Reversing Insulin Resistance: A Guide for Women’s Metabolic Health

# Dr. Ben Bikman: How To Reverse Insulin Resistance Through Diet, Exercise, & Sleep
# https://www.youtube.com/watch/gMyosH19G24

00:00:00.000 No text
00:00:00.080 I unapologetically embrace the view that to some degree insulin resistance is a
00:00:05.279 common root cause for most chronic diseases. Obviously, type two diabetes, obesity is
00:00:11.360 in there, Alzheimer’s, fatty liver disease, infertility. So, why is that?
00:00:17.279 Insulin is one of the few peptide hormones that will literally affect every single cell of the body. For
00:00:23.760 example, the connection between insulin resistance and breast and prostate cancers. I’m not saying insulin
00:00:28.880 resistance is the singular contributor, not at all. But it is absolutely a contributor. I kind of wanted to start out with
00:00:34.960 something a little provocative. Right now, there’s a big trend in weight loss
00:00:40.000 that’s made very easy um by taking GLP-1 agonist drugs, things like Ozic and Wego
00:00:46.719 V. GLP-1 is a naturally produced hormone. My concern is that the dose of GLP1 that
00:00:52.079 we’re using now, it’s just a little too much of a good thing. What are some of the best strategies people can do now to
00:00:58.640 really make a difference? The one I like to talk about the most because the evidence is so compelling
00:01:03.760 and it’s so easy to get. My one thing would be welcome back to the podcast. I’m very
00:01:09.520 excited to be sitting here with Dr. Ben Bickman who is a professor of cell biology at Brigham Young University and
00:01:16.560 uh he specializes in all things metabolic disorders and metabolism. So, I’m pretty excited to have a very
00:01:23.280 well-rounded discussion today, Ben. This is this has been a while. I’ve been following your research for some time
00:01:28.720 now. So, I’m excited to have this conversation with you. I’m too. Yeah. Thanks. This will be great. I I kind of wanted to start out with
00:01:33.000 No text
00:01:34.960 something a little provocative and I don’t and I want to say surprising. Uh this this question for you is a lot of
00:01:42.960 people that have normal blood glucose levels quote unquote
00:01:48.640 can actually be insulin resistant, right? Why is that? And what what is this state
00:01:55.520 of like pre pre-diabetes and why is it something that is not caught soon?
00:02:01.360 Yeah. And yet so common, right? Right. I mean that that adds an extra layer of
00:02:06.479 reason to talk about this because it is it’s become the most common problem. People much of modern clinical care has
00:02:14.160 what I call a glucosecentric paradigm when it comes to monitoring metabolic health or even cardioabolic health given
00:02:19.599 how relevant diabetes and metabolic problems are to cardiovascular disease. But the the consequence of the
00:02:26.400 glucosecentric paradigm and there’s reasons for it. So I don’t mean to s to state this in any kind of incriminating
00:02:33.519 way. They they have their own justification for the glucosecentric paradigm, but it’s increasingly harder
00:02:40.959 to overlook because of what we know with regards to insulin. So insulin
00:02:46.640 resistance is the state where insulin levels are higher. The body’s having to
00:02:51.680 use more and more insulin in order to keep glucose in in check. Uh but because
00:02:57.440 it is able to keep glucose at that normal range, it flies under the clinical radar because of our glucose
00:03:04.000 centric paradigm that the the conventional clinician is only measuring glucose every time the patient’s coming
00:03:09.920 in for an annual visit with no regard uh to the patient’s insulin levels. If we
00:03:15.760 were able to broaden the paradigm a little bit and include insulin, then all
00:03:21.440 of a sudden we are measuring the earliest signs of insulin resistance because it is insulin itself that ought
00:03:28.239 to be measured when we’re trying to get that view of the patient’s not only metabolic health but insulin resistance.
00:03:35.680 So to say all that another way, type 2 diabetes is when both insulin is high
00:03:40.720 but it’s starting to really lose the war and now glucose rises as well. Then the
00:03:46.560 conventionally trained clinician says a glucose is elevated so you have diabetes or pre-diabetes. But in its earliest
00:03:53.680 stages the glucose is still normal but there’s this cold war happening in the
00:03:58.799 body where the insulin levels are still two or three or four times higher than they used to be. it needs to be that
00:04:04.799 high but and it’s working well enough to keep the glucose in check and so the
00:04:10.560 glucosentric paradigm has us miss the earliest
00:04:15.760 metabolic canary in the coal mine which is insulin. So the sooner our paradigm
00:04:21.199 with modern medicine includes insulin, then the earlier we can detect these metabolic problems in a person who’s
00:04:27.520 progressing towards type 2 diabetes. But also it changes the treatment protocol
00:04:32.639 too because not to go off on a tangent too soon off the very first question
00:04:38.720 here, but if the longer we ignore the insulin, the more the clinician may be tempted to push the insulin up even
00:04:45.120 higher by giving say a type 2 diabetic an insulin therapy. Now they’re pushing
00:04:51.440 the insulin from high to super physiological all in an effort to control the glucose.
00:04:57.680 little realizing that in the process you’re actually killing them faster because so much of what kills the type
00:05:04.479 two diabetic is not the hypoglycemia, it’s the in the hyperinsulinemia and the insulin resistance.
00:05:11.120 Oh, I definitely want to get into that. Well, just just sort of as a follow-up question, in this world we live in now
00:05:13.000 No text
00:05:17.360 where glue continuous glucose monitors are so becoming very popular, many people have them without a prescription,
00:05:23.280 you can get them. Yep. Is there any signs or tests using those
00:05:29.039 that people can do to kind of look for this potential problem with, you know, having perhaps high insulin? In fact,
00:05:36.400 they’re not measuring insulin, but glucose. Yeah. Right. Yeah. So, to answer the first uh the question very directly, I’m
00:05:42.960 an enormous advocate of CGM use. The more we democratize access to CGMs, I
00:05:49.360 think the better we put individuals in a position to be their own coach, you
00:05:54.560 know, they don’t need to have someone like me or you berating them and telling them to change their habits and eat a
00:06:01.280 little better. When you see how your body’s responding to what you’re eating, and the CGM enables that, you end up
00:06:06.960 making your own lifestyle changes. So, with the with the use of the CGM, fasting, glucose isn’t going to be the
00:06:13.120 best indicator. It’s going to be the dynamic glucose. So, if you’ve eaten a carbohydrate heavy meal or or a simple
00:06:19.840 carbohydrate, I shouldn’t call it a big meal, but a simple carbohydrate like two pieces of bread, if your glucose levels
00:06:26.560 aren’t back down to normal by about 2 hours, that suggests a problem. So, in
00:06:31.600 my mind, the greatest utility of the CGM is to monitor the dynamic changes rather than the static where am I at every
00:06:38.160 morning. That has less value. The dynamic changes are what has value. But
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00:06:43.280 beyond the use of the CGM, if a person’s curious about their insulin resistance,
00:06:48.319 in many instances, you don’t even need to get a blood test, the the skin is a window to the metabolic soul where if
00:06:55.600 there are two things you can observe just on your skin, and they’re both generally going to be right around the
00:07:00.720 neck. One of them is a a condition called aanthosis nigricans which is when
00:07:06.639 around the little skin fold that most people have around their neck. The skin will get darker pigmented which can be
00:07:14.160 harder to tell depending on the pigment of the person’s skin. But what is obvious regardless of pigment is the
00:07:21.680 kind of crinkled tissue paper texture of the skin. So the skin will be very sort
00:07:27.039 of roughed like crinkled tissue paper. So that’s echanthosis nigricans around the neck. And then the other one people
00:07:33.919 know is called skin tags. And that is those little it’s not like a rounded
00:07:38.960 little mole but rather a distinct little kind of mushroom stock column of skin.
00:07:45.039 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
00:07:51.759 little like a little mushroom stock almost of skin. Skin tags. Both of those are very very strong evidence of insulin
00:07:59.520 resistance. And the nice thing is as the insulin sensitivity improves, those problems go away just like everything
00:08:05.919 else will. So many researchers, including yourself, do view insulin
00:08:07.000 No text
00:08:11.280 resistance as a sort of root of causing
00:08:16.400 many different types of chronic diseases, age related diseases, obviously type two diabetes, obesity is in there, cardiovascular disease,
00:08:23.520 Alzheimer’s, fatty liver disease, infertility. So, so why why why is that
00:08:29.440 Yeah. some something that people think as the root cause of so many chronic diseases? And again, you know, why do you you’re
00:08:36.479 talking about insulin resistance being common and certainly like this pre pre-diabetic state being pretty common.
00:08:41.760 Uh what do you think the reason for that is? Yeah. Yeah. So the first part of the question I unapologetically embrace the
00:08:48.000 view that to some degree that’s italicized wording there to some degree insulin resistance is a common root
00:08:55.200 cause for most chronic diseases. Uh so I’m not claiming that it’s the singular
00:09:01.360 cause. For example, the connection between insulin resistance and breast and prostate cancers, the two most
00:09:06.959 common cancers in men, in women and men respectively. I’m not saying insulin resistance is the singular contributor.
00:09:12.959 Not at all. But it is absolutely a contributor. With regards to Alzheimer’s disease, insulin is not probably the
00:09:19.760 singular contributor, but it is one undeniably. And the same goes for polycystic ovary
00:09:26.320 syndrome uh the most common uh infertility in women or erectile dysfunction in men and fatty liver
00:09:31.600 disease and hypertension. So when I in fact this question is the question I
00:09:38.320 asked myself as an academic in in at my university when I got tenure I thought I
00:09:45.120 looked at the rest at at my future career and I thought do I want my career to be defined by the number of
00:09:50.560 peer-reviewed papers I publish in science journals and I thought no that’s not enough because most people will
00:09:56.320 never read those articles no one will ever get a direct benefit from them and I thought what would be the one message
00:10:02.959 as a biomedical metabolic scientist that I would want to convey to people and it was this one. It was that to some degree
00:10:11.120 most of chronic disease can be attributed to one common origin. And so rather than trimming at the branches of
00:10:18.959 this sick tree where we are giving the patient a a drug for their Alzheimer’s
00:10:24.480 disease, we’re giving them a patient for a drug for their hypertension, we’re giving them a drug for their infertility.
00:10:30.800 What if all of those were actually just branches coming off of one tree? Let’s
00:10:36.160 just cut down the tree. So when we can acknowledge a sort of common soil hypothesis,
00:10:41.360 it starts to simplify the clinical approach. So
00:10:47.360 all of this in my mind is a reflection of just how powerful the hormone insulin is. Most individuals only think about
00:10:53.680 insulin as being a hormone that controls blood sugar, which is fantastically unfair. Insulin is one of the few
00:11:00.800 peptide hormones that will literally affect every single cell of the body from from brain cells to bone cells,
00:11:08.160 lung cells to liver cells, and every cell in between. There’s no exception. Insulin will have an effect at every
00:11:14.320 cell of the body. And the the particular pathology with insulin resistance is unique because you have some cells that
00:11:21.920 aren’t responding very well to insulin. Like in the case of erectile dysfunction, insulin is less capable at
00:11:28.959 producing nitric oxide in the endothelium of the blood vessels. So there’s less vasoddilation. Less
00:11:34.720 vasoddilation means compromised erectile function. So on one hand, you have some cells that suffer because they’re not
00:11:40.959 responding. But on the other hand, you have some cells that are overstimulated
00:11:46.000 because insulin resistance is insulin not working the same at all cells of the
00:11:51.680 body and blood insulin levels are higher. So there’s too much insulin.
00:11:56.959 Some cells are responding too much to that insulin. So with polycystic ovary syndrome, for example, that’s not a
00:12:02.720 problem of the insulin signal not working well. That’s a problem of there being too much insulin stimulating the
00:12:09.360 ovary to inhibit the conversion of testosterone into estrogens and thus she
00:12:15.200 manifests with polycystic ovaries. So to to some degree most chronic diseases can
00:12:21.120 be connected back to insulin resistance and to me that has a a tremendous power. That’s a reason to focus on that
00:12:27.360 disorder. So some researchers think that the high insulin is more of a response to ectopic
00:12:28.000 No text
00:12:34.800 fat accumulation, obesity sort of being the underlying cause of the high
00:12:40.399 insulin. So how do you kind of differentiate between this cause and effect? What what
00:12:46.399 role does ectopic fat accumulation have in insulin resistance causing high insulin?
00:12:51.519 Yeah, that’s a great question. In fact, that’s a big question. Uh, and I already am too longwinded with my answers, so
00:12:56.880 I’m going to try to be concise here. Um, I look at the origins of insulin resistance as being one of two, one of
00:13:04.079 two origins where you have what I call fast insulin resistance and then slow insulin resistance. And what you’re
00:13:09.839 touching on is the slow insulin resistance, which I’ll come to in just a second. Within the fast insulin
00:13:16.000 resistance side, there are three what I call primary stimuli that in humans have been confirmed and in rodents and in
00:13:22.880 isolated cell cultures that can cause insulin resistance quickly like within
00:13:28.480 hours but at the same time if the stimulus is removed the insulin resistance is resolved in short order
00:13:35.360 and that is stress. So elevated stress hormones whether it’s cortisol or epinephrine adrenaline will cause acute
00:13:42.160 insulin resistance in humans. As that stimulus goes away the problem resolves.
