about it and invoking it as a problem, I think it's very appropriate for you to say,

Starting point is 01:51:16 Yeah, but it also, like it's in mother's milk, for goodness sakes. It's in every meat source. And I'm a huge defender of meat. I think meat is very healthy, and yet you're going to have linoleic acid in it. I would maybe counter, or not counter, by just stating that those also in nature, when you have the omega-6 linoleic acid, you often also have an omega-3 that comes with it. That to me is key. That if you're, and often it'll have some degree, even minuscule levels of vitamin E. vitamin E will help that linoleic acid not go down the pathway of peroxidation.

Starting point is 01:51:52 It'll help it just go down the pathway of oxidation even. Dr. Stephen Cunane, this incredible man, just a delightful individual, he's done a lot of work documenting the fact that linoleic acid, when it's allowed to just be burned for fuel, burns so high and so rapid that it allows the brain to create its own ketones. He has a fascinating area of research on the, this. So I've always tried to have a little bit of a nuanced view of linoleic acid in that it's everywhere. But when we get it in nature, it'll come with an omega-3 and it'll come with some

Starting point is 01:52:27 amount of often vitamin E, which will help prevent the linoleic acid from going down the pathway of becoming a villain, which it can. Linolaic acid will undergo proxidation very readily and become a very harmful series of metabolites that are harmful to cell membranes and mitochondrial membranes. Is that, is that, though, more, because I, you know, I've looked a lot at the literature here, and I remember I first was, I was submitting a paper and I was going off about how terrible omega-6, high omega-6, and, you know, it wasn't necessarily from seed oil, but it was kind of going that way. And a reviewer just kind of just got me hard, and I started to really have to look at this with a different perspective and going to the literature. And I really was shocked by how much of the literature is showing with these, you know, linoleic acid and even, you know, switching saturated fat with these polyunsaturated fat seed oils were either neutral or beneficial with the exception of like maybe one study, but like the bulk of them were not showing that. Yeah. And it wasn't until I started to really dive deep and see like, okay, it's like this heated seed oils.

Starting point is 01:53:38 And when you start to heat them, especially if you're like heating them very, very high temperatures or you're heating them over again. Yeah. Where they're becoming problematic, at least with respect to some of the biomarkers that were being looked at like inflammatory biomarkers. So I'm wondering, like, is the heating the seed oils the bigger problem that consuming them in this really concentrated form and heating them and the whole package that they're, you know, the friends that they're bringing along, right? People are consuming these seed oils in processed foods, right? They're all in processed foods. Yeah. Versus eating some, like you said, meats, you know, walnut.

Starting point is 01:54:13 I mentioned nuts because they have a higher ratio, but they also, you know, have omega-3s as well. So I do think it's a nuanced topic as well. I do. But I don't want people to, like, be so scared of just anything with linoleic acid. Right. No, and I totally agree. I would also just say I'm also not the person to tackle the seed oil topic. Same.

Starting point is 01:54:32 There would be other people who would be way more. on both sides, attacking and defending. I've only tried to view that, I've tried to kind of stay in my lane, which is I'm an insulin mitochondria guy. And that's why I've tried to be a little cautious, because as much as people will invoke linoleic acid for causing all heart disease, all fatty liver disease, etc. I just sort of say, okay, great, that's not my forte. I'm looking at it in the context here of I'm looking at metabolic outcomes. So, having said all of that, I think what you just said is what I would agree with in that I think it's appropriate to scrutinize seed oils because of how we eat them. We eat them from refined seed oil sources. Dr. Christopher Ramsden at the NIH a number of years ago published a report finding that soybean oil has become the number one consumed source of fat calories in the human diet. That's not good.

Starting point is 01:55:30 And so I think it's appropriate for us to call them seed oils rather than, than linoleic acid coming from all natural animal sourced foods, which I'm always an advocate of, dairy has linoleic acid in it, meat has linoleic acid in it. They all do. Seeds have linoleic acid in it, but they also come with other things like a degree of vitamin E and an omega-3 to some degree. And those help to varying degrees reduce the pathogenicity, even if the linoleic acid had the potential to be harmful, which it does through peroxidation more than the other fats do, these other characters that are coming along with it help it behave and act in a way that we want it to act because it is everywhere it is ubiquitous and so i think where you and i would agree and maybe others would disagree i don't have a fear of linoleic acid per se as an omega-6 insofar as it's going to come in every natural source of fat that i'm eating but where earlier i'd said control carbs if you're controlling your carbs by and pardon me for a eating again, not getting your carbs from bags and boxes with barcodes, you've also eliminated

Starting point is 01:56:37 essentially all of those refined seed oils from your diet too. And that's why I also don't like getting caught up in the, is it seed oil or carbs, they always, these refined carbs, they always come together. So as much as I am the guy who's saying, well, refined starches and sugars are a real problem. And someone else would say, no, it's the seed oils. And I'd say, you know what, fine, they're coming together anyway. Because it's in that, it's you opening up. that pack of chips or treats or some refined snack, that's going to have, the first ingredient is going to be a starch. It's the potato chip, you know, as it's been fried. But what's it been fried in? It's been fried in corn oil or whatever. So you not only have a concentrated source of omega-6,

Starting point is 01:57:21 but it's undergone this superheating. And now it's absolutely gone through some proxidation. So if the person's just eating whole fruits and vegetables and natural sources of fats and proteins, you're going to get linoleic acid, and I would say there's no reason to fear it. Yeah, I think also it can be a distraction if you're not focusing on like avoiding avoiding the refined carbohydrates, avoiding the refined sugars, making sure you're getting exercise, making sure you're not overeating, like all those things. And then like I look, full disclosure, I don't cook with seed oils. Yeah, exactly. I don't cook with them. I don't use them. But I will say that an unbiased look at the literature, I still think, I think cooking them,

Starting point is 01:58:04 I think heating them, I would stay away from that for sure. Same. But if someone wants to put a little bit of, you know, of this uncooked oil on their salad, do I think it's like the worst thing in the world? I'm not sure that it is. I don't either. I don't know. Based on the current evidence. But, you know, at the end of the day, I think that that person's probably already doing things right. Yeah. And that's really what matters. Right. I agree. That's kind of where I'm at. Well, you'll get someone else on here who can articulate the seed oil point much more eloquently than I can. Yeah, if there's a researcher doing that, I'll look into that. But kind of going back to this, fat cells and shrinking, and you were talking about the adipocytes kind of becoming insulin resistance first, insulin resistant first. And that kind of leads into something that I forgot I wanted to ask you about, as we were talking about some of this before. And that is, you know, insulin resistance doesn't happen at the same time.

Starting point is 01:58:56 in all tissues. And so it'd be kind of nice to just talk about that briefly. Yeah. We continue on in terms of like the muscle, the adipose tissue, the liver. Yep. What happens when each of those become insulin resistance? And you also talked about adipose tissue. Yeah. Maybe first. Yeah. Is that then contributing to the other ones then becoming insulin resistant? Yeah. Yeah. So I absolutely. So there are people who would say, no, the fat is first when it becomes. So what is the first domino? If if it's a sequence of tissues, which is the first of fall, when it comes to, here's the person healthy, here they're progressing through insulin resistance with type 2 diabetes being the most obvious outcome at the end of it.