00:13:47.519 Next is inflammation. If you increase the levels of inflammatory cytoines in
00:13:52.800 cells or rodents or humans, they will be insulin resistant very quickly. In fact, people wearing CGMs may notice this,
00:14:00.079 that the CGM may reveal that they’re starting to get a cold or a flu because they notice that their glucose levels,
00:14:06.320 they’re having a much harder time controlling them even though their habits haven’t changed. That’s often a
00:14:11.440 sign of inflammation. But even with autoimmune diseases, uh, where you have people where the autoimmune disease will
00:14:18.160 eb and flow, so too will the insulin resistance. It will track very well with the how active the disease is. And then
00:14:25.360 lastly of the primary fast causes of insulin resistance is too much insulin
00:14:30.880 itself. So we know in humans, rodents and cells, I’ve published my own work on
00:14:36.240 this topic that too much insulin will result in a resistance to the stimulus.
00:14:41.440 So too much insulin can cause insulin resistance. Now none of those touch on what you had mentioned which is the
00:14:47.519 ectopic idea. That idea is very important be uh and there’s a lot of
00:14:52.639 nuance to it where we have to define the the fat first of all and by that I mean
00:14:59.120 what of the many of the hundreds of thousands of types of molecules that we call a lipid or a fat within a cell
00:15:05.040 which are the ones that actually matter to insulin resistance. Some people will think of just triglycerides which is the
00:15:11.760 main form of storing fat and yet triglycerides are totally inert metabolically. There was some a case in
00:15:18.240 point. Brett Good Pastor and David Kelly 30 years ago described this phenomenon
00:15:23.600 of the the athletes paradox where they noted that in obesity with type two
00:15:30.720 diabetes and insulin resistance, if you pull a muscle biopsy, there’s really high levels of fat in the muscle of triglycerides
00:15:37.279 and they’re very insulin resistant. And so some people would say and did at the time, well, high muscle triglycerides
00:15:42.959 causes insulin resistance. And yet when they did muscle biopsies from very lean,
00:15:48.000 exceptionally insulin sensitive marathon runners, they had just as much fat in
00:15:53.120 their muscle in the form of triglycerides as the obese type 2 diabetics did. And and again, they were
00:16:00.320 very insulin sensitive. So it couldn’t be the fat that was being stored in the muscle. The same could be said of the
00:16:06.399 liver. If the liver has triglycerides, it’s not the triglycerides that are causing insulin resistance. So
00:16:14.079 what is it? If there is any lipid that’s to blame, it’s going to be a lipid called ceramides. And those do not track
00:16:20.480 the same across these say these the lean marathon runner and the obese type two diabetic. When you start measuring
00:16:26.720 levels of tissue ceramides or its precursor dihydroamides, there’s still some debate as which of the two matters
00:16:33.199 most. I’m very strongly just saying it’s one of them. And so I’ll just say ceramides as a family.
00:16:39.759 You can in any biological model cause very strong robust insulin resistance
00:16:46.320 just by increasing the ceramides because ceramides will block the insulin signal. When ser when insulin binds to its
00:16:52.480 receptor then you have a series of of of phosphorilation events. Ceramides block that very well. It’s a very well-defined
00:17:00.000 pathway. And if you can just do one thing and just resolve the ceramides, you correct the insulin signaling. So
00:17:07.280 when it comes to ectopic fat, it’s not a matter of how much triglycerides you’re storing, but rather what is the entire
00:17:13.439 metabolic millu to be promoting ceramides in various tissues throughout the body. Interestingly, all of those
00:17:20.640 primary stimuli, the quick insulin resistance all induce ceramide biosynthesis and acrruel. But with the
00:17:27.359 slow insulin resistance, I still think it’s appropriate to invoke fat. Um, but
00:17:33.840 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
00:17:39.840 level insulin resistance is it starting in the muscle or the liver or the fat. I’m very much an advocate of the fat
00:17:45.840 first focus when it comes to insulin resistance from that slow progressive. It settles in over years and it may
00:17:52.880 take, you know, weeks to months in order to reverse. Yeah. Well, this is we we’ve got a lot
00:17:58.720 to dive into here. I mean, it’s funny. I remember my one of my first projects as a budding young scientist was to look at
00:18:08.160 insulin resistance like like free fatty acids and and and can you make like a little nematode worm insulin resistant
00:18:15.120 and you know it it it from my understanding had to do with the atyposite cell and
00:18:21.600 this sort of spillover of ceramides that are then attack it all had to do with the AKT signaling pathway which you know
00:18:28.240 stopping basically the insulin receptor That’s exactly and that’s where in that’s where ceramides act. You
00:18:33.520 mentioned AKT that’s what we would measure and you must have too. We would measure a particular protein in AKT for
00:18:40.160 or an amino acid residue for phosphorilation and then look at one other downstream signal and then we
00:18:45.280 could do some other more complicated metrics but that was always the absolute baseline. In fact, I’ve run so many
00:18:50.400 western blotss measuring phosphoic that next time I if I have to have if I ever
00:18:55.520 have to run another I’m going to like shove the pipet in my eyeball. I’m so tired of it. Well, it’s just one of those things that, you know, when you do
00:19:00.960 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
00:19:08.240 nutrition, you know, later on down the line and it’s like, well, it always stuck with me like there’s
00:19:13.440 there’s a role for fatty acids in causing insulin resistance. Oh, there is. So, so that was something that kind
00:19:18.720 of stuck in my head. But um and I think we’re going to get we’re going to get into some of the dietary causes in just
00:19:20.000 No text
00:19:23.919 a minute, but like um beyond you know we’re talking about you kind of hinted at this earlier. Insulin has many roles
00:19:31.840 and oftent times the general public thinks about its role in just regulating blood glucose levels
00:19:38.640 but maybe you could just talk about some of the other roles insulin plays for example in fat accumulation.
00:19:43.679 Oh yeah for sure. Yeah. Uh, in fact, we’ve I’ve already touched on a few. Like, for example, who would have
00:19:49.039 imagined that insulin regulates the enzyme that’s responsible for the conversion of testosterone to estrogens
00:19:54.799 for goodness sake. And yet, it does. Insulin has a direct inhibitory role on aromatase, that enzyme that mediates the
00:20:01.440 conversion and the synthesis of estrogens in men and women. It also regulates nitric oxide production,
00:20:07.760 regulating dilation of blood vessels and other hormones throughout the body that affect water retention, salt signaling,
00:20:14.720 neuron conductant of of signals and and more. But when the at the fat cell insulin probably has its most um
00:20:18.000 No text
00:20:22.720 powerful effect where the you cannot under now we’re touching on a broader
00:20:28.559 topic of why do we get fat here and I I welcome that topic. Uh in fact of all
00:20:34.240 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
00:20:41.280 my lab a few years ago and that’s the tissue we study the most. So I’m very comfortable talking about atapost tissue
00:20:48.080 physiology. There is as much as there is the debate in two camps of what makes fat cells
00:20:54.159 grow. It’s just purely a matter of thermodynamics or no it’s purely a matter of endocrinology. The truth is of
00:21:00.559 course you actually have to have both. You cannot under any circumstance make a fat cell get big unless you have both.
00:21:08.159 Just to make a put a fine point on that. If you have all the calories in the
00:21:13.520 world, so I grow fat cells in in petri dishes in my lab right now back at BYU. I got students growing fat cells in the
00:21:20.000 incubator. Um they are swimming in a culture medium filled with calories.
00:21:25.600 Everything the fat cell needs is all the calories that fat cell could ever want are around it right now. And yet they’re
00:21:32.799 teeny little cells. They’re not getting big at all until we add one thing. And the moment
00:21:39.200 we add insulin into that culture, now the fat cells start to get big. If we check them six hours later, there’s a
00:21:44.799 big lipid droplet. 6 hours still later, it’s even bigger. So in other words, the
00:21:50.400 fat cell knows what to do with the energy that it has access to. A cell doesn’t have any kind of intuitive
00:21:55.679 intellect to think, okay, there’s calories here, or more accurately, carbons that I can turn into
00:22:01.120 triglycerides, and I’m going to take them in and store them. But in the context of the body, the fat cell needs
00:22:08.000 to know, am I playing nice with the rest of the body? How stupid would it be if
00:22:13.280 we got up and went extra, we go out on a jog outside, our fat cells are breaking
00:22:18.720 down triglycerides as free fatty acids by activating lipolysis. and yet at the same time they’re pulling them right
00:22:24.080 back in to store them. That would be stupid. The fat cell wants to cooperate well and be part of the orchestra of the
00:22:31.679 of the body. And so it will be releasing its fat so that the muscle can take it up. But if insulin were elevated, so
00:22:39.360 insulin acts as the signal basically telling the fat cell when it’s time to eat and when it’s time to share. So to
00:22:46.000 to and then let’s if we flip it, in fact actually I’ll stay there for one more second. We even see this. Someone could
00:22:52.320 say, “Well, Ben, that’s just uh in fat cells.” What about humans? In fact, humans provide the most convincing
00:22:58.159 evidence of all that you cannot get fat unless insulin is elevated. Because one of the more common eating disorders
00:23:04.799 among young people with type 1 diabetes is a condition called diabelmia, which is this terrible tragic scenario where
00:23:12.640 the person feels such pressure to be lean. And they have learned that that little
00:23:18.480 syringe of insulin is the absolute gatekeeper of the fat cell. So they will
00:23:23.760 deliberately underdose their insulin in order to stay as thin as they want. They can eat as much as they want. And as
00:23:31.360 long as they underdose their insulin, and it’s not even at zero. They’re just doing a deliberately lower dose. They
00:23:36.640 will be as skinny as they want. Now there’s metabolic hell to pay, right? They’re hypoglycemic. They’re getting
00:23:41.679 into keto acidosis. So they’re dying, but they’ll be as thin as they want. So as much as people want to say, “No, it’s
00:23:47.919 just calories.” We have a human case study that absolutely proves that wrong, that it’s not just calories. Now, having
00:23:54.559 said all that, I’m not claiming calories don’t matter. Because on the other hand, if you just have high insulin in the
00:24:01.679 absence of sufficient calories coming in, that’s also incompatible with life and the person will die. Because if you
00:24:08.559 if you and I were fasting, in fact, Dr. George Cahill did these studies about 40 years ago. You could never get IRB
00:24:14.480 approval to do it now. He would fast men for days and then give them an insulin
00:24:19.760 dose and drive their glucose levels down to about 20 milligrams per deciliter just to see how low could the glucose
00:24:27.039 get and the person maintains consciousness. And they did. But suffice it to say, if you spike insulin, which
00:24:33.120 is telling the body to store energy, but there’s not energy coming in, then the total energy available in the blood
00:24:39.520 drops to essentially zero. Glucose goes down to zero. Ketones go to zero. Fatty acids go to zero because you’re you’re
00:24:46.159 inhibiting lipolysis. You’re inhibiting ketogenesis. You’re stimulating glucose uptake. Now, the brain has no energy
00:24:52.080 because it doesn’t have a reserve of energy like the liver or the fat cells or the muscle. And so as blood energy
00:24:57.520 goes to essentially zero, the brain shuts off. So coming back to the fat cell, you have to have both. You have to
00:25:04.799 have elevated insulin sufficient to tell the fat cell to store that energy, but
00:25:10.000 then you have to have the energy to store. So calories matter, but so too
00:25:15.279 does the insulin stimulus because in the absence of the insulin stimulus, there is no such thing as fat storage. And
00:25:21.200 indeed, the body can’t stop breaking down the fat. And in fact, that’s what ketones are. Ketones are nothing more
00:25:28.400 than sign a a sign of the liver burning a lot of fat where it’s burning so much
00:25:34.960 fat. It has such an abundance of acetal COA that it can’t it can no longer feed
00:25:40.559 the acetal COA into the citrate cycle because it’s too full. It cannot divert it to lipogenesis because insulin’s low.