Starting point is 01:59:37 What's the progression? Some would say it's the liver. Some would say it's muscle. Some would say it's fat. It's the fat. In my view, very strongly, it's the fat tissue. So insulin resistance in its earliest stages is high insulin, but normal glucose. the problem with invoking a muscle-centric view or a liver-centric view, or I need to add one, an alpha-cell

Starting point is 02:00:03 centric view, because that's also relevant of the pancreas for a reason I'll touch on in a moment. The moment those become insulin-resistant, glucose is not going to be controlled anymore. And so then you skip a step, because insulin resistance, if you look at the progression of the person towards type 2 diabetes, the insulin has come up first, and then the glucose is normal and the glucose will start to climb, and that's when we detect the problem. So my view is the fat cell falls first. It's the first tissue to become insulin resistant as it starts to experience some degree of hypertrophy. That then starts to facilitate the other tissues becoming insulin resistant, and at that point,

Starting point is 02:00:44 there's no order in my mind. It'd be hard to distinguish if there's another order. But I actually, when I teach this very idea to my students, one of my undergraduates, assignment is a class called pathophysiology. And these kids are fortunate enough to learn the true origins of type 2 diabetes from an expert. But I actually show the fat cell first. And then the next step, I say, I teach it in this concept of, all right, well, what flips the switch from pre-diabetes, insulin resistance to type 2 diabetes? What is it that makes the glucose go up? That is then when the muscle becomes insulin resistant. You have lost access of the main glucose

Starting point is 02:01:20 consumer, so you're clearing the glucose out far of the blood, far worse, less readily than you were before, resulting in a hyperglycemia. When the liver becomes insulin-resistant, insulin can no longer inhibit glycogenalysis. So normally, one of the mechanisms whereby the liver works with insulin is by storing glucose as glycogen. Insulin inhibits the breakdown of that glycogen unless the liver's become insulin resistant. Now the liver is breaking down glycogen and releasing it as glucose, even when insulin is attempting to tell it not to, thereby further compounding the hyperglycemia.

Starting point is 02:01:58 Then the last one is the most overlooked, but absolutely relevant, which is the alpha cell. The alpha cell is the yin to the beta cell's yang, where the beta cell releases insulin, and insulin's most famous job is to lower blood glucose. the alpha cell releases glucagon, and its most famous job is to increase blood glucose. So it's very important for fasting and exercise the opposite of when insulin would be up, basically. But the alpha cell knows when to not release glucagon when the beta cell is releasing a lot of insulin.

Starting point is 02:02:33 Because insulin, and their next door neighbors within the islets of the pancreas, insulin will flood the beta cell with, rather the beta cell will flood the alpha cell with insulin. and insulin will inhibit the production of glucagon, which is good because then that helps insulin overall affect blood glucose to bring it down. But the alpha cell can become insulin resistant. Dr. Roger Unger at UT Southwestern over years published a series of mind-blowingly cool papers, finding that in type 1 diabetes, if you just control the glucagon excess, you don't even need to give the patient insulin that you could correct all hyperglycemia by just inhibiting the glucagon.

Starting point is 02:03:14 So that's just a weird little feature of the fact that when the alpha cell becomes insulin resistant and it does, it starts releasing uncontrolled glucagon, which comes to the liver and once again is telling the liver to make glucose and release it into the bloodstream. So the fat tissue becomes insulin resistant first. That facilitates the insulin resistance of the glucose controlling tissues, muscle, liver, and the alpha cells. and when those start to become insulin resistant in any particular order, that's when you start to see the glucose start to climb. But we know decades potentially before the person ever starts to have hyperglycemia, they have hyperinsulinemia. That's why I think the fat cell is subtle enough in its metabolic demands that it doesn't really need a lot of glucose. Its metabolic rate is so modest. So it can become insulin resistant without really affecting fasting glucose levels.

Starting point is 02:04:11 so the person's fasting glucose levels can stay normal. But once the glucose handling tissues, like the three I've already articulated, become insulin resistant, now glucose is uncontrolled. Going back to this fat cell hyperplasia, like a lot of, you know, forming lots of different fat cells versus this, you know, swelling of it, the hypertrophy. If a person loses weight, like let's say they're on a weight loss day. They're, you know, doing, restricting their calories, they're doing low carb, they're exercising any of the combination of those.

Starting point is 02:04:44 What happens to the fat cells? Do they shrink? They shrink. Do they ever die? They do. Yeah, they do. Yeah, but they shrink. So I actually say, when I talk about this in my class, I say the patients on a fat cell shrinking journey. That's exactly how I describe it, because that is weight loss. All weight loss is shrinking of the fat cells. Now, however, a fat cell has a lifespan of about 10 years. And so, to depending on the utility of that fat cell, it may not be replaced, or it may be replaced. And so you can, over time, lose fat cell number.

Starting point is 02:05:17 And indeed, you do. At around 60 years old, 60 to 70, a person, so during infancy, childhood, puberty, we're making fat cells. And then for the most part, the number of fat cells we have is set. Now, women have a little buffer, like I said earlier. But even then, you could have a person who gains 100 more pounds or 200 more pounds in adulthood. for the average individual, that's hypertrophy, not a result of hyperplasia. But then when we get to older age, then the number of fat cells stop turning over. So as they start dying at their 10-year lifespan, we don't replace them.

Starting point is 02:05:53 And so at the end of life, we have a little drop-off in the number of fat cells. So, no. So weight loss is shrinking the size, not changing the number. And in fact, if you force artificial weight loss by sucking out fat cells, where you are just sucking out the fat cells and reducing fat cell number, then you don't improve any cardiometabolic outcome whatsoever. So there's many studies that show that you can have people lose a significant amount of fat through liposuction, and not a single outcome has improved.

Starting point is 02:06:25 Whereas if that same person had lost that 20 pounds of fat through normal lifestyle interventions, like you'd mentioned, they would have had improvements in every cardiometabolic outcome. But you don't do that with liposuction because you haven't changed the size of the fat cell. The size of your fat cells is the same. You've just sucked out a lot. But the remaining ones are still there. And now, in fact, you've put a greater pressure on them because a person, an adult, doesn't make new fat cells very readily. So what will happen is the remaining fat cells will be forced to grow through size because they can't share the burden with their other neighbors that you've sucked out already.

Starting point is 02:07:00 So when a person starts to regain weight, the cardiometabolic outcomes are amplified. When people do lose weight and they're shrinking their fat cell size, are those fat cells, like, let's say someone was even insulin resistant, right? And there's a problematic fat cell. And it shrinks in size. They lose weight. It shrinks in size. I mean, is it still problematic? No. No. No. In fact, that's why with the slow insulin resistance, the reversal of that, like over the 90 days in the type 2 diabetic patients that we had in our published case series, That would have been, not that we measured this, but it would have been because of a shrinking of the fat cell. Now, let's say they grow those fat cells again, the same problems will come back. So whatever intervention, one of the problems I have with diet, whatever the intervention is, low carb or, you know, calorie restricted, whatever, people will complain and they'll say, well, but it's only short term. Yeah, of course it is. whatever a person has done to reverse their metabolic problems will only persist as long as they adhere to those changes. The more they go back to their old habits, the more the same consequences will return because it was those old habits that caused it.