00:25:47.520 So that pathway is inhibited or not activated. Then the only other option of all that acetal COA is ketogenesis. So
00:25:54.320 ketones are simply sort of this overflow, this metabolic release valve
00:26:00.000 of of fat burning, but they go one step further if you’ll allow me where how do
00:26:05.760 we then reconcile it? What is it about insulin? Like if in I’m not saying calories don’t matter. I’m not trying to
00:26:11.520 break the laws of thermodynamics. In fact, my PhD is bioenergetics. I have a unique appreciation for energy in
00:26:17.279 organisms. So that those carbons need to be accounted for. But the more insulin
00:26:24.159 is low, uh, you have two adaptations that allow the body to stay lean or to
00:26:30.960 not store that excess as excess that they’re eating as fat, which is one, a
00:26:36.240 higher metabolic rate by several hundred calories a day when insulin goes down as
00:26:41.360 so the body’s just burning a little hotter. The the engine is revving higher. So the overall energy
00:26:46.960 expenditure is up again by 2 to 500 calories a day. And when you’re in ketosis, you’re eliminating ketones
00:26:53.760 through the breath and the urine. And every ketone that a person’s breathing out or urinating out has a caloric value
00:27:00.080 roughly similar to glucose. So you’re just excreting calories from the body.
00:27:05.279 So the net effect of all of that can be up to 800 or so calories a day that the person’s just wasting.
00:27:12.000 No text
00:27:12.159 Okay. Um well it’s not we’re we’re really getting into this sort of underlying cause of what you know what’s
00:27:19.120 causing the insulin resistance what I mean obviously the what’s causing the
00:27:24.960 high insulin as well. Yeah. And then ultimately obesity is in in that mixture as well. And I think you
00:27:31.279 know refined carbohydrates is something that you’ve mentioned and I think a lot of people think that refined
00:27:36.480 carbohydrates definitely play a role in insulin resistance perhaps the a primary
00:27:41.679 role but um aside from the obesity as you’re talking about obesity being that slow
00:27:46.880 forming insulin resistance um what role can we talk a little bit deeper about carbohydrates refined
00:27:53.200 carbohydrates saturated fats is also something you touched on the camide y you know as well we know palmitate
00:27:59.919 yep kind of plays into that pathway. And so what role do dietary carbs, refined
00:28:07.679 versus maybe complex saturated fats play? And then is this all in the the
00:28:14.000 background of caloric excess or or you know being in a deficit? Does that matter as well? The mixture of the two
00:28:21.039 sort of like because there’s nuance here. Oh yeah, there is kind of get into it. In fact, the big a big nuance is the
00:28:26.720 calories. And this is where I need to be careful because the the degree of studies that have looked at these
00:28:32.240 interventions that you’re alluding to and I’ll touch on more now in low calorie or hyperc calorie, it’s not been
00:28:38.559 fully fleshed out, but I would think it’s safe to say if there is a caloric
00:28:43.760 deficit, then it becomes less relevant um which of the the balance of saturated
00:28:50.080 fats to refined carbs. Now then someone would say, “Well, then let’s just always live in a caloric deficit.” Yeah, good
00:28:55.679 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
00:29:01.279 diet for the rest of my life.” So, so if you’re in a if you’re in a caloric deficit and you’re eating, you know, some refined carbs, then it’s not wiggle
00:29:09.039 room. You have more wiggle room for insulin. Yeah. Yeah. Um I I’m I’m comfortable saying that. And then again, I just have
00:29:15.600 to counter that by saying that’s not really feasible long term. You know, people get hungry. Hunger always wins.
00:29:21.440 Yeah, you got to eat nutritious. Yeah, you got to eat. You got to fuel the body. So you can’t be in that kind of
00:29:26.799 chronic low calorie state. So my view on so saturated fats is one of the more
00:29:32.399 polarizing topics and I’m very comfortable talking about it because my entire post-doal fellowship was looking
00:29:38.960 at I shouldn’t say entire my biggest paper ever published was looking at the degree to which different fatty acids
00:29:45.440 are capable of causing insulin resistance through the conversion into ceramides. And I’m going to upset some
00:29:53.760 people, but in cell cultures and if you treat cells with saturated fat,
00:29:59.200 pulmitate, which is the main saturated fat in the body, you get insulin resistance very quickly. Now, if you
00:30:05.279 block ceramides, you resolve that insulin resistance. If you treat those cells with monounsaturated fatty acid,
00:30:11.679 no insulin resistance. If you treat those cells with polyunsaturated fatty acid, no insulin resistance. So, as much
00:30:18.960 as there is and I believe it’s justified, a very heavy focus on seed oils, I I approve of that focus, I think
00:30:26.880 they’re pathogenic, but I grimace when people invoke them as a primary cause of
00:30:31.919 insulin resistance because the data do not support it. Again, I think they’re very harmful. Um, but not when it comes
00:30:39.039 to insulin resistance because you can in fact we would treat cells with palmitate
00:30:44.720 cause insulin resistance, co- treat them, co-incubate the cells with either oleic acid or linoleic acid and we would
00:30:51.279 reverse the insulin resistance. Now, I do not mean to give seed oils a pass. I
00:30:57.279 think they’re highly pathogenic, but not with insulin. Well, there’s other dietary sources of linoleic acid. There are and there you can’t even avoid
00:31:03.520 them really. Yeah. Yeah. And and meat, I mean, literally any animal source of of fat, any animal food has some linoleic
00:31:10.640 acid in it. It’s it’s it’s ubiquitous. You would just, you know, want to control it, I guess. So, with regards to
00:31:17.440 saturated fat, that my own work when I published that paper in
00:31:22.880 uh 2010 maybe, um I I left that project with this idea that saturated fats are
00:31:30.159 thus a cause of insulin resistance. And I had to challenge my own assumptions
00:31:35.440 when I saw the work of Dr. Jeff Volic, a friend and a legend in the realm of low
00:31:40.880 carbohydrate studies because he published some incredibly compelling papers
00:31:46.320 over a few papers. He found that I I had to sort of challenge the model
00:31:52.000 where I thought all right I was treating cells with saturated fat. Is that the same as a human eating it? And of course
00:31:57.120 it’s not. And now to touch on his work, you can have uh humans that if if the
00:32:04.080 carbohydrate levels are going down, they can eat two or three or four times more saturated fat than a high carb group.
00:32:11.120 And then they’re circulating levels of saturated fat. So the saturated fat in some in the plasma is significantly
00:32:18.480 lower. That’s because most of the saturated fat that’s flowing through our veins is
00:32:24.159 coming from the liver. When the liver is told to make fat through denovo lipogenesis, the fat that it makes is
00:32:30.640 palmitate. So most of the fat, most of the saturated fat we have flowing through our blood that’s going to get to
00:32:36.080 a cell is going to be coming from what the liver is making, not from what we’re eating. And he showed this very, very
00:32:42.399 well, but that’s only in the background of low carb. Exactly. Yeah. So, in fact, I won’t even elaborate more on that if that point’s
00:32:48.640 clear. So, the lower carbs are getting, the more you can eat saturated fat and appear to have no deficit.
00:32:55.200 I’m very comfortable with that. No deficit in no problem with insulin resistance. Insulin resistance. Okay. And indeed,
00:33:00.960 but calories aren’t an issue in that in that context. I don’t recall whether they had it in a
00:33:06.240 low calorie context or not. I would suspect because insulin is low. Once again, you probably have a little more
00:33:11.440 of that metabolic wiggle room um with the higher metabolic rate and then the ketone wasting. So, it starts
00:33:17.840 to get a little cloudy as to because the saturated fat scenario is they that there is definitely a pathway
00:33:24.080 to insulin resistance. Um, however, it seems as though if you’re more of a ketogenic type of
00:33:31.360 eater, low carb, ketogenic type of eater, that pathway doesn’t seem to be
00:33:36.799 relevant relevant. I I’m very comfortable with that. Yeah. In fact, that’s a great way of stating it that the lower the carbs
00:33:41.840 are getting, the less the dietary saturated fat matters. Now, in the context of a higher carb diet, as much
00:33:44.000 No text
00:33:48.480 as it pains me to admit because I’m such a defender of saturated fats, there are a couple studies that are very well
00:33:54.320 done. If I recall, it was some groups in Europe um in the European Journal of Clinical Nutrition where they had in the
00:34:00.960 context of a high carb diet and then manipulating the saturation of fats, the high carb and highsaturated fat was the
00:34:07.760 worst for insulin resistance and insulin signaling. And so when it comes to again
00:34:14.239 the background of high carb then I as much as it pains me to admit because I’m such a defender of of saturated fats
00:34:21.280 from natural sources I I which is where they come from that begins to be problematic.
00:34:26.639 I I think it’s problematic and not just you know for for for metabolic health but cardioabolic health. I mean that’s
00:34:33.040 where you get small dense LDL particles. Again it’s the combination of the saturated fat and the refined
00:34:39.760 carbohydrates. Are we talking about when you’re having, you know, a high saturated fat diet in combination with
00:34:46.239 what you call carbohydrate, high carb? I mean, is this what if you’re eating, you know, fruits and vegetables and, you
00:34:53.839 know, maybe some oats? Is that the same as eating cookies and
00:34:59.119 fruit? Yeah. No. Of course, the easy answer would be no. But, but I can’t recall the spec the specifics of that study. And
00:35:04.640 anytime I can’t site a study, I want to be careful in the answer. But my view would be what is the underlying insulin
00:35:11.520 effect of those carbs. So if these are low glycemic load type carbs where the insulin response is going to be very
00:35:17.839 modest, right? Insulin itself causes insulin resistance and again rapidly and and so what I
00:35:25.200 think is if you take the context of an insulin spike with a saturated fat load,
00:35:30.400 that’s uniquely harmful with regards to insulin resistance. So, back to the idea of what are the carbs. I think if you’re
00:35:37.119 talking about the low glycemic load carbs like cruciferous vegetables and berries and citrus fruits, for example,
00:35:43.839 now there’s almost nothing and then you chase that down with a tablespoon of coconut oil, the most sat the most
00:35:49.359 concentrated form of saturated fat on the planet. I think you’re fine. Well, coconut oil is a bit of a an outlier
00:35:56.079 because so much of it’s MCT which doesn’t follow which is not a substrate for ceramides. So, it doesn’t quite fit.
00:36:03.440 But in that case, no, I think that’s would be perfectly fine. But you are touching on what is to me the obvious
00:36:10.240 villain. As much as we have increasingly two camps of people saying no, it’s the seed oils and I’m generally more just
00:36:16.160 because I’m an insulin resistance guy in the notes refined starches and sugars. The fact is they always come together.
00:36:22.160 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
00:36:29.280 get your food from bags and boxes with barcodes, you’re getting rid of both the refined starches and sugars and the
00:36:35.599 refined oils. Anything else is going to be fine for the average for most people.
00:36:40.960 Just less bags and boxes with barcodes, mole more whole foods, you’re fine. And but what about like fructose versus
00:36:46.000 No text
00:36:47.920 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.
00:36:53.839 No, it absolutely is not. No, fructose itself will not elicit an insulin response whatsoever. Now, the body will
00:36:59.200 convert some of that fructose to glucose, which is why the diabetic who’s gone hypoglycemic can just drink a cup
00:37:04.640 of orange juice and within minutes it’ll start to, you know, that’s such a concentrated load of fructose that they
00:37:10.160 will see a glycemic excursion. But no, fructose isn’t the same. But even still,
00:37:15.680 depending on the person, you know, you and I, we’re two lean healthy people. We could get away with it. If I’m talking
00:37:20.880 to an overweight type two diabetic, then I say, “All right, well, the most sugary of the fruits, just be more careful with
00:37:27.359 like say mango or a banana.” Um, then I would say, “All right, you maybe want to
00:37:32.880 be a little more careful because your disorder is you don’t burn glucose. You don’t burn sugar very well. And so you
00:37:38.320 just be careful with the most sugary of the fruits, but then everything else enjoy liberally.
00:37:43.000 No text
00:37:44.320 Um, so with respect to insulin resistance and
00:37:50.320 weight loss and obesity and what’s causing like the cause of these things, right? I mean, this is where we get into
00:37:55.839 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
00:38:03.359 the other better? And that’s where Kevin Hall’s study was kind of interesting. I’d love to get your thoughts because
00:38:08.800 so he’s published a study back in 2021. NAH did a pretty well-controlled study
00:38:14.400 where people were on a high higher carb diet or they were on a ketogenic diet and they were isocaloric so same
00:38:20.960 calories but if I recall the no in fact they were they were able it was ad limitum
00:38:26.960 and then they found they found that the plant-based group just spontaneously ate less. So yeah, so the 2021 study they
00:38:35.760 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
00:38:41.839 freely but you got to follow these kinds of balance and you follow this pattern you follow that pattern and if I recall
00:38:48.240 the plant-based he he um rejoiced in the fact that it challenged the carbohydrate
00:38:54.480 insulin theory of obesity which I can articulate in a moment because they found that the higher carb group
00:39:00.640 spontaneously ate about 700 calories a day less. Does that
00:39:05.680 sound right? I think that’s right. So they they just spontaneously were eating less because they could eat freely. They
00:39:11.359 just ate and 700 calories a day is a meaningful amount to just spontaneously eat less of. That did challenge the idea
00:39:19.599 because one view I actually don’t like. But they lose more fat as well. Yeah, they did. They did. Yeah. But it
00:39:26.240 was this is modest. I mean to to to to be fair to the study, they did a good
00:39:31.280 job controlling it. To be a little critical of the study, the findings were
00:39:36.320 exceptionally modest. This is the kind of thing where it was like one pound versus two pounds and it was 2 weeks and
00:39:42.960 it was a very small study. And and a lot of what Kevin has done is a lot of these kind of mathematical modeling outcomes
00:39:48.560 where they sort of speculate or extrapolate beyond the data that they get. So they they found that they
00:39:54.400 spontaneously ate 700 calories a day less. That challenged one of the central
00:40:00.320 ideas of the carbohydrate insulin model, which is if you spike insulin, you get hungry. And he was saying, well, they
00:40:07.760 ate all these carbs. Mind you, it was mostly plant-based complex carbs. Exactly. Fiber. So that’s right. And so it’s almost it’s
00:40:14.640 a little unfair because that’s not how most people are getting their carbs these days. And and just to put a fine point on that point, 70% of all calories
00:40:23.119 consumed globally, it’s about 60% in the US, are carbohydrates. And they’re not coming from leafy greens and berries and
00:40:30.000 and you know, citrus fruits. It’s coming from bags and boxes with barcodes. But nevertheless,
00:40:35.520 that’s an interesting finding. My my criticism of that is one, it’s an
00:40:41.680 extremely short-term study, and there are longer studies that we ought to highlight just to offset this very short
00:40:48.560 study, but at the same time, when you’re eating so much fruits and vegetables,
00:40:53.599 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
00:40:59.680 weeks on this diet were just probably having a lot of bloating and gas um from
00:41:05.119 eating a lot of plants. when they probably weren’t eating that many plants before they started the diet. So, it
00:41:11.119 didn’t entirely surprise me that they were spontaneously eating less. I would personally enjoy eating more meat than I
00:41:19.119 would big leafy greens and and other fruits and vegetables. So, I would probably eat more calories. The fact at
00:41:25.200 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,
00:41:32.960 and you’re telling me they only gained like one more? they only had one more pound of fat. If anything, you could
00:41:39.839 have looked at all that data and said, “Wow, there is a metabolic advantage to a low carb diet.” And in fact, some of
00:41:45.760 the studies Kevin Hall of his own work that he’s tried to distance himself from is finding that in a ketogenic state,
00:41:52.560 people have a significantly higher metabolic rate. And so perhaps one outcome of that study is that when a
00:41:58.400 person gets to ketosis, they were able to eat 700 calories more
00:42:03.440 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
00:42:09.000 No text
00:42:11.119 something that’s become a theme for my lab where if you’ll allow me very briefly, I will try to be brief. I’m not
00:42:17.359 very good at that. But um uh over a hundred years ago, two famous legendary
00:42:23.200 scientists um Francis Benedict, who you and I may recall wrote uh created what’s
00:42:28.640 called the Benedict equation, which is an equation that is still used to this day to try to assess metabolic rate
00:42:34.400 based on someone’s body size. So the Benedict equation, this legend of energy
00:42:39.440 expenditure, he collaborated with Elliot P. Joslyn the who the most famous
00:42:46.480 endocrinology clinic in the world the Joslyn Diabetes Center is named after him. So you had these two legends in
00:42:52.640 their own realm who tried to understand the metabolism of people in what they called severe diabetes which we would
00:42:58.400 call type one. They found that their metabolic rate was about 20% too high.
00:43:03.920 And then years later when insulin began to be a therapy, a group at Minnesota uh
00:43:09.440 the first author is N Share N AIR they not only confirmed the findings from 60
00:43:16.240 or 70 years earlier that in type 1 diabetes the metabolic rate is too high like something’s broken they’re burning
00:43:22.079 too hot but when you gave them insulin within minutes the metabolic rate began to slow down and so all of this back to
00:43:29.359 that study from 2021 the reason I even brought all of this up is to me That’s further evidence of the lower insulin
00:43:35.839 gets like with a low carb diet, the more metabolic wiggle room a person has where
00:43:41.119 energy expenditures up by several hundred calories a day. And and we found
00:43:46.160 in human work that part of it is because the fat tissue starts having a much higher metabolic rate when insulin comes
00:43:52.880 down. There’s much more mitochondrial uncoupling. So the engine is just revving and revving and burning energy
00:43:58.400 just to create heat. But at the same time, the more you’re making ketones, the more you’re expelling those ketones.
00:44:03.920 And ketones are calories. And so maybe those 700 calories a day that the low
00:44:09.359 carb group was eating in excess, the fact that they only had one other pound of fat could be that they were just
00:44:14.880 burning the rest off because of these metabolic advantages. Well, speaking of wiggle room, I mean,
00:44:18.000 No text
00:44:20.079 we’re talking about a variety of scenarios here where people can have wiggle room. We talked about, you know,
00:44:25.440 being in caloric deficit gives you a little more wiggle room. Yep. being in a ketogenic or, you know, close to a ketogenic state seems to give you more
00:44:31.680 wiggle room. Um, but what about being like highly physically active? Absolutely. Yeah. Good. I love how
00:44:38.000 you’re framing that with this context, these themes of wiggle room. Where do you have a little bit of margin to work
00:44:43.839 with? Yeah. Absolutely. Exercise is one of those other uh outlet, if you will, where if you
00:44:51.680 have energy that you need to account for, exercise is going to be a wonderful way to do it. Um I I often don’t focus
00:44:59.680 so much on ins on exercise because I don’t want to convey to people that it can outdo the diet. There there was a
00:45:06.800 paper published in women where they looked at a very structured and intense
00:45:12.319 exercise program with just it was I think it was just low carb diet and the low carb diet had better metabolic
00:45:18.160 improvements than the strength training did. And so diet is going to generally
00:45:23.839 smart smartly done diet. So changing nutrition is going to yield better long-term benefits with metabolic
00:45:29.680 health. However, the I’m an enormous advocate of exercise. Uh and to me, you are not
00:45:38.640 going to go it’s one thing to be metabolically healthy and lean, but then
00:45:44.319 it’s something else to be lean and sick or or or weak or frail. And that’s where to me the exercise comes in. So my my
00:45:52.000 view is you eat smart to be lean and metabolically sound. You exercise to be
00:45:57.359 strong and capable and metabolically sound. So muscle of course is the great
00:46:02.560 glucose consumer. When if someone’s wearing their CGM and they see the glucose come up and down, 80% of that
00:46:09.440 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
00:46:16.720 muscle you have, the more you’re going to have this big buffer or what we’re calling wiggle room where you’re going
00:46:22.400 to clear uh you’re going to clear that glucose much much faster. So, if you had two people of equal body mass, but one
00:46:29.119 having more fat and one having more muscle, but otherwise the same, and that’s a big difference, though, I know
00:46:34.400 they eat the same amount of carbs, the guy with more muscle is going to have his glucose curve come up and down, and
00:46:39.839 it’ll be back down to normal in an hour, maybe 90 minutes. the person who has less muscle,
00:46:46.319 even more fat, so same body mass, they’re it’s going to take much much longer for that glucose to come down and
00:46:52.480 thus it take longer for the insulin to come down because muscle is the main place where insulin is going to escort
00:46:57.599 the glucose to. And it does so very well if so. The more muscle mass a person has, the more sort of metabolic wiggle
00:47:05.200 room they have to clear that glucose and then the more carbs they can eat. As much as I really point the finger at
00:47:11.839 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
00:47:19.040 who was training for a marathon, he would eat over 200 grams of carbs per day and still be in deep ketosis the
00:47:24.800 next morning. You’d think, well, no, normally a ketogenic diet is no more than 50 grams. Well, unless you’re just burning that
00:47:31.359 glucose, right? And and also you you mentioned this the study that was comparing strength training to to the you know low
00:47:38.960 carb right well I think also high-intensity interval training when you’re doing you know there’s there’s a lot of work on so
00:47:45.520 we’re talking about how exercise can improve metabolic health and I think it is a really important um le lever to
00:47:53.040 pull here because you you’re you’re activating these glute for transporters and it does that like that activation
00:47:59.599 happens through lactate the generation of lactate which is happening when you’re really pushing yourself hard and
00:48:05.119 and so at that point, you know, you’re you’re becoming insulin sensitive, too, right? So, you’re you’re really kind of
00:48:10.400 changing the the the scenario in some ways. It doesn’t I don’t personally think it should give people the um
00:48:16.800 justification to go and eat tons of pizzas and, you know, ice cream and all all that stuff. Um, all you know,
00:48:23.359 cheating once in a while is fine, but like I I I think that pe you can’t you definitely can you can’t um out you can
00:48:31.520 out eat exercise in other words. So, but you can out exercise badly, right? Exactly. You can’t exercise bad diet. But I do think exercise is
00:48:39.200 extremely important especially like there’s different types of exercise and that that was kind of another question you know the strength training
00:48:42.000 No text
00:48:45.200 versus like really going hard or or the long endurance training, right? So high-intensity interval training, you
00:48:50.800 can kind of get away with doing less time, but you’re going really hard, right? You’re pushing that limit. And I am unapologetically an advocate of
00:48:56.559 that. As much as people may look at their day and say, “I have one hour.” I would say everyone, man, woman, old,
00:49:02.480 young, strength train. Strength train. Um maybe someone I I sometimes question
00:49:08.800 my own motivations where I just think if I were in a crisis situation, would my ability to run away from the challenge
00:49:15.440 be better than my ability to face the challenge? No, I don’t think so because I’m going to be with my wife and kids
00:49:20.640 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
00:49:25.680 need to. But even beyond that silly dramatic scenario, the bigger the muscle, the hungrier the
00:49:32.160 muscle. And given the time constraints that most people have, but even then there are studies to show that minute
00:49:37.920 form minute at that shorter end, if a person spending, I think it was like 30 minutes a day, the strength training
00:49:43.839 group had better improvements in insulin sensitivity than the aerobic training group. So if you have constrained time,
00:49:49.359 and let’s face it, everybody does, default to strength training. Whatever degree of strength training you can get.
00:49:55.520 And just your to touch on your point about intensity, just try to go to failure at least at some point during
00:50:01.839 that overall muscle or that movement. Get to it doesn’t have to be a high
00:50:07.839 weight, low rep. Even if you’re doing a lower weight, higher rep, just get to failure.
00:50:13.359 Fatigue yourself. Yeah. Fatigue yourself. Yeah. Yeah. And that’s where like if you’re in the context of aerobic training, I think
00:50:19.359 that’s also like there’s a spectrum, right? Like what were they doing? They were they able to talk, you know, if they’re really going hard,
00:50:25.280 which zone are they in, right? You know, it really it does make a difference with respect to your how
00:50:30.720 you’re pushing that lever for for you know, insulin sensitivity and your glute transporters and them sort of
00:50:36.559 transllocating up to the muscle and opening the floodgates. And so, um, yeah, it’s it’s nice to know. In other
00:50:43.280 words, there’s there’s many roads to Rome and and so I do I I’m just trying
00:50:45.000 No text
00:50:48.720 to, you know, there’s 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
00:50:55.440 lot of things going on here. And yes, having a low carb diet can be very beneficial for insulin sensitivity, for
00:51:02.559 staving off insulin resistance, but there’s also people that are not going to eat a low carb diet and they can
00:51:08.319 still be very metabolically healthy, particularly if they’re avoiding refined carbohydrates. they’re exercising, they’re not overeating, they’re not in a
00:51:14.720 caloric surplus. Um, and then there’s people that hear saturated fats okay and
00:51:20.160 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
00:51:27.760 scenario where you’re combining the two. Yeah. Well, anytime Yeah. To me, highfat, high carb is the worst
00:51:33.920 combination for every outcome. You’d mentioned cardioabolic with regards to adverse changes in lipoprotein profile.