Starting point is 02:08:15 With respect to the visceral fat, and I mean, particularly the visceral fat, since it's the fat that's really got that expansion of the fat cells. It can only go through hypertrophy. Right, only going through hypertrophy. what what sort of targeted diet lifestyle interventions would be suggested or evidence-based to actually decrease the visceral fat? Yeah, that's a great question. So visceral adipocytes are more responsive to the lipolitic signal, the fat breakdown signal of epinephrine. So anything that increases epinephrine will have sort of pound for pound or site-for-site visceral versus subcutaneous is going to have a better visceral response. So the more the epinephrine is being targeted. So that's going to be things like exercise and like

Starting point is 02:09:02 cold therapy. For example, cold immersion. Talk about an epinephrine spike. So anytime you're really activating the sympathetic nervous system, you're going to be sort of molecule for molecule, cell for cell, targeting the visceral more than the subcutaneous. So it is more responsive to that sympathetic tone than subcutaneous fat is. Interesting. So epinephrine, high intensity interval training is really like more intense exercise again back to that and then yeah deliberate cold exposure is another one great and i'm a big advocate of cold immersion great yeah okay well that's interesting um i didn't know about the the the fact that epinephrine was was linked to that as a as a mechanism okay so a little bit about we talked a little bit about the the muscle mass and i think just the

Starting point is 02:09:46 the one thing that was kind of on my mind was that sort of anabolic paradox of insulin yeah and and kind of what your thoughts are with respect to you like i'm You know, some bodybuilders are injecting insulin, right? So how, yeah, like, let's talk about a little bit like reconciling insulin's role as being this, you know, anabolic versus, you know, storing fat being metabolically problematic. Yeah, yeah. So I want to be careful in answering this because I'm an insulin guy, but I'm not a muscle cell guy. But because I'm familiar with insulin, I'm comfortable enough answering this question. So there was a group, in fact, I think it was the same guy I mentioned earlier, Sri Nair.

Starting point is 02:10:25 N-A-I-R, at Minnesota at the time, they published a paper finding that insulin wasn't necessary for muscle protein synthesis. So here we have the muscle, and we have the protein formed, giving the bulk of the muscle. You have to look at both the stimulus, building it, and the signals that are breaking it down. They documented that insulin was not necessary for muscle protein synthesis, but it was very helpful for inhibiting the breakdown. So it, they suggested that insulin's main effect of muscle is an anti-proteolytic effect rather than a stimulating effect. So that my general view is

Starting point is 02:11:06 that that's where insulin is going to be favorable, but it also didn't take a lot of insulin to inhibit the proteolysis. So I do not think it's at all justified to take insulin as an intervention to try to promote muscle growth. And in fact, just as a very unscientific observable, When I compared the physiques of Arnold and Lou from the old 1980s bodybuilders to the modern day bodybuilders and the almost bizarre phenotype of this like bubble belly, you know what I'm talking about? Anyone listening probably knows what I'm talking about. But I want to be polite. You know, these are real guys. But we can all agree that there's an odd physique.

Starting point is 02:11:43 You know, whereas Arnold and Lou were extremely tapered, very, very narrow waist. Modern bodybuilders, yes, they're more jacked. but they're also oddly distended with their abdomen. I can't help but wonder whether insulin has been somehow facilitative to promoting some degree of visceral growth because insulin wants to promote fat growth. It wants to. It's like a fertilizer for fat cells. And so someone who's wanting to overdose on insulin in an effort to promote muscle when you're just maybe enhancing some proteolytic, anti-proreolitic effect, I'd say there are better ways to do it. Like, not that I'm endorsing any intervention like this, but you'd be better off just focusing on growth hormone than you would injecting yourself with insulin.

Starting point is 02:12:28 So I am not a fan. Now, I appreciate some big, yoked bodybuilder looking at relatively spelty, small Ben Bickman and saying, well, what do you know? Maybe I don't know a lot. No, I think that was a, that's a really good, those are great points that you made, for sure, for sure. I think we covered a lot of the muscle effects on insulin and, you know, how exercise is so important, growing muscle tissue and exercise is important for, you know, allowing the muscle to be that, you know, site of glucose disposal. But let's kind of then shift gears and talk about this weight loss. And obviously, I think right now there's a big trend in rapid weight loss and weight loss that's made very easy by taking GLP1 agonist. drugs, things like OZembeck and WeGoV. And I'd love to know what your thoughts are on, maybe first you can explain just, you know, generally how these GLP-1 agonists work and why they're causing

Starting point is 02:13:30 weight loss and how they affect metabolic health, but also whether they're addressing the underlying root cause of obesity. Yeah. And, you know, if, or if there's sort of short-cutting around that. Right. Well, there's no question. It's a bit of a shortcut. And I am worried about the long-term effects. So with GLP-1, I have had my finger on the pulse of GLP1 probably since, well, not since its inception, but since the late 90s, early 2000s. My Ph.D. Lab was one of the first labs funded in the U.S. looking at the study of Incretins by a drug company. And so I've long been familiar with GLP1 and the other Incretins, Incretins, being a word to describe these gut-derived hormones that have metabolic effects. But it's been interesting for me to note the evolution in their use, because originally they were only used as anti-diabetic drugs. And then the, what was considered kind of an off-target effect of controlling satiety is now the mechanism of action at these much higher doses, as the dose has been multiplied up to the kind of current Wagovi weight loss dose. So it's really just been

Starting point is 02:14:43 evolution in the dose of this small of semaglutide for the most part although there are other glutides that fit in this as well but semi glutide is the main one so at the lower dose originally used these glp1 activators worked actually by inhibiting glucagon so back to the alpha cell that i mentioned earlier it's we come back to them now where in type two diabetes the insulin resistance of the alpha cell results in a chronic elevation of glucagon chronically then telling the liver to be releasing glucose, leading to the hyperglycemia that defines the diabetic state. At this low dose, semaglutide inhibits the alpha cell. It inhibits glucagon. And by inhibiting glucagon, you're helping correct blood glucose. So it was an effective anti-diabetic.

Starting point is 02:15:31 Now, some people have the very mistaken view that semaglutide or GLP1 activators also release insulin. That is not true. That has been shown to happen in isolated. cell cultures, but in humans, there's no evidence. And the authority on the subject is a guy named Arnie, A-R-N-E-A-S-R-U-P, A-S-T-R-U-P, Arny-O-R-U-P-R-U-P-R-UP in Denmark. He's one of the absolute authorities on this topic. He's published multiple papers in humans showing that no amount of GLP-1 elicits an insulin release. So that, we need to put that idea to bed. In humans, that does not happen, GL-P-1 does not act as what's called an insulin secretagogue, or hormone that a drug that forces the beta cell to make insulin. GLP1 inhibits glucagon, which helps correct

Starting point is 02:16:20 blood glucose. Now, as the dose starts to go up higher, just, I guess just for the sake of time, I'd mention two effects, which is one in the guts and then one central. Within the intestines, GLP1 will act to delay gastric emptying and slow peristolsus. So that has the effect of a person eating and having that bulk sit in their stomach much longer, which is going to generally discourage them from wanting to eat more. At the same time, it's going to take a lot longer to get through the intestines. Now, that is good for weight loss because it forces them to eat less. A consequence of that is it ranges from the uncomfortable to the problematic.