00:51:40.400 Absolutely. I agree with that. But high carb and highfat just bringing it back to the fat cell. You are now giving it a
00:51:46.880 stimulus of insulin which is telling the fat cell to get big and the fat cell wants to get big most easily just by
00:51:52.720 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
00:51:59.520 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
00:52:05.359 but then having touched on what causes the growth of the fat. So naturally, it begs the question, well, what shrinks
00:52:10.720 the fat cell? Well, you look at those two levers, the the high insulin and the high calorie, you have to pick one. My
00:52:17.760 only worry is as much as people are so ardently defending the caloric view, which they have for a century now. Um,
00:52:24.160 if you just cut calories without addressing someone’s underlying high insulin, you’re going to make them
00:52:29.359 hungry very quickly. And that’s one of the reasons why I speak to the insulin
00:52:34.480 side. As much as I acknowledge the calorie side, I think that is a step to take, it just shouldn’t be the first
00:52:39.680 step. What I like to see as the first step is control your insulin. Okay, how
00:52:45.200 do I do that? Well, reduce your consumption of refined carbs. So, make sure you’re getting a lot of good
00:52:50.240 protein and fat and then fruits and vegetables. That’s going to help your
00:52:56.000 insulin come down. Don’t worry about your calories yet. We’ll get there later. And just by focusing on the
00:53:01.119 lowering insulin aspect, you have the metabolic advantages come into place, which is metabolic rate goes up, calorie
00:53:06.880 wasting through ketone excretion goes up. And so you’re going to start to lose weight. And then if you get when you get
00:53:12.160 to that next sort of plateau, all right, now we can look at that calorie side because with lower insulin, your brain
00:53:18.880 is more accustomed to using ketones now and you’re more accustomed to you mobilizing fat. You have more
00:53:24.880 mitochondria because you’ve been burning more fat with low insulin. Now you can start cutting calories and
00:53:31.119 not have to worry about hunger kicking you out. The most obvious example of the
00:53:37.200 problem with just going after calories without addressing a high insulin would be perhaps like The Biggest Loser where
00:53:44.000 you never see a reunion tour with those poor contestants because they gain
00:53:49.440 everything back, right? Hunger always wins. It’s true. Um, I definitely we’re going
00:53:54.000 No text
00:53:55.280 to I want to get more into some of what you touched on, but I I kind of want to just complete this um, you know, talk
00:54:00.720 about a little bit more about what’s the underlying cause of insulin resistance. We’ve talked about diet composition.
00:54:06.640 Um, that’s a big one. What about meal frequency? So, how often
00:54:12.640 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
00:54:18.640 worker, how does that play a role? Yeah. Oh well, we pity the the shift workers and bless them for everything
00:54:24.000 they’re doing for community, but that’s the worst way to do it. So, um, with regards to meal frequency, I think that
00:54:31.760 our the advice that we’ve been giving since the 19 unofficially since the
00:54:37.440 1960s, officially since the late 1970s of high carb diet and then what
00:54:42.640 transitioned into with the food guide pyramid and then what transitioned into eating multiple small meals per day. I
00:54:48.079 think the proof is in the pudding, which is that’s how most people eat. They eat a starchy, sugary, terrible breakfast,
00:54:54.480 then they need a mid-m morninging snack, then they need a lunch, then they need an afternoon snack, and then dinner, then an evening snack. We can see the
00:55:01.599 consequences, which is insulin resistance and obesity are the most common problems. Even where obesity is
00:55:07.599 not common, insulin resistance is still common. Um, not to go on a tangent too much, but even countries like Japan or
00:55:14.640 Singapore, my second home, one of my kids was born there. I did my fellowship in Singapore. Why would the beautiful
00:55:20.160 little island of Singapore care so much about diabetes when the average Singaporean is incredibly lean? Because
00:55:26.480 their rates of diabetes are higher than ours by a lot. We’re not even close to the most diabetic country. And that
00:55:32.559 actually comes back to how we store fat. So with regards to meal frequency and
00:55:38.319 what we eat, I think high carb diet with abundant calories and eating multiple
00:55:45.520 times a day is the worst way to do it. Uh so I would think it’d be better to have fewer meals, two to three meals a
00:55:50.960 day where you are controlling carbs. So whole fruits and vegetables, enjoy them. And then good proteins and fats, enjoy
00:55:58.240 them liberally. But this isn’t convenient in social or
00:56:04.079 family situations. But the more you can stack your meals to be earlier in the day, the better. So studies that have
00:56:10.480 looked at humans finding where they do the kind of intermittent fasting or timerestricted eating of you have one
00:56:15.839 group eat breakfast and lunch, one group eat lunch and supper, the lunch and supper group has worse outcomes. Not
00:56:23.520 that they’re not better. I mean, any one of those is better than the standard, but when you compare the two, the
00:56:28.799 outcomes are better for the meals being earlier in the day. Now, you and I are parents. How awkward would it be for me
00:56:35.920 to come home and just sit around the dinner table and look at my darling wife and kids eat dinner while I’m not? I’m
00:56:42.160 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
00:56:48.319 lunch and fast through later part of the day, including supper, I’m not going to do that because I care more about being
00:56:55.359 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
00:57:02.240 maybe I without I don’t need to explain my own situation but I think that intermittent finding one meal of the day
00:57:09.119 or at a minimum just have three meals a day and try to have about four hours between those meals and then the most
00:57:14.000 No text
00:57:15.520 important thing I would say and this is where we pity the shift workers and thank them it would be evening do not
00:57:22.799 snack in the evening especially one of the things I think that people don’t appreciate is as much as they’re
00:57:28.960 monitoring their sleep and they’re wondering why they have night after night terrible sleep habits. The most
00:57:34.079 common cause of insomnia is elevated body temperature. So they’re too hot.
00:57:39.359 And one of the most common causes of being too hot is hypoglycemia. Most people don’t appreciate that. When your
00:57:45.440 blood glucose levels spike, you you activate your sympathetic nervous system. And of all the times of the day
00:57:52.000 when your sympathetic nervous system is activated, you don’t want it to be turned on when you’re trying to go to
00:57:57.040 bed. That’s when you want the parasympathetic to dominate. So when someone eats that evening snack of
00:58:03.760 spiking their blood sugar, then they go to bed in a hypoglycemic state. They’re going to have all of the signs and
00:58:09.760 symptoms of anxiety. They’re going to be laying there hot. Their heart is going to be beating hard and fast and they’re
00:58:16.960 going to feel that pulse pounding and wonder, “What am I anxious about? Why can’t I just sleep?” Well, it’s not because you have anxiety. It’s because
00:58:23.920 you went to bed hypoglycemic. But unfortunately, that is the one time of day where people are at their weakest.
00:58:29.040 And I’m very sympathetic to that because I feel the same thing. People can walk past treats and junk food all day and
00:58:36.400 and and deny themselves that knowing that it’s not good for them. But the moment 6:00 comes around or 7:00,
00:58:43.599 then all of a sudden the temptation starts to take on a new form and they can’t. They indulge and that is the
00:58:49.680 worst time. It would be better for them to indulge in that at lunch for example than it would be at that point of the
00:58:54.720 day. not only metabolically and in maintaining good insulin sensitivity but not to mention sleep then the
00:59:00.480 compounding consequences of poor sleep just creates this vicious cycle.
00:59:05.680 Yeah. Okay. So the meal frequency it sounds like you know the more you’re each time you’re elevating each time
00:59:06.000 No text
00:59:12.160 you’re having an insulin response that insulin is then you’re you’re getting into the fat storage.
00:59:17.200 Yeah. And you will get hungry. Yeah. So so as much as we highlighted that 2021 study what I ought to have
00:59:22.400 done is highlight the work of Dr. Dr. David Lewig um Cara Ebling and others
00:59:27.760 and shy at all in New England Journal of Medicine in 2012 where there are there’s so many decades worth of evidence
00:59:33.920 showing that as much as we had that one study suggesting well the insulin higher insulin group didn’t had less hunger.
00:59:39.599 Yeah. There’s a lot of evidence showing the opposite. So where you you end up creating this roller coaster of glycemia
00:59:46.240 and hunger where the person eats a starchy sugary breakfast which let’s face it most breakfasts are these days.
00:59:52.880 they have this big spike and then when you go high you inevitably go low and then when you go low hunger comes again
00:59:59.040 even though you may still literally have food in your stomach and yet your brain is starting to sense well I’m hungry
01:00:04.880 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
01:00:11.440 David Lewig’s main contributions so anyway it puts the person on this roller coaster of glycemia and every time it
01:00:17.920 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
01:00:23.920 to eat six or seven times a day. And if they’re not eating, they’re drinking something sugary, either a soda or a
01:00:29.839 sugary fruit juice, right? And and the difference between, you know, this sugary type of like
01:00:35.839 breakfast you’re talking about and perhaps like some something that’s more of a complex carbohydrate would be the fiber is slowing that glucose response
01:00:42.400 and and causing some satiety as well. Um, so that would be something that you would contrast. Not to mention even
01:00:48.799 in that study in 2021, they probably were doing more complex carbohydrates and not they were Yeah. And it was it was
01:00:53.920 plant-based. And that that’s again another reason why I thought we need to be careful. Not I don’t mean to sound overly critical of the study. I
01:00:59.760 appreciate it, but at the same time, I think we need to um elaborate on the limitations, which is most people aren’t
01:01:06.240 starting with a breakfast of a big leafy green salad. Um but there is an a group
01:01:12.000 uh that found that when you have a breakfast and they looked at breakfast and the name of the article was
01:01:17.119 something like more rapid return of hunger. They it was something like return to hunger was in the title and if
01:01:23.119 the breakfast isocaloric breakfast so same number of calories protein was clamped and it just differed in the
01:01:29.520 ratio of fats to carbs. The high carb group was hungrier much sooner and then
01:01:34.559 ate more for their next meal than the low carb group. And and so I would say
01:01:39.839 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
01:01:47.119 and fats, that’s going to be a winning combination of satiety. And then have a
01:01:52.480 nice lunch and then my view for me personally, I don’t eat breakfast as much as I said I wouldn’t elaborate on
01:01:59.119 my own uh approach. I eat a big lunch. um that’s my main meal of the day
01:02:05.040 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
01:02:12.079 not snack in the evening. But as much as I know, one of the great ironies of being a metabolic scientist and yet a
01:02:19.440 fallible human um with bad habits sometimes is that evening time is still
01:02:24.480 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
01:02:30.240 don’t really bring a lot of cereal into the home. I make breakfast for the kids every morning for the most part and it’s
01:02:35.839 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
01:02:41.200 little darling babies, but I do it because I don’t want cereal in the home because if there’s cereal in the home,
01:02:46.720 daddy is a meth addict when it comes to cereal. And if it’s there, as much as I
01:02:52.240 know, I will like go through this like I can almost script it out where
01:02:58.960 I’ll put help get the kids to bed. I’ll clean the house, straighten things up, and then everything’s quiet, and then I think, I I need six bowls of cereal
01:03:05.839 right now. And so then I will eat myself sick. And like a true addict, I will
01:03:11.119 tell myself, I’ll just have one bowl. What’s the problem with one bowl? And then yet there’s this little shoulder
01:03:17.440 angel telling me, “Oh, but you know, you’re not going to stop at one bowl.” But then there’s the addiction inside of me saying, “Yeah, I am. I want this. I’m
01:03:23.680 just going to have one bowl. I never My wife can, though. My wife has this
01:03:29.280 uncanny alien-like ability to eat something like this, something sweet like an ice cream or a cereal and just
01:03:36.000 have a little bit of it and be done. I can’t do that. She is a moderator and I
01:03:41.440 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
01:03:47.280 modern the most popular modern mantra when it
01:03:52.319 comes to nutrition is moderation and all things. What if you can’t moderate? then it would be better not to even start,
01:03:59.119 right? Um I want to talk about you talked you sort of alluded to this and
01:04:01.000 No text
01:04:04.240 this has to do with the other contributing factors to insulin resistance and you were talking about
01:04:10.079 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
01:04:15.920 also you talked about some very interesting stuff that I hadn’t really thought about before but also you’re digesting you know when your your
01:04:22.480 systems are all activated thermic effective food you’re hot. So I mean it makes it makes perfect sense and um in
01:04:28.400 fact I remember a friend of mine um Dr. Sachin Panda he’s done a lot of research on timerestricted eating and he’s got this app um my circadian clock where
01:04:37.039 people were you know uploading pictures of their meals and it was timestamped and they’re putting comments and like
01:04:42.880 the most one of the most common comments he was getting was um is disrupting sleep. Eating later was disrupting
01:04:48.480 sleep. And finally it was like like he’s like we got to look into this. I mean, there’s like, you know, dozens of people talking about
01:04:54.319 this and and it’s kind of funny when you kind of get that reverse thing that you’re looking at when you’re when you get the data and then something else
01:04:59.760 kind of pops up. Wow. So, eating late at night seems to be disrupting people’s sleep and that’s that’s that’s a real
01:05:05.200 thing. I’m convinced I’m convinced that given that the natural uh temptation and inclination people have to indulge
01:05:11.440 before bed. I’m and and the sleep epidemic, the poor sleep epidemic, I’m
01:05:16.559 convinced that more of it isn’t blue light. It isn’t evening light exposure or evening activities. It’s you’re going
01:05:21.599 to bed hypoglycemic and and full. And you’re full. And so, like you said, your your stomach, you’re bubbling, you’re
01:05:27.280 digesting when No, you ought to have you give yourself at least a few hours before from your last meal. Yep. Before
01:05:34.319 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. Um,
01:05:41.000 No text
01:05:41.680 that’s the one thing, sleep. So you you were talking about these fast causes of insulin resistance, inflammation, the
01:05:47.599 the chronic stress, high cortisol, um and then the last one, insulin,
01:05:52.960 right? Too much insulin. Where where does lack of sleep come into that? Because I have seen I’ve read
01:05:58.799 studies and we were talking a little bit about this before before we you know started the podcast and that is first of all when I became a new parent and I my
01:06:06.799 sleep was entirely wrecked. I mean just entirely wrecked. I mean I aged like 10
01:06:11.839 years and like but for a good cause but for a good cause. I would do it all over again in a heartbeat. Um
01:06:18.400 my my postprandial glucose which is what I was monitoring at the time with my continuous glucose monitor was
01:06:24.720 I mean it was not my normal I mean I was pre-diabetic. It was unreal. Um and so I started looking into
01:06:31.039 literature and this was the most surprising thing when I when I wanted to wear a CGM. I was more like how is watermelon going to affect my glucose? I
01:06:37.359 was more the fruit and the oh look what a grape did. this is insane. And and then and then it was like the disrupted
01:06:43.280 sleep and everything else. Nothing mattered anymore. I was like, this is real. Like this is the real deal here.