Starting point is 02:17:04 So on the uncomfortable side, the person will have food that's sitting in their stomach for up to 20 hours. And so they will start burping a lot. And they will have, like, people who go through general surgery and have to be put under for general anesthesia, they found that normally you tell the person don't eat for 24 hours and their stomach's empty. So they're not going to vomit food up while they're asleep. But when they found that if people were on these, were on semaglutide, the food was still there. And they would still have food in their stomach, even though they hadn't eaten for 24 hours. So this results in what people colloquially just call ozempic burps where they just have. have putrid breath and burping and just stomach nausea. But because of the change in gastric

Starting point is 02:17:47 emptying, even some medications like birth control medications don't work anymore, for example, because you've so changed how long it takes that drug to get from the stomach into the small intestine where it would have been absorbed. So it starts to change the absorption of certain compounds and drugs, as well as potentially affecting the absorption of nutrients, which may be part of what the person is observing with regards to other changes in, say, muscle mass, maybe that's a result of just poor nutrition because even though they're eating, they might not be getting, they might not be digesting and absorbing everything they're eating anymore because of how the rate of the peristalysis has changed so much.

Starting point is 02:18:29 So anyway, numerous changes of the guts, and then there's a central nervous system effect to activate satiety centers. Now, the combination of those two is powerful where you have the, I'm full signal here, and I have a lot of stuff in my stomach here, resulting in a person who has a much better control over their appetite, I guess, to say that a polite way, or to say that another way, they just don't have as much of an interest in eating. So that's the main mechanism of action. And GLP1 is a normal hormone. I didn't mention this. GLP1 is a naturally produced hormone from the gut. We have it.

Starting point is 02:19:06 We know that we can change its levels based on what we eat, and that might explain why some people eat more or some people eat less. But still, my concern is that the dose of GLP1 that we're using now has gone. It's just a little too much of a good thing. What is the dose range that you were referring to talking about? Yeah, yeah. So I think that the commonly used doses are going to be, the order of actually in this case it's I know it in milligrams I think it's about five milligrams

Starting point is 02:19:36 or so two and a half plus milligrams and a once weekly injection and if people are thinking of that in units I think that's going to correspond to units of about 25 to 30 units of gLP one so that to me is too high and and two and a half milligrams being the low dose that is the yeah that that's the low dose of what is used now. Right. And the underlying the dressing, obviously this was, these were used for, like you mentioned, this was a, you know, diabetes drug, right? I mean, this wasn't necessarily meant to treat obesity.

Starting point is 02:20:15 Yeah, right. But I guess that it all depends on, you know, the cause of obesity. Overeating is partly a cause of obesity. Oh, no, for sure it is. Yeah. In fact, I am, as much as people will hear me describe this and think that I'm being just universally opposed. I actually do think there's a place for these GLP1 drugs. A paper was published in 1996 that looked at the changes in GLP1 in two populations. They took otherwise healthy humans

Starting point is 02:20:42 and split them up and they noticed changes in the obese group and the lean group. So when they gave both groups a high fat meal, they looked at the GLP1 response and it was roughly similar in both groups. That whether they were obese or lean, they ate a high fat meal and and GLP1 was the same, heavy overlap, suggesting that the satiety effect of that meal would be roughly equal. Now, I'm speculating a little bit there. I'm adding that last part in. So if you look at the GLP1 response, given GLP1's effects on satiety, which is very meaningful,

Starting point is 02:21:16 the high fat meal elicited a similar response regardless of body's fat mass. However, when they gave them a high carb meal, the lean group had a huge increase in GLP1. the obese group had no statistically significant response whatsoever there was a little noise but the error bars were big enough that there was no statistical difference it again it wiggled around a little bit but at no point did it reach a significant increase suggesting that you may now have two people who sit down to eat a meal one person eats that carbohydrate heavy meal and they have a big g lp1 response they pat their tummy and slide the plate away the other person eats that same amount and asks for seconds, or even thirds, because they aren't getting that GLP1 response. So to me, the best use of these drugs in the context of weight loss isn't for weight loss per se, but it's rather to acknowledge some people aren't going to get that off switch when they eat carbs in particular, that apparently people responded the same way to fat, but there are not, there are differences in how people respond to carbohydrates with GLP1.

Starting point is 02:22:25 This study made it very, very clear. It was published in the journal, Gut, in 1996. To me, that's the best use of the drug. To say the physician or the clinician, the expert would be talking with the overweight patient, and they would say, you know what, you need to control carbs. These refined sugars and starches, you got to eat less of them. Then the person says, yeah, but that's the problem. I can't eat less of them.

Starting point is 02:22:50 I'm addicted to them. All right, let's use a low dose. And this gets into that range of, you know, five to ten units or 0.05 to one gram. Milligram. Milligram per week. That is going to be kind of a microdose level. To me, that's the best use where the physician, the expert, the clinician is saying, let's just give you a low, low dose of this drug.

Starting point is 02:23:15 And it's going to, and I want you to think of it as helping you control your cravings. Because what do people crave? People don't crave a plate of bacon and eggs. They don't crave a handful of walnuts. They crave something sweet and gooey or salty and crunchy. And usually it's going to be potato chips, crackers, cereal, ice cream. And that's what we want to help them control. So rather than saying this is a weight loss drug,

Starting point is 02:23:39 what if we change the conversation and said, this is a drug that is designed to help you change your eating habits? While you're on this low dose, we're going to put you on this low dose for three months. And I'm going to see you again in three months. I want you to be thinking about your evening cravings. these refined foods that you're always eating, and then you get them back three months later. Ideally, they say, boy, for the first time, I can control my cravings, and I'm doing better, and I'm losing weight.

Starting point is 02:24:07 Then I would say, let's see what happens when you cycle them off and say, all right, you've learned how it, what it looks like and what it feels like to eat differently, let's see whether you need to still be on this microdose. Maybe they need, maybe they're done. I know people who've done this, and they say it changed me, and it's been a year, and I've knock on back to my old habits. It just helps them rewire their habits. In 90 days is a good length of time to change your habits. So at 90 days, let's do a check-in. How are you doing? Oh, it's not really working. All right, well, let's keep it going. Maybe we increase it from 0.05 to 1 or something.

Starting point is 02:24:38 But basically, my view without having it outlined as a specific protocol would be microdose and cycling. Let's put you on it with the intention of helping you change your habits. Let's take you off it to see whether the habits have stuck. If they haven't, let's cycle you back on, but always using these very, very low doses, not for weight loss, but for changing habits. That's interesting that in your experience, people can do this microdose, and after about 90 days, they can keep the appetite regulation under control, because when you look at studies with people using, you know, the clinically, clinically relevant doses that they're using now of these different. and GLP1 agonists, a lot of most of the people end up gaining weight back because it, you know,

Starting point is 02:25:28 they go back to your old habits. Yeah, and I think that's because they're not framing, I think a part of it's the narrative or the story, which is let's frame the conversation in the context of helping you change your dietary habits rather than this is just a magic bullet and you're going to lose weight. I think in that instance, the person has changed the way they're eating, but maybe they're not, this is, I know kind of getting into this hokey pseudo area of science perhaps, but when the conversation is focused on the habit, I think it helps change habits. Oh, I mean, absolutely, the, the, the way you're thinking about something can change the outcome. Yeah. For sure.

Starting point is 02:26:01 I want to kind of go back to something that you mentioned that was very interesting to me, and it has to do with the way, you know, this food is sitting in your gut and the, in the way digestion's kind of changed and perhaps, you know, nutrient absorption. I hadn't really thought about it in that way, because what I'm sort of alluding to is, you know, the, I guess it's pretty well known now is that when people are rapidly losing weight, whether it's on a GLP1 agonist or it's from caloric restriction, they can lose a lot of muscle along with the fat. It's not just all fat, particularly if people are not getting enough dietary protein, which is a big signal for muscle protein synthesis, and if they're not engaging in resistance training, which is the

Starting point is 02:26:43 other very important signal for growing muscle mass. So my question to you was going to be, you know, is there kind of a way around this muscle loss by increasing dietary protein? Obviously, the resistance training would be key, perhaps even more key now, because, you know, for one, if people aren't eating, I mean, I don't know how many meals a day people are eating. It probably varies depending on the person and what their side effects and stuff are. But eating the protein and then like are they absorbing all the protein? I don't know if anyone's even looked at that, but that's interesting. Yeah, I haven't seen it either. Yeah, but it does beg the question. Is it is the use of semical, so it's very real. The evidence is

Starting point is 02:27:24 very real showing one of the best look papers in the New England Journal of Medicine about two, three years ago found that about almost 40% of the weight loss that a person was losing was fat-free mass. Now that is itself a big pool, but some of it would be muscle. and bone mass, but I have not seen data that has determined whether it is a direct effect of the semaglutide. In other words, is the drug actually harming muscle and bone, or is it just an artifact of the poor nutrition? It might be a little bit of both, but it also might matter in the dose where I've heard reports.

Starting point is 02:28:00 In fact, my lab is doing a muscle cell culture now looking at varying doses of the drug, where it's possible at a lower dose, it's facilitative, and at a higher dose it may be a more it may be more catabolic when it comes to muscle mass and the dynamics of muscle protein synthesis. But even still, as far as I'm aware, it's unknown. Is it a direct effect of the drug or is it an artifact of just poor nutrition because the person's not eating? And what they are eating, they're not absorbing very well. They're certainly not eating enough protein. Yeah.

Starting point is 02:28:30 This kind of, there's another interesting point here, and that is like GLP-1 receptors. And, I mean, they're all over many different. organs. The muscle has them. And so does bone. Bone. Yeah. Right. Yeah. So that is that is an neuron do. Yeah. I mean, and it also starts to touch on the broader use of GLP1 drugs where you and I both know people are using them well beyond the as much as I bemoan the fact that it's now an obesity drug where it was once just a diabetic drug. Now people are saying, well, it's a blood pressure drug. It's an Alzheimer's drug. It's a fertility drug. I just don't know. In fact, as far as I am aware, there's very few studies to touch on that broader, on the mechanism.

Starting point is 02:29:13 And even all of that could simply be an outcome of improving metabolic health, because back to the origins or the beginning of our conversation, because metabolic health is so foundational to chronic disease, all of this could just be a consequence of improving metabolic health. But it still is worth the pursuit of determining, well, maybe it is a direct effect. Maybe there is the direct effect of the drug at the neuron or at the muscle cell, etc. As far as I'm aware, that's not been elucidated yet. Yeah, that was my next question for you. I mean, we do have these observational studies that have looked at, you know, people on, you know, various forms of the GLPA-1 agonist. Yeah. And a reduced incidence of cardiovascular disease, obviously type 2 diabetes, Alzheimer's disease now.

Starting point is 02:29:59 And you have to wonder, like, is this a, is there a direct effect of, you know, agonizing these GLP1 receptors on different tissues, or is this an indirect effect of weight loss and improved metabolic health? Yeah, yeah. Yeah. So I don't know. But we, what I can speak to is our unpublished results right now in muscle cells, we're treating them with varying doses of semaglutide. At the higher doses, there is catabolism of the muscle and they're far less resilient and far more fragile. So we challenge the muscle with a chemical challenge and they die way more readily. At doses used now at the level in which you see the dose in the drug in the plasma.

Starting point is 02:30:39 So it's a physiological dose. Okay. Well, then this gets back to the microdosing. And this is kind of, you know, I feel like you're talking, you were talking about microdosing GLP1 agonist for a very different reason than I'm going to ask you about now and you're talking about appetite regulation. And I think that's super interesting.

Starting point is 02:30:58 interesting, particularly for people who don't have real good control of their appetite, or perhaps they're, I mean, who know, their hormones are out of whack, right? But there is now this sort of growing, budding interest amongst, you know, many people about this potential GLP1 agonist being a longevity drug because of these different, you know, outcome studies that have been observational in nature, right? You're looking at correlation here. But the question is, well, like, some people are now sort of starting to whisper about, we think now maybe these drugs are actually affecting, they're actually pro-longivity. And so microdosing, you know, these drugs in the, in the, in the ranges that you've been discussing earlier, might be a way of getting the benefits. And

Starting point is 02:31:46 you're also getting the side effect benefit of appetite regulation. So maybe you're not going to be eating as much as well. Maybe it's just easier to not eat as much. Right. Yeah, yeah. So I, I, I appreciate the way you framed that, which is you mentioned a word that for a basic scientist is a dreaded word, correlation. I don't look favorably on correlation because I'm a basic scientist. I want to do one thing and observe a direct effect from that one thing. So one reason I am extremely cautious and even a little chagrined with the entire realm of longevity is that it's not to disparage it necessarily, but it's entirely based on correlation when it comes to humans. We can only speculate and predict and model these sorts of things. Now, I'm not saying there's no utility to that, but I also think it behoves us to be mindful of the limitation that comes with that. So with GLP1, in fact, it's worth noting another paper was just published this week, finding that the risk of blindness doubles, more than doubles in people on high-dose GLP-1s. It was just, a paper was just published. So you look at the degree of blindness that occurs in adults, and those using the drug, it was more than twice,

Starting point is 02:32:57 the risk of developing blindness. Now that's correlational. We don't know what else they may be doing. And so I don't mean to suggest that I truly don't mean to suggest the drug is causing blindness. No more than someone could say the drug is promoting longevity, although you actually can do a hard outcome with blindness. You can't really do the hard outcome with when does the person die very well. But there's so many variables that get worked in here that I cannot say it's because of the drug. But it is worth another reason to have some caution that what's the point? So maybe we just come back to the dose, that maybe that's where we can find a common ground for all the enthusiasts. And those who are enthusiastic but also a little skeptical on my end, where I am enthusiastic, but I also just want to bring in a note of caution.

Starting point is 02:33:45 Maybe where we do have that common ground is the dose. So with regards to GLP1, at the risk of seeing everything through a singular. lens, one of the most common variables that predicts longevity within families, there's one paper that actually mentions the word of familial longevity. And then the longevity studies, like the Amora study in Sweden or the Honolulu aging study or the Shanghai aging study, some of the most consistent variables is metabolic health, optimal glucose levels and insulin sensitivity. In fact, that one study, I think it was in the Mediterranean that looked at families where you have a high number of centenarians. They found that the most common theme was that they

Starting point is 02:34:29 were all very insulin sensitive. And as much as people have a, over the years, there's been an ideology of villainizing protein as a villainizing protein as a villain of aging because protein activates mTOR and when mTOR is too activated, it promotes aging. I find that view unfortunate because for reasons you and I've mentioned like muscle and bone mass you have to have mTOR turned on you have to or you can't have any anabolic no retention of lean mass let alone building it but when you vilify protein because of mTOR you ought to vilify insulin because insulin activates mTOR much higher than even the most anabolic amino acids like lucine does and it keeps it active, one dose of insulin can activate mTOR for up to 24 hours, whereas lucene, the most

Starting point is 02:35:18 anabolic of the amino acids, will only activate mTOR for about an hour or two. And so if mTOR matters for longevity, and I know I've sort of contorted the whole thing about longevity here, all the more reason to come back to these kind of metabolic first principles. And so looking at insulin sensitivity and glucose control, and I would just say the same thing with GLP1. While we may find that GLP1 has a direct effect of, say, activating autophagy? Maybe it could, and that could be a mechanism whereby it promotes longevity. At the same time, I don't have to go that far because I could just say, does it improve insulin sensitivity? Okay, good. Then it's probably going to correlate and predict and even cause improved longevity because of the evidence we have in that realm.