01:06:49.039 Um and I started looking into the literature where sleep, you know, sleep deprivation after one night,
01:06:54.799 like half you’re getting four hours of sleep instead of eight. You can be insulin resistant the next day. And I’m
01:07:00.079 like, what? Oh yeah. So I’d love to hear about that and how that’s contributing to this, you know,
01:07:06.000 fast cause of insulin. Yes. Well, everything you just said I am nodding to because I I can relate. Um uh
01:07:12.319 where I when I’ve worn CGMs, I absolutely see that the single most predictive variable of my glycemia in
01:07:19.599 any given day is how did I sleep? Nothing. And that I’ve played around with nothing has even come close.
01:07:26.160 So when you get one bad night of sleep, the stress home so it fits under the stress category to put a to make it very
01:07:33.520 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
01:07:40.880 result in a much higher and disrupted rhythm of cortisol. And and so cortisol
01:07:47.599 is will cause insulin resistance in every biological model very quickly. So too will epinephrine. And epinephrine is
01:07:55.039 another stress hormone, sort of the faster stress hormone, the cortisol being a little more delayed. But both of
01:08:00.559 them are higher um with regards to sleep deprivation. And even even epinephrine,
01:08:05.920 even adrenaline can cause insulin resistance in humans. If you do a steady little drip in a human of adrenaline,
01:08:11.119 they’re going to be insulin resistant with demonstrabably insulin resistant within just an hour or two. To make so
01:08:17.040 that’s how sleep deprivation causes uh insulin resistance. And to make matters
01:08:22.640 even worse, what is the most common intervention to try to offset the negative consequences of sleep
01:08:28.880 deprivation? Well, it’s more caffeine. Well, more caffeine is going to increase epinephrine even more. Epinephrine
01:08:34.960 causes insulin resistance. So, even the solution to the sleep deprivation ends up inadvertently compounding the
01:08:41.198 metabolic consequences of the sleep deprivation. Now, that’s not to say epinephrine uh it’s not to say caffeine
01:08:47.120 doesn’t have some metabolic benefits. It can when used correctly, like I would say when used in the context of
01:08:53.279 performance. But for someone who’s trying to offset the consequences of their sleep deprivation, you may have
01:08:59.120 some increased alertness. Yes, but the metabolic consequences of the sleep have now just been added on. Before we
01:09:05.439 continue, I just want to mention something important. If you’re finding these episodes valuable, please consider
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01:09:28.080 it. Now, back to the episode. Um, what about So, we’re talking about um other
01:09:31.000 No text
01:09:36.719 causes of insulin resistance. You’ve also kind of looked into some of this other stuff that’s very interesting with
01:09:41.839 respect to environmental toxins. Yeah. and how air particulate matter from air pollution perhaps even
01:09:48.880 plastic associated chemicals or microplastics how those those can contribute is that something that’s
01:09:54.320 meaningful like the sleep deprivation the cortisol sounds pretty meaningful um are these other talk about it and
01:10:00.159 whether or not they’re pretty meaningful in the cont yeah yeah super question and really fair of you to to state it that way
01:10:05.840 because as much as I found that work and still do really really cool and we’re
01:10:11.120 doing more of it so so to articulate what we’ve done So far we’ve published reports looking at PM2.5 diesel exhaust
01:10:18.080 particles and we published another report looking at cigarette smoke with
01:10:23.120 the cigarette smoke particles that was purely in the context of ceramides
01:10:28.320 forced mitochondrial fision and insulin resistance and the cigarette smoke did all of those things. The newer paper
01:10:34.400 that we published about a year or two ago was I think the first to find that if you just have increased diesel
01:10:42.480 exhaust particles, even when we calorie clamped these, we pair fed these animals and the animals that were inhaling more
01:10:48.719 of the diesel particles at physiological levels like at a level that a human could be exposed to, they had much
01:10:54.880 fatter fat cells. So they had much more atyposite hypertrophy um which accounted for a higher body fat
01:11:01.679 mass even though they were eating the exact same amount of calories. Again we pair fed them. We only let them eat as
01:11:08.000 much calories as the other group was eating and they still had more fat. So it does suggest that there are
01:11:13.199 non-nutritive stimuli. You’d mentioned some others. We’ve not done work on microplastics or
01:11:19.920 the plasticizers those like dethyl stillbsterol and and BPA but those also
01:11:26.480 have been shown to promote greater fat expansion in the absence of calorie changes. That’s another reason why I I
01:11:34.560 think that it’s we don’t do ourselves any favors when we only have a calorie centric view of obesity because there
01:11:40.239 are more variables that come into play here. Now, to answer the last part of your question, which is to what degree
01:11:45.600 should the average person be worried about that I pains me to say this
01:11:50.719 because it’s my own work. I think that’s a that’s a lower tier concern. It’s also
01:11:55.760 one that some people may not literally be able to do anything about. You know, like if you are simply living in an
01:12:01.760 inner city area and there’s just pollution, there’s nothing you can really do. Maybe you can replace your intern your inhome
01:12:08.320 air filter more frequently and get one and but those aren’t cheap either. So I’m very mindful of the financial
01:12:14.400 constraints of the person who we may be fictionally talking about. But I guess other than that would be the only thing
01:12:20.159 you could do if you could have a better in-home purifier, great. But for the vast majority of people who couldn’t
01:12:26.560 even quantify their their pollution exposure, let alone afford an intervention to reduce it, the good news
01:12:33.840 is that’s going to have a much lower effect than just changing your nutritional and exercise habits.
01:12:39.440 Yeah, there are there are some more affordable hepailters now that do seem to kind of u make a dent in reducing
01:12:45.280 particulate matter. And um but it’s interesting that this this air pollution is really
01:12:51.840 it seems like pretty pervasive like it’s not just metabolic health but it’s Alzheimer’s disease. I mean it seems
01:12:58.320 like it’s a cardiovascular disease. I mean it’s really affecting lungs of course you know respiratory health. It’s
01:13:04.159 affecting so many different chronic diseases as well. And so um it is it is important to keep the context in
01:13:10.320 perspective right obviously diet you know exercise these things are the most important when it comes to metabolic health but But but matter they
01:13:18.400 do and not just for metabolic health for a variety just our overall health right and
01:13:23.000 No text
01:13:23.440 it’s interesting of wedding smoking or vaping vaping right in fact that’s the new project that we’re starting we have just what’s
01:13:29.440 preliminary data now when we look at the superheated particles which is what you’re inhaling we’ve we finding we
01:13:36.080 haven’t published this yet so this is unpublished my master student is this is her thesis project right now so the data
01:13:41.120 is forthcoming but the early data suggests that it’s it actually at at a
01:13:46.159 relatively controlled um dose matching it for the cigarette smoke dose that we used previously it’s worse so with now I
01:13:54.560 can’t speak to the consequences of the tumor agenesis effects like maybe the person’s going to have slightly better
01:14:00.080 outcomes with cancer but when we’re looking at forced the outcome we’ve measured so far is mitochondrial um
01:14:06.159 outcomes looking at the degree to which the mitochondria can take in oxygen and convert it to ATP rather than the oxygen
01:14:12.880 being converted into super oxide radical It’s worse with the superheated particles from the vaping than from the
01:14:19.360 cigarette smoke. Do you think this is coming down to nicotine or other things in the vape?
01:14:24.719 I don’t know. So, we have just the whole animal data so far and then the next step will be isolating individual particles to try to find out all right
01:14:30.960 which culprit if one culprit is more uh to blame with regards to the EIG
01:14:37.040 exposure versus the cigarette because it is different chemicals. Yeah. Right. No, I’d be I’m going to you
01:14:42.880 have to let me know. I’m in that. Yeah. Um I before we get into some solutions here, I’d also love to touch on one more
01:14:45.000 No text
01:14:50.159 thing that I you know you’ve you’ve also looked at with respect to other causes
01:14:55.760 of insulin resistance and and metabolic health and that is you know commonly prescribed medications. M
01:15:01.440 and this is something, you know, that I’ve I’ve witnessed firsthand and and friends where they’re, you know,
01:15:08.719 metabolically healthy, lean, lean and metabolically healthy, and they get on an antid-depressant, for example,
01:15:15.440 and all of a sudden gain a bunch of weight. I mean, unbelievable amount of weight, you know, 30 to 40 lbs,
01:15:21.440 and are no longer metabolically healthy. So, um, there’s a there’s a whole host of commonly prescribed medications out
01:15:28.320 there from lipid lowering medications like statins to antid-depressants and other neuroscychiatric, you know,
01:15:34.800 disorders and medications that help with those disorders. What what what is that something to be concerned about?
01:15:40.640 Oh, for sure. Yeah, it absolutely is. And I’ll just mention one that you just mentioned, which is statins, just
01:15:45.920 because of how common they are. So, there’s no evidence that statins that I’m aware of are going to create weight gain, but there are metabolic
01:15:52.239 consequences to messing with cholesterol, lest people forget, cholesterol is a precursor to an
01:15:58.640 essential component of the electron transport system. And so, it’s no surprise that if people are waging war
01:16:04.159 on cholesterol synthesis, the mitochondria may suffer. And in women,
01:16:09.360 uh, middle-aged and older women have a 50% greater risk of developing type 2 diabetes when they get on a statin.
01:16:15.520 That’s a meaningful increased risk. Women appear to be much more susceptible to the consequences of statins,
01:16:21.520 metabolic consequences of statins. Not to mention the increased risk of Alzheimer’s and even certain cancers
01:16:26.719 that come with statins. Now, I’m not intending to sound like I don’t think there’s a ever a place for statins, but
01:16:32.080 I do think they’re overprescribed. Now, more heavily metabolic, any steroid uh
01:16:38.640 that’s been prescribed to control inflammation is going to be deeply problematic for weight gain. So if a
01:16:44.719 person has an autoimmune disease or a chronic inflammatory condition and the clinician has prescribed a
01:16:50.640 corticosteroid, they’re going to gain weight very very quickly because that starts to play on that stress pathway
01:16:57.040 where the more cortisol is that pathway is being activated, which is what that’s doing, the more you’re going to make the
01:17:02.560 body insulin resistant. Higher insulin promotes fat gain. And then just for the sake of time perhaps I just mention the
01:17:08.159 atypical antiscychotics. The any drug that ends with an apne
01:17:13.199 um at the end of it the suffix being apne is generally going to promote weight gain. That’s probably through a
01:17:20.400 central insulin resistance of the hypothalamus. When the hypothalamus becomes insulin resistant, you have a
01:17:26.320 reduced satiety signal and the person’s just going to start eating more. All right. So, let’s kind of shift gears and
01:17:30.000 No text
01:17:31.600 talk about some solutions here, protocols to maybe enhance some sensitivity. People that are, you know,
01:17:38.400 we talked, we started this conversation talking about people who are a large population of people that are actually
01:17:44.480 pre pre-diabetic. They might be, you know, on their way to insulin resistance or already insulin resistant
01:17:49.520 and not even really know it. Um what what are some of the best strategies
01:17:55.440 people can do now to really make a difference and you know dietary
01:18:00.960 strategies, you know, stress reduction, physical activity, but but also how how
01:18:07.520 soon can they expect to see changes and what should they look at? Yeah. To see and monitor those changes.
01:18:13.600 Yeah. Well, in fact, I’ll I’ll start with that last part of your question, which is how quickly can it turn around.
01:18:18.719 We published a a clinical report. So working collaborating with a local clinic in Utah, we took 11 women with
01:18:26.239 newly diagnosed type 2 diabetes and their A1C was 8.9%. So very much
01:18:31.679 diabetic range. And the physician who’s very much on board had given these patients two options. And he said, “You
01:18:39.679 can leave the office with a prescription for an anti-diabetic drug like metformin
01:18:44.719 or you can meet with the nutritionist and go through this lifestyle nutrition counseling.” And in just 90 days, their
01:18:52.960 A1C went down. The average A1C, the average was 8.9 and it went to 5.6. So
01:18:58.880 no sign of diabetes whatsoever after just 90 days without a pill popped or a
01:19:05.040 needle injected. So I have often taken that 90day span as a very reasonable
01:19:11.120 amount of time to reverse insulin resistance. Now depending on the scope of the problem, it may take a little
01:19:16.320 longer to get rid of all of the consequences of the insulin resistance, but I think 90 days is a very reasonable
01:19:23.360 justified timeline. Again, I say justified based on our own evidence.