Starting point is 02:36:02 So, yeah, what you're saying essentially is that the improved metabolic health is probably what's driving the longevity benefits. And I would... It's at least low-hanging for it. Yeah, I would agree that makes the most sense. Yeah. You know, and it is important to obviously keep everything in context as well. Obviously, there's people that are obese and metabolically and healthy that have really just changed.

Starting point is 02:36:22 It's changed their lives, right? Yep. But the question is, do they have to keep taking it? Yeah. And in fact, 70% in the U.S., 70% of Americans get off the drug at two years, either because of cost or nausea or whatever, 70% stuff. taking it. And like you said, when they stopped taking it, if habits haven't changed, maybe that's an important caveat, they gain it all back. Not to mention, those who stay on the drug, a paper was published within the past six months. I think it was within the past six

Starting point is 02:36:51 months, definitely within the past year. The risk of suicidal behavior doubles and the risk of major depression triples in people who were on the drug for up to two years. On any dose of it or the high dose? On the currently used Wagovi dose, which is the higher dose. which is common. So not a microdose. Uh-huh, right, yeah. Yes, well, my view of this is, I don't know the mechanism. I don't know what the central effect is of this drug.

Starting point is 02:37:15 But as much one way, and this is my own kind of philosophical view, we rejoice in the fact that this drug has helped me, it's reduced my cravings for junk food, let's say. And we would say that's a wonderful outcome. What if in the midst of reducing the cravings for junk food, it reduces their cravings for everything they enjoyed. Where you hear, this is anecdotal now, people lose interest in their old habits.

Starting point is 02:37:47 A gal, the gal who used to like walking around the block with their girlfriends doesn't really want to go anymore. The guy who used to like getting on and playing video games, he doesn't want to do that anymore. They don't go play pickleball with their friends anymore, whatever. Maybe what we describe as improved eating control is actually just a reduced joy for life in general. But regardless of the mechanism or the philosophy behind it,

Starting point is 02:38:14 the evidence is extremely clear. The major depression risk, people were three times more likely to have clinically diagnosed major depression. And again, twice more likely for suicidal behavior and twice as likely it was like 106% increased risk of anxiety. And this is after the weight loss and after being on the drug.

Starting point is 02:38:33 Yeah, that's right. It was two years on the drug. So this is part of why I'm cautious where I respect the power of this tool. It is extremely powerful because it's so powerful. I think we should be mindful of going too far with it, which is why I am such an advocate. If it's going to be used at all, let's use it in a very specific context at a very specific dosing regimen with a cycling protocol where we want them to have in their mind, we don't want you on this drug indebt. Definitely. This is not a lifetime solution. It is a crutch until you've learned how to walk on your own, if you will, and change your habits. That to me is, so microdose cycling with the conversation surrounding eating habits. I think that that's a pretty balanced view. Thank you. I think so too. Yeah. I mean, there's definitely more to discuss here, but we'd have to have another three hour conversation. So I kind of want to just circle back and end on, you know, this.

Starting point is 02:39:36 you were talking about metabolic health being a predictor of longevity and, you know, there's metabolic health and inflammation is another one that I've seen where it predicts, which they're linked, right? They are. They're very much linked. So if, you know, if metabolic health is so important for longevity and the opposite is true, right, where you're metabolically unhealthy and that is essentially accelerating aging, You mentioned something that kind of surprised me early on, and that is you were kind of talking

Starting point is 02:40:08 about mechanisms by which insulin is so damaging, independent of glucose. And I was sitting here thinking one of the main reasons why being metabolically unhealthy, being insulin resistant is so unhealthy is because you're having high levels of glucose, which is glycating everything from your endothelial cells on your blood vessels to your mitochondium, your skin, heart, your skin, proteins, DNA, lipids, everything's getting stiffer and damage. What's, what are the mechanisms that are that are involved here with, you know, accelerating aging and just the glucose alone? Yeah. Well, yeah, well, yeah, in general, is it the glucose alone or what else? Yeah, yeah. Well, so insulin will promote aging by,

Starting point is 02:40:56 by, by, a persistent chronic mTOR activation. So, I mean, in insulin, in his, it's autophagy. If autophagy is a mechanism for aging that we want to leverage, I'm unaware of any signal that will inhibit autophagy stronger than insulin will. It abhors catabolism. It only wants anabolic, which can be favorable when leveraged wisely. But when it comes to aging, if you are inhibiting that catabolic process of autophagy, that's not going to be facilitative. So I rarely, I have the benefit. Having sort of staked my claim as insulin matters, I can defend that so well that I don't often need to step out of it. But when I want to, as much as some people will be here, say, Ben, it's all seed oils.

Starting point is 02:41:37 I'll say, no, you got the seed oils covered. I'm going to stay where I'm at because I'm so familiar with this. But glucose is a partner in crime. I just sort of say it's sort of who would be the partner. So it's sort of Joker, the main villain is the insulin. And then the glucose would be like Harley Quinn, sort of Joker's right-hand gal in this case to invoke a comic book reference, which I am delighted to do because of a misspent childhood. So insulin, I believe, matters most.

Starting point is 02:42:09 But glucose on its own is pathogenic. But before I even defend glucose, I just want to say, because so much of modern medicine is obsessed with glucose, at a cost, as I articulated earlier, that obsession not only causes us to miss the metabolic problem as early as we could by focusing on insulin. insulin, but it also leads us to unhealthy interventions where you have a hyperglycemic, hyper-insulinemic type 2 diabetic, and you're only caring about lowering the glucose, and you do so by pushing the insulin higher, if the glucose were the main pathogenic signal, this should result in improved outcomes, and nothing gets better. When you give a type 2 diabetic in insulin therapy, they get fatter and sicker and die faster, all while glucose looks good.

Starting point is 02:42:56 This is well documented. Their risk of dying from heart disease triples, their risk of getting dying from cancer doubles when you give them insulin. So I defend. What do you do with the type one diabetic? Ah, well, that's different. Yeah, because in a type one diabetic, there's no insulin. And so you have to give them insulin therapy just to bring them to normal insulin.

Starting point is 02:43:14 In the type 2 diabetic, they're already super, they're already high insulin and you're putting even higher. Okay. So that's the difference. It's, they're diseases of total opposites. The only thing they have in common is. that the glucose looks the same in that it goes high. Now, glucose is not benign, as much as I have an insulin-centric view. Unapologetically, glucose is a problem through multiple mechanisms.

Starting point is 02:43:39 You mentioned glycation. That is a huge one. Not only because of the change in the structure of that protein or that molecule itself, like skin, a lot of, like you can induce premature wrinkling by undergoing, by forcing glycation of the skin. You can result in a compromised glyco calyx of the endothelium by all that glucose compromising with glycation. So glycation itself is a way to irreversibly alter a molecule and eliminate its utility. And indeed, at the same time, when you form an advanced glycation end product, it becomes a substrate for or a molecule that can bi-ligand for rage, the receptor for advanced glycation end product. And when rage gets activated, you have a lot of inflammation.

Starting point is 02:44:27 So the glycation goes beyond the altered structure of the molecule itself, leading into some chronic subclinical inflammation. But there's another mechanism, too, where when you elevate glucose substantially, you will have cells that are taking in that glucose, but it's overwhelming its ability to undergo glycolysis. And if most cells, if you, you know, there's so much glycolysis happening that it starts to inhibit entry into the glycolytic pathway. Then you divert the glucose into the sorbitol pathway.

Starting point is 02:44:59 Now you have glucose turning into sorbitol, which the cell can't do anything with. And so sorbitol begins to accumulate in the cell, and that starts to increase the osmotic gradient into the cell. And now you have basically a water balloon that's getting overfilled, and you can have overfull, and you have this what's called hydropic degeneration, where you basically force water into the cell because of this glucose, tabalite and then the cell can burst. And this is a large part of the problem with like macular degeneration and retinopathies and the nephropathies of the kidney. The main mechanism whereby the

Starting point is 02:45:32 glucose is damaging, or one of the main mechanisms, is the conversion of the glucose into sorbitol. And when sorbitol accumulates in the cell, it can't go anywhere and it starts pulling in water and the cell will burst. Wow. I was just starting to think about prunes because prunes are like high in sorbitol. Yeah. So what's funny, though, when I teach this context, to my students, you can tell I'm an ultimate professor here. I teach all these ideas. I actually have my students as a funny little assignment look up the customer reviews of sugar-free gummy bears. And it's so funny because these derivatives of glucose, like sorbitol or manitol, they can't move across cell membranes. And so wherever they are in the body, they're doomed

Starting point is 02:46:17 to stay there, including if it just comes into the intestines. So part of the humor for these 18, 19-year-olds is finding these people giving customer reviews of how the gastrointestinal distress of these sweetened gummy bears that are like sorbitol that all stays in the guts, and it pulls a lot of water in the guts anyway, creating some socially awkward situations for these poor people, to put it politely. I also like how you're talking about this insulin-centric sort of model of how that's really the most damaging. And it really is. When you think about insulin you know, shutting down, I mean, I guess I should say that another way. When you think about like insulin's role in activating AKT, which then is shutting down all

Starting point is 02:47:02 these stress response pathways, everything from autophagy to, you know, making stem cells to just, just everything. Yes. Being being shut down by the action of this one hormone. Yeah, a humble little peptide. Yeah, I mean, in most people, it's one thing for like a steroid hormone to have a kind of global effect, but peptide hormones don't often do that. You know, glucagon, for example, insulin's opposite, muscle doesn't have glucagon receptors. Like, it's very much tissue-specific, but insulin

Starting point is 02:47:31 just operates at a different level. And I'm glad to see that you're a, maybe you always have been, but you're converted. You can see the value of insulin. I think I told you this on a phone call where, again, one of my first, you know, experiments as a young biologist, I was a chemist before I was a biologist. So I had a previous... You had an evolution. Yeah, yeah. Yeah, I was like lots and lots of chemistry and peptide synthesis and stuff. And then I was, it's funny, as a chemistry major at UCSD, there's only a little bit of biology requirements. So I didn't really have vast experience in biology until I graduated from, you know, UCSD with my degree in chemistry, biochemistry, then decided I was kind of like, I don't know that this is really what I want. And I'm going to like go work for a little bit.

Starting point is 02:48:17 And I went to the Salk Institute in La Jolla and started working in an aging lab. And again, one of my first experiments was what happens, you know, when you, when you shut down the insulin signaling pathway and these little nematode worms that share a lot of homologous genes with humans, including the insulin receptor and IGF1 receptor. And it was so clear to me that when you decreased the insulin signaling in these little worms, they, you doubled their life expectancy. Exactly. Doubled it. 15 days to 30 days, boom, like that. And their health span, I mean, you look at these worms and you get to know them after about, you know, 15 days. You name them.

Starting point is 02:49:02 They're like, yeah, you name them. And you see, like, you know, as they're reaching after a week, they start to like move slower. And then like they're, they get old like we do. They get old. They like move less. They like, it's very clear. When you shut down insulin signaling, that doesn't happen. They are youthful.

Starting point is 02:49:19 They're moving your. around like they're young worms when they're supposed to be dead already. Yes. And that was like, wow. No, in fact, I love that you mentioned this. So you are, most people maybe, but I know you're familiar with Cynthia Kenyon's work. Yes. Where when I first heard about that kind of pathway, it was further justification of this

Starting point is 02:49:39 insulin-centric view. Now, not to the extent, not that either of us, I am certainly not suggesting there aren't other variables. Oxidative stress is a variable. stress is a variable but there's one that I know and the reason I focus on insulin so much is because of these kinds of results

Starting point is 02:49:56 where you can just control one single variable and a simple one at that because insulin is a signal that we can control within 24 hours like a person listening to this who's thinking okay I have all these signs and symptoms of insulin resistance what do I do control your carbs that is the main signal

Starting point is 02:50:14 now I'm not again I don't want to get off topic I'm not saying don't eat them, but just be smarter about what carbs you are eating and be a little, and then focus on these good sources of protein and fat, which aren't going to have an insulin spike. That's why these other variables, people want to invoke the mitochondria. I am extremely familiar with mitochondrial bioenergetics. And yet, why don't I invoke the mitochondria as a primary source of disease? Because you can't measure it in the average person.

Starting point is 02:50:40 Like someone listening could say, well, it's my mitochondria. All right, well, good luck. Getting any marker of your mitochondria. I could do it in my lab if you're willing to give me a same. of your muscle tissue or something, but it's not a clinically kind of supported focus. So I don't mean to ever suggest other variables don't matter. We know insulin matters. You saw it in the work with the worms and aging.

Starting point is 02:51:02 I've seen it in the context of neuron bioenergetics and fat cell dynamics and everything else we've been talking about. And it's just a variable. It's a lever when you mentioned lever earlier that you can grab and immediately start to turn down. Okay, so let's talk about these key biomarkers for aging, like from a metabolic perspective. What do you think would be, you know, the most indicative of biological aging and what biomarkers are good to look at? Yeah. Yeah. My first one would be fasting insulin. If I could change health care policy and practice in the United States, my one thing would be to have insulin be a standard measurement on every blood test.

Starting point is 02:51:42 As much as the average individual is going to go in and get their annual checkup, they're going to. going to get their glucose, they're going to get their A1C, they're going to get all their lipids and uric acid. Those can be great, and there's some worth revisiting in a moment, but to me, the fact that we don't include insulin on that panel is an absolute travesty. It is, in my mind, the best overlooked marker. So fasting insulin, if a person can get their fasting insulin measure, do it. If that measurement is six microunits per mill or less, it's a great sign. If it's up to about the mid-teens or high teens that's maybe an okay sign because insulin can be dynamic. But then if it's in the high teens to the 20s, it's a problem.