01:19:28.719 Now, what did we tell them? That could sort of segue into the first part of your question. We gave them in fact just
01:19:34.400 three pieces of advice based on the three macronutrients and I’ve actually kind of already alluded to this which
01:19:40.560 the first one is control carbs and that was simply this admonition to eat whole
01:19:46.719 fruits and vegetables. You don’t even need to count it just whole fruits and vegetables. But in the case of these
01:19:52.320 type 2 diabetics we said try to be mindful of the most sugary fruits and ve or the starchy fruits and vegetables. So
01:19:59.360 um the tropical fruits we said please be careful with like b bananas, pineapples,
01:20:04.640 mangoes and then the starchy if the vegetable grows in the ground eat
01:20:11.040 less of it relatively but all other fruits and vegetables and that’s still a lot enjoy liberally and then prioritize
01:20:18.080 protein and don’t fear the fat that comes with that protein. And that was an important caveat because we didn’t want
01:20:23.520 them to be drinking fat. Uh but we wanted them to acknowledge that in nature all protein comes with fat. Don’t
01:20:31.600 be afraid of that fat. Um when humans eat fat with the protein, we digest the
01:20:37.520 protein better and it’s more anabolic. There’s there’s studies in humans to show that people work out, give them
01:20:44.000 protein, they’ll have a certain degree of muscle protein synthesis. If you give them protein and fat, it’s even higher
01:20:50.480 than it was with just the protein alone. Yeah. And that’s most people don’t appreciate that bile when when the
01:20:56.800 gallbladder from the liver releases the bile into the intestines, we always just think of that as being relevant to fat
01:21:02.320 digestion and it’s critical for that. But it also enhances proteolytic enzymes. It makes the proteolytic
01:21:08.400 enzymes more active uh better. They work better. So we digest the protein better
01:21:13.679 and that may be the mechanism that explains the enhanced muscle protein synthesis from the combination. So that
01:21:19.679 was the dietary advice we gave them and I would just say that for people that manage your macros, control carbs,
01:21:26.159 prioritize protein, don’t fear fat. And then when it comes to eating time, I
01:21:32.800 mentioned it earlier, the more you can stack your meals earlier in the day or at least the bulk of the calories coming
01:21:38.800 earlier in the day, the better so that you can taper off through evening. And by all means, or please don’t eat within
01:21:46.560 that 3 to four hour window before bed. As much as you can, don’t don’t eat. And
01:21:52.639 then exercise. And my view on exercise, as much as we both are, I am an enormous
01:21:57.760 advocate of exercise. I was a personal trainer back in the day during my master’s degree, and I hated every
01:22:02.800 minute of it, but I did it. And I appreciate the role of exercise, and I enjoy exercising every day. If people
01:22:10.560 are wondering what’s the best exercise, my somewhat pathy answer is the one you’ll do. Just do something. If you can
01:22:18.880 do the sort of higher intense strength training that we were talking about, then please do it. But if this is like
01:22:25.120 some 80-year-old grandma who just likes walking around with her girlfriends, just walk around with your girlfriends.
01:22:30.560 Keep doing that habit. Whatever exercise you can do and you’re going to do, then just do it. But there is something to be
01:22:37.600 said for timing it where perhaps you can do your exercise session, if it is a walk around the block a few times with
01:22:43.600 the gals, do that after your biggest meal. where if you just do 10 to 15 minutes of
01:22:50.000 physical activity after your biggest glucose spiking meal, you will blunt that glucose excursion by half if not
01:22:57.360 even better. So what would have been a huge big long glucose spike and a and a
01:23:02.560 commensurate insulin dose as well, you’re going to cut that down substantially if you did if you do time
01:23:09.199 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
01:23:14.719 exercise snack where you had your big meal, maybe hopefully it was lunch, go
01:23:19.840 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
01:23:26.400 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.
01:23:33.760 And so just find a way to get up and do something in little bits, little bits of activity throughout the day, but then
01:23:39.920 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
01:23:46.400 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.
01:23:52.080 Um that’s something that I’ll, you know, try try to do after a meal, particularly when I’m on vacation and uh get the
01:23:59.760 gelato that I never ever ever eat unless I’m in Rome. Yeah. Well, that’s the place to do it. But um Okay. Well, that’s great. So,
01:24:06.800 many people ask about these supplements and you know, are there these supplements that can improve insulin
01:24:07.000 No text
01:24:12.239 sensitivity? So, they you know, you hear everything from magnesium to alphaic acid to bourberine, apple cider vinegar,
01:24:18.159 and if if there’s any merit to that or taking it before a meal or or is this
01:24:23.199 just like dropping like a drop of water on the in the pool to like try to fill the pool up? Yeah. Well, in fact, every one you just
01:24:29.360 mentioned works. Um, frankly, the one I like to talk about the most because the evidence is so compelling and it’s so
01:24:36.400 easy to get. So, bourberine is undoubtedly effective. No doubt it works. Bourberine absolutely works. I
01:24:43.040 love apple cider vinegar as a personal favorite. Maybe it’s because of my old man palette where I like really tart
01:24:49.920 things the older I’m getting. So, I just love the taste when I dilute it in water or sparkling water. But apple cider
01:24:55.920 vinegar that really that that’s the shortest of all short chain fats that acetic acid and the short chain in the
01:25:03.199 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
01:25:10.159 spectrum of fats because we don’t really eat a lot of fermented foods anymore. So we don’t get the mediumchain fats and
01:25:15.760 because we don’t eat any much fermentation fermented foods, we don’t get any short- chain fats for the most
01:25:21.199 part. So short- chain fatty acids, which is what apple cider vinegar is, is a
01:25:26.800 really it it that’s a small little molecule that punches well above its its weight, where the acetic acid will
01:25:33.520 reduce hippatic um gluconogenesis to help control glucose. Um which is very
01:25:38.960 relevant in a person with diabetes with especially type two. There’s so much glucagon always in their bloodstream,
01:25:45.920 it’s constantly pushing the liver to make more glucose. Apple cider vinegar
01:25:50.960 will inhibit that and so it it helps the blood glucose by just having the liver dump less glucose into the blood but it
01:25:57.360 also stimulates and you’d mentioned glute 4 at the muscle. The reason
01:26:03.440 exercise is able to open glute 4 or transllocate it and get the glucose in
01:26:08.560 without insulin is because of EMPK. Uh so it’s that interesting paradox of
01:26:14.000 exercise where insulin comes down and yet glucose is taking in more the muscle taking in more glucose than it ever was.
01:26:20.159 It’s because of this kind of backdoor of the muscle exercising. AMPK gets turned
01:26:25.760 on through a series of events that moves glute 4. Well, apple cider vinegar will do the same thing in the absence of
01:26:32.560 exercise, albeit to a more modest degree. So, that’s a couple mechanisms among others, including mitochondrial
01:26:38.639 biogenesis and a little bit of uncoupling, where apple cider vinegar is one of my favorites where if you take a
01:26:44.719 couple tablespoons before your most starchy meal, you absolutely could
01:26:49.920 compare the glucose curve from one day to the next and you’ll see that it’s significantly lower with just that tart
01:26:56.880 little bit of drinking. That’s fascinating because when you’re talking about the short- chain fatty acid, you
01:27:02.560 know, and I’m thinking, you know, acetate. Yep. So, acetate, acetic acid, we’re going
01:27:08.000 from acid base. Um, I’m thinking of lactate, lactic acid, lactate, lact, and
01:27:13.280 that’s when you’re generating with exercise and lactate signaling is to amkin is it’s it’s it’s very much
01:27:19.760 Yeah. You know, and then I’m thinking, well, is this like a short chain fatty acid sort of like they’re signaling molecules, right? They are. And is there
01:27:27.600 is there something that would be so interesting to look at to see if there’s something going on with lactate acetate
01:27:33.120 malate, right? Like that’s in like a Granny Smith apple or something like the more sour apple, right? Yep.
01:27:38.400 I mean, all these different short chain fatty acid. Well, the short chain fatty acids that you’re getting from foods and then there’s another mallet’s also in
01:27:44.719 like blueberries, malic acid, malic acids in them. And so so I just my my sort of wheels are
01:27:51.600 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
01:27:57.199 acetic acid work working? We know lactate works too. Yeah. Um and so I think acetic acid I know beta
01:28:01.000 No text
01:28:02.880 hydroxybutyrate one of the one of the ways that main ketone not that we’ve talked about ketones but some of my work is on
01:28:09.440 ketones. I’ve been wonder I’ve wondered in the past the ketone is unique because on one hand it’s a nutrient. It’s a
01:28:16.000 calorie to be burned but at the other hand it’s a signaling molecule and it is known to elicit some of its signaling
01:28:22.080 like anti-inflammatory effects and antioxidant effects. Part of it is through changes elicited because of a
01:28:28.719 groin coupled receptor where it does have a cell surface receptor that it will activate. I don’t know the degree
01:28:35.199 to which acetic acid may do the same thing but with regards to beta hydroxybutyrate
01:28:41.120 even exogenous ketones um that wasn’t one you mentioned but there are increasingly increasing studies showing
01:28:47.120 that you can have there was just a a study in women with PCOS the only
01:28:53.760 intervention was to give them exogenous ketones and every outcome related to
01:29:00.000 metabolic markers and PCOS got better and the only change was the supplementation with exogenous ketones.
01:29:06.960 I don’t know that that was an effect of the bioenergetics of the ketone. It was probably more of the signaling effect.
01:29:12.239 And so that would be another thing if a person’s becoming increasingly curious about ketones. And that’s not without
01:29:18.400 justification. The evidence supporting the the value of ketones is growing uh
01:29:24.320 and and growing quickly and it ought to. I have never in the past wanted to be
01:29:29.920 seen as a drum beating advocate of a ketogenic diet. simply knowing that that’s not everyone’s cup of tea. But
01:29:36.239 increasingly, I will vigorously defend ketones as very beneficial, viable
01:29:41.440 signaling molecules in the body. So even when it comes to uh controlling the
01:29:46.719 metabolic response, you’re probably going to eat less because ketones have a very satiating effect um more so than
01:29:53.920 say glucose does. Um but then they also will impact uh mitochondrial uncoupling
01:30:00.159 and help the body burn through that glucose faster. No, it’s it’s it’s it’s interesting. Ketone ketones are definitely signaling
01:30:06.560 molecules and I also think there’s a lot of overlap between lactate and beta hydroxybutyrate as well. I mean, they’re
01:30:12.239 activating a lot of the same like brain drive neurotrophic factor being one that you know
01:30:17.360 um and and the you know, I’ve had Dom Dagustinino on the podcast twice. We talked a lot about ketogenic diets and
01:30:24.000 uh you know, Eric, Dr. Eric Berden talked about them as well. Um, I do
01:30:29.280 think they’re not the easiest diet for people to follow for for several reasons. Um, including, you know, social
01:30:35.840 too, being social. No, no, they’re it’s restrictive. It’s definitely restrictive. Um, but, you know, perhaps cycling them. I’m I’ve
01:30:42.159 been interested in in cycling it. I’ve I’ve only done it like a couple of times. Um, for me, it’s also very hard
01:30:47.520 to do as well, but I’m interested in the brain benefits of ketones. Yep. Um, and
01:30:53.280 this is where exogenous ketones, I think, become so helpful. Where if you have someone who just says, “I just
01:30:58.800 don’t want to do the ketogenic diet, but I still would like some of the benefits.” Um, there are so many good
01:31:04.719 options nowadays that I think I think it becomes a viable approach for someone to say, “I want the ketones, but I want I
01:31:09.920 don’t want ketogenic, so I’m just going to drink them.” Do you think the dose matters? So like
01:31:15.679 not only in respect to wanting the right dose of ketones to activate you know these beneficial signaling pathways
01:31:22.639 but also to make sure that you’re not like dipping too low like your glucose doesn’t go too low where you’re kind of
01:31:28.880 like what’s going on here a little bit anxious a little bit yeah like you can get I can get you know when
01:31:34.480 I haven’t eaten for like many hours I like forget to eat cuz I’m so busy all of a sudden I’ll start to get a
01:31:40.000 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
01:31:45.440 actually even the earlier in our discussion I mentioned on one of my many tangents Dr. George Cahill’s work and he
01:31:52.159 was really one of the more more famous prominent what they called at the time
01:31:57.840 starvation scientists we would call fasting scientists but that same study I mentioned where he they it made you
01:32:05.280 wonder why was it that these patients who got down to 20 milligrams per deciliter of glucose many people will
01:32:11.440 say that’s lethal like it’ll kill you and yet they not only didn’t die they had no cognitive deficit whatsoever the
01:32:17.920 speculation I don’t know whether it was him or maybe Richard Vch in a sort of follow-up commentary, a ketone scientist
01:32:24.400 who’s also passed away now, where uh if if the brain has adapted to
01:32:29.920 ketones, it may be more resilient to tolerate a low glucose,
01:32:35.440 but most people one haven’t adapted to ketones and two don’t even have any
01:32:40.800 ketones. That’s the problem is because the same intervention for the most part that’s going to drop the glucose in
01:32:46.400 someone like someone who eats a really sugary meal or drinks it their glucose
01:32:51.520 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
01:32:56.960 hypoglycemia. You would say well I should be able to weather that drop because I have
01:33:02.800 ketones. No, because the same thing that’s that’s helping you reser reverse your glucose, the high insulin is going
01:33:10.639 to inhibit ketogenesis. And so you’ve deprived your brain in that acute moment
01:33:15.679 of its primary fuels, uh, glucose and ketones. Although the brain does use lactate
01:33:20.800 um, as a fuel as well, albeit to lower levels. But if glucose and ketones have
01:33:26.159 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
01:33:31.920 earlier, the brain doesn’t have a reservoir of stored energy, a very very modest amount, but its metabolic rate is
01:33:38.080 so high that it it needs constant supply. Right. Okay. Well, let’s talk a little
01:33:42.000 No text
01:33:43.280 bit more about, you know, fat. And we kind of talked about this a little earlier about, you know, not all fat
01:33:49.120 being equal and a lot of people are thinking about fat as just stored calories, but I mean, there’s much more
01:33:55.280 to this picture, right? So there’s there there different ways we store fat and there’s the subcutaneous way, there’s
01:34:01.600 visceral fat. Um these fats are not the same. Yeah, I know when you were talking you were talking about liver biopsies,
01:34:07.440 you kept pointing to the abdominal reg region and I was wondering if you were talking about you were getting visceral fat biopsies or probably not. But um
01:34:15.360 can you talk a little bit about these different types of fat and what determines whether or not you’re going
01:34:21.360 to store fat subcutaneously versus viscerally? Yeah. why visceral fat is so dangerous.