Starting point is 02:52:23 That's a warning that you're metabolically off. And then let's come back to some of the common ones. The triglyceride-to-HDL ratio is a great surrogate marker for not only metabolic and like insulin resistance, but also cardiometabolic, where we focus so much on LDL, for example, but the triglyceride to HDL ratio is a way better predictor for cardiovascular risk than LDL is. So triglyceride to HDL ratio, so you take your triglycerides, which you're always going to get on a blood test, and divided by your HDL cholesterol, which you're always going to get on a blood test, if that number is less than 1.5, that's a great sign that you're doing well

Starting point is 02:53:06 metabolically. And then maybe uric acid is another one, although I could go on, but I did mention uric acid. It's another one of those that really well done longevity study, the amorous study from Sweden. It found that uric acid was one of the very few predictors that when they looked retrospectively at these people measuring the same markers for decades, their glucose control was a predictive variable and their uric acid was a predictive variable as to who lived the longest, healthiest lives. So lower uric acid is going to be better. And just for general metabolic health, would you add in some of the HBA1C and, you know, maybe APOB? So you mentioned LDL. I mean, they don't even directly measure LDL. They don't. Apobe would be obviously a more direct

Starting point is 02:53:52 measure, but then looking also at particle size, which I again, I again think is important. It's the small dense LDL particles. Yeah. So I do two. Yeah. So LDL, as you mentioned, and I actually described this in my book, why we get sick? I talk about the, like, why is it that we have such conflicting data across LDL? Some studies say it predicts. Some studies say it doesn't at all. Maybe it's because we're not accounting for the diameter differences. Even then, most people won't have had their diameter measured. The triglyceride to HDL ratio is an awesome surrogate. There's a beautiful figure of a study. I can't remember the citation, but I can recall the figure perfectly. It actually looks at the difference in population of the big LDL, the buoyant versus the small-dense LDL,

Starting point is 02:54:38 and wouldn't you know it, right around that triglyceride-HDL ratio on the x-axis of 1.5 is that crossover. So as the triglyceride to HDL ratio was higher, it reflected a higher particle B, or type pattern B, rather, LDL. The lower the triglyceride to HDL ratio was, the more it reflected a pattern A, the large buoyant. apparently less atherogenic. So once again, we could come back to that pretty reliable surrogate. Okay, great. I think if you could leave people with just one practical takeaway about insulin, about their metabolic health, how they can improve their life, their health span, a long run, what would it be? Yeah. Yeah. So I would say the simplest strategy would just be change breakfast tomorrow. Overnight, fasting is incredibly therapeutic. Um, insulin,

Starting point is 02:55:29 insulin will come down during a fasted state, and that sort of resensitizes the body to insulin. So in the morning, you've finally been fasting overnight. Insulin has come down. The last thing you want to do is spike your insulin with a starchy, sugary breakfast. And of course, tragically, breakfast is almost just a dessert nowadays all over the world, where it is just like pure dessert. It's pure sugar and starch. I would say change breakfast tomorrow.

Starting point is 02:55:58 either fast through breakfast, like a drink, I like to drink a cup of Yerba Mata, fast drink some coffee or tea, which is not going to break your fasted state. Even if you put a little butter, I don't consider that as breaking a fasted state because I define fast as the endocrinology, the nutrients, rather than the calories. but that's a topic for another time. Or don't consume anything, but if you do, then if you do want to eat, then let it be the low glycemic load vegetables and berries and then more protein and fat. So whatever you can do to keep your insulin in check for as long as possible until, say, lunch, the longer the insulin is low, the more you're improving your insulin sensitivity. and the more you are allowing that metabolic flexibility where the human hybrid burning glucose or sugar burning or fat burning,

Starting point is 02:56:53 it's insulin that dictates that fuel. And most people are stuck in sugar burning mode because they never bring their insulin down long enough to shift over to fat burning. So you get to get into this fat burning state, enhancing metabolic flexibility, and you're improving your insulin sensitivity. So my one piece of advice,

Starting point is 02:57:12 change breakfast and change it tomorrow. So you want to extend that? Yeah. That state where you're basically improving insulin-sensitive. Yes, that's right. What if you eat dinner early? Is it as awesome way to do it too? Yeah.

Starting point is 02:57:24 Yep, that would be another way to do it. It's just, I don't focus on dinner so much because it's just so complicated. You know, you and I, we have families. And so sometimes there are, for me, for me personally as a busy dad and husband, even though I'm home for breakfast, the fact that I'm not eating breakfast in the midst of the chaos, no, it doesn't disrupt the family dynamic at all. The kids are eating. We're talking and I'm sipping on my cup of Yerba Mata while we're helping get lunch ready and everything else.

Starting point is 02:57:52 It's not at all disruptive. And then lunch, I'm at work. I have whatever lunch I'm going to have. And that'll be my biggest meal of the day. But as much as I am absolutely a fan of being careful with dinner because the evidence is so supportive of it, I also recognize that it's the trickiest meal because of social dynamics, family dynamics. But insofar as you can eat earlier, then just stop eating. The very best you can do, whether it's drinking some apple cider vinegar or having something bitter in your mouth to reduce the sweet cravings because bitter tastens can reduce sweet cravings, I would say do it.

Starting point is 02:58:28 Whatever tool, whatever leveraging you need in the evening to not crave or snack on junk, do it. Great. Yeah. I mean, I probably should have mentioned this earlier when we were talking about the late night snacking, but the fact that melatonin shuts down insulin production and the, the pain. pancreatic beta cells is... Yeah, hyperglycemia disrupts melatonin too. So even back to the glucose mechanism, another reason to not go to bed hyperglycemic is it disrupts the melatonin

Starting point is 02:58:56 rhythm at the same time. Oh, interesting. So it's like a two-way thing here. It's an ugly little battle. Well, this has been a very enlightening conversation, Ben. Thank you so much for coming on this show and talking to me about all things and getting uncomfortable at times. I really appreciate it.

Starting point is 02:59:12 My pleasure. People, so you mentioned your book. Yep, yeah, why we get sick. Why we get sick? And then a follow-up companion, how not to get sick. How not to get sick? That's to be coming soon. No, it's out. Oh, is it out already? Oh, okay. So you're writing a third book. I'm writing a third book. I see. Okay. We'll do that next time.

Starting point is 02:59:29 And then benbickman.com is your website where people can find all things. You have a YouTube channel. Yeah, yeah. So Benbickman.com is kind of my education. And then I also am a partner with insulin IQ. So we provide some coaching at InsulinIQ.com and then just straight education at Benbickman.com. And you're on social media, too. You're active on X. I am. Yeah, and that's just Ben Bickman, Ph.D. Yeah, I try to be active on social media, but you know how it is. It's like a black hole. The more I give it, the more it takes, and so I tend to have a bit of a light touch. Same, same. Well, thank you so much, Ben Bickman. For bringing such clarity and depth to the conversation around insulin, metabolic health, and longevity. His insights are always nuanced, actionable, and firmly grounded in science. You can find out more about his work and his research. at ben bickman.com. And before you go, if today's discussion piqued your curiosity or if you're hungry for more, you'll probably enjoy my weekly research newsletter. Every issue breaks down a new scientific study that matters, often one misunderstood or overlooked by mainstream media, into practical takeaways you can immediately apply. If topics like brain health, longevity,

Starting point is 03:00:36 exercise, and nutrition are your thing, this newsletter is designed for you. It's quick, insightful, and it's free. Join hundreds of thousands of readers, sign up at found my fitness.com forward slash newsletter. Once again, that's found my fitness.com forward slash newsletter, N-E-W-S-L-E-T-T-E-R. Thanks so much for listening and I'll talk to you soon.

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

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