01:34:26.719 Yeah. Yeah. So, a lot of that conversation, there’s so many topics I could take with this and perhaps just
01:34:32.960 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.
01:34:40.159 So earlier I’d mentioned and it’s a perfect opportunity to bring in different ethnicities because different
01:34:45.520 ethnicities will store fat differently. And this all is underlying the earlier
01:34:50.880 conversation of the slow insulin resistance where I said it starts in the fat cell and I very much advocate that
01:34:56.880 view. So why is it that Singapore 15 years ago was recruiting young scientists to come do diabetes research
01:35:04.320 where you look at the average body weight in Singapore and by American US standards they’re very lean people and
01:35:10.400 that’s reflective of all East Asians and and most and many South Asians as well.
01:35:16.080 So India up through Japan and the Koreas. Um why is it that these are
01:35:21.199 people with such low body weights and even low body fat levels and yet their diabetes rates are way higher than we
01:35:28.080 have in the US and that is the difference in how people store fat. So if a human body is gaining fat mass, it
01:35:35.040 will gain that fat mass through two different mechanisms. It will either be a function of multiplying the fat cells.
01:35:42.719 So the person will have the ability to make new fat cells. That’s called hyperplasia. And when the fat is
01:35:48.400 undergoing hyperplasia, the size of the fat cell is staying very modest. So the size of the each individual fat cell is
01:35:54.719 small, there are just a lot more of them. On the other hand, you could have someone who’s storing more of their fat
01:36:00.000 through hypertrophy where the number of fat cells is not changing, but the size is the hypertrophic fat cell is a very
01:36:08.719 sick fat cell for two reasons. And then I’ll explain the ethnic predisposition
01:36:14.320 predisposition predispositions because of it. So firstly, the fatter the fat
01:36:19.360 cell gets, the more insulin resistant it becomes to prevent further fat growth.
01:36:24.639 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
01:36:30.719 of. It can get 20 times bigger than its original volume. And as it starts to reach this point of maximum dimension,
01:36:37.920 it has to start limiting its growth. And so it becomes insulin resistant to stop growing. But at the same time, it starts
01:36:45.760 to become hypoxic where the fat cell has become so big that they’ve pushed each other too far from capillaries and now
01:36:53.040 it can’t get the oxygen from the capillaries. And so it starts releasing a bunch of pro-inflammatory cytoines
01:36:59.440 because some of them will work like a trail of breadcrumbs resulting in one capillary having a little budding
01:37:05.840 capillary grow off and follow the cytoines to the hypoxic or suffocating
01:37:11.520 fat cell. So the hypertrophic fat cell becomes insulin resistant to stop growth
01:37:16.880 and it becomes pro-inflammatory to try to correct blood flow. All of which results in a very insulin resistant on
01:37:24.480 the course to cardioabolic disease body. Now back to the various ethnicities.
01:37:29.920 Some ethnicities like whites and blacks have the ability to make new fat cells.
01:37:35.360 So these are ethnicities that can be a little fatter than other ethnicities and yet have lower levels of insulin
01:37:40.960 resistance and type 2 diabetes. And that’s what we see in the US. High rates of obesity but relatively modest rates
01:37:47.600 of type2 di as much as we think the problem is bad here. I think the US ranks somewhere in the 70s of if you
01:37:54.239 look at all the countries in the world and how diabetic they are, we’re about number 70. Whereas Singapore, for
01:37:59.920 example, and Japan is not too far back. Singapore is I think number nine. this and and all the countries of the Middle
01:38:05.920 East are actually numbers one through eight are like Oman, Dubai, Jordan, these countries in the Middle East and
01:38:12.800 and then the other countries sort of round out through Southeast Asia and the Middle East are the and the Pacific
01:38:18.080 Islands the most diabetic places these ethnicities especially so India has
01:38:24.080 among it is among the highest most diabetic countries on the planet East
01:38:29.119 Asia, Southeast Asia their fat cells on average are sign
01:38:34.239 there the one paper I’m recalling where it looked it took Caucasian men and South Asian men and did an atapose
01:38:40.960 subcutaneous biopsy and it found that the average South Asian man had
01:38:46.480 atyposytes that were about four times larger volumetrically than the fat cells in the Caucasian at the same body size
01:38:53.600 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
01:39:00.080 up what is more problematic about fat storage storage. It’s not the mass of fat that matters most, but the size of
01:39:06.320 each fat cell when it comes to slow insulin resistance and the consequences of too much fat mass. And this explains
01:39:13.040 why say an East Asian fellow will just be moderately overweight
01:39:19.040 compared to his obese Caucasian counterpart and yet he has all of the
01:39:25.040 complications of insulin resistance and this guy just doesn’t look good in his speedo and is otherwise fine
01:39:30.239 metabolically. It’s because his fat cells are small because he has so many of them. His fat cells are so few, but
01:39:36.880 they’re much larger. And so he has a lower body fat mass, but it’s more harmful because his fat cells are
01:39:42.719 bigger. And that is the problem with visceral fat. The main there’s nothing
01:39:47.920 inherently pathogenic about visceral fat. Those fat cells aren’t mystically
01:39:53.360 harmful. It’s just that that visceral cavity is so limited in volume that it
01:40:00.000 only allows fat growth through hypertrophy because that is a way to limit the total amount of fat you can
01:40:05.840 grow. If our visceral fat was able to grow through hyperlasia, then it may
01:40:11.119 expand so much that it starts to compress our our tissues. It starts to squeeze the liver or squeeze the
01:40:17.679 intestines or squeeze the kidneys. And so by only allowing visceral fat to grow through hypertrophy, you do limit how
01:40:24.800 much it can grow, but it also becomes much more pro-inflammatory because hypertrophic fat cells release a lot
01:40:31.360 more pro-inflammatory cytoines than smaller hyperlastic fat cells. So
01:40:36.800 there’s very much a genetic ethnic component to this that influences how
01:40:42.239 ethnicities are able to stimulate the growth of new fat cells. And then there
01:40:47.760 is there’s absolutely a sex component to it as well which of course is still genetic where women because of the
01:40:53.920 effects of estrogens are able to stimulate a higher degree of hyperplasia than her male counterparts are. And so
01:41:01.520 women will have that ability to and this explains why the average woman both has higher fat than her male counterpart and
01:41:08.320 yet is healthier in every single cardabolic metric. If it was just a matter of fat mass, then women should be
01:41:14.639 dying more from all these cardioabolic diseases. And yet, they’re not. It’s men. Because women will have more fat
01:41:20.960 cells, but smaller because of estrogens. Men have relatively lower levels of estrogen. So, we don’t have that
01:41:26.960 hyperplasia as much as the females do. So, if we’re getting fatter, it’s more through hypertrophy relative to the to
01:41:34.880 the ladies. Um so with respect to these hyperplasia versus like hypertrophy fat
01:41:36.000 No text
01:41:40.960 cells and I probably should have mentioned the visceral fat the fat lining the organs. You mentioned the
01:41:46.080 visceral cavity is so this this fats usually like the lining the organs and you usually find it around the midsection
01:41:51.679 as well. But um you mentioned the the fact that the the
01:41:57.600 the fat in the atapost tissue will become insulin resistant to basically shut down growth like as a response like
01:42:04.400 an adaptation like okay we got to stop growing. What about spillover of fat? like is
01:42:10.080 this feeding into that whole ceramide pathway that you started to talk about where is is visceral fat and is this you
01:42:16.400 know this hypertrophy like swollen fat cell also causing more camides to go
01:42:22.080 into your system. Right. I’m I’m so happy you brought that up. I did I deliberately chose not to cuz I thought I’m already being too
01:42:28.159 long-winded, but here you are slow pitching the the ball to me anyway. So yeah, the problem with that hypertrophic
01:42:34.719 fat cell is that it’s becoming insulin is trying to still force-feed it to
01:42:40.400 store more fat and insulin’s main mechanism of promoting fat storage is by
01:42:45.840 inhibiting lipolysis. So insulin will promote the growth of the fat cell. It does enable the feeding to some degree,
01:42:52.719 but its most powerful effect is blocking the breakdown. And so the fat cell is saying insulin, I can’t keep you keep
01:43:00.159 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
01:43:07.040 together. It’s like a balloon that’s being filled too much. And so, it becomes insulin resistant,
01:43:13.119 which is manifested as insulin not being able to inhibit lipolysis. Now, we have
01:43:19.040 a metabolic millu that’s quite odd, where you have
01:43:24.080 high insulin and high free fatty acids. That does not happen unless the fat
01:43:29.360 cells are insulin resistant. So just to make that clear, in a fasted state or a low carb state, insulin is low and so
01:43:36.639 you have more lipolysis. So free fatty acids will be higher. That’s a that’s a very common feature. This is the fasted
01:43:42.800 state. Low insulin, high free fatty acids. In contrast, the fed state, especially if it has some carbs, now
01:43:49.440 insulin has gone up. It’s inhibited lipolysis and so free fatty acids will be down. This is the normal. It’s one or
01:43:56.480 the other. Unless the fat cells are insulin resistant. Now you have high insulin reflective of insulin resistance
01:44:03.040 but it can’t inhibit lipolysis. Thus we have high free fatty acids. This is a
01:44:08.159 problem back to the ectopic aspect that you’d mentioned earlier where normally if free fatty acids are high the muscle
01:44:14.880 will just burn it and the muscle will happily burn free fatty acids or any tissue any cell with the mitochondria
01:44:21.520 would burn it. But if insulin’s elevated you can’t burn fat. um then fat burning
01:44:26.880 uh beta oxidation has been inhibited at virtually every single step with high insulin. So now we are storing more fat
01:44:34.159 as triglycerides which is the ectopic fat deposition. So that’s where you start to have fatty liver. In fact the
01:44:41.119 main cause of fatty liver is spillover from fat from fat cells especially
01:44:46.159 visceral fat. That’s the main origin of all that fat. As much as we talk about fructose and other nutritional variables
01:44:52.000 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
01:44:58.880 burn it. Normally, the liver would take those fatty acids and just say, “Well, I’m going to burn it into ketones.” But
01:45:04.800 if insulin’s elevated, it can’t happen. The liver has to store it. The pancreas starts to store it. But as I mentioned
01:45:10.719 earlier, the triglycerides are not the cause of insulin resistance. But now we have the high insulin, which is an acute
01:45:17.360 cause of insulin resistance. and a lot of free fatty acids and where some of those are going to be palmitate because
01:45:23.520 palmitate is some of the stored triglycerides you have pulmitate coming out that will directly be activating
01:45:29.840 TLR4 the receptor that’s going to then drive ceramides bio uh to be synthesized
01:45:35.360 so you have a lot and not to mention the inflammatory cytoines that are also being released from the hypertrophic fat
01:45:41.840 cell at the same time also stimulating ceramide acrruel thus we end up having
01:45:47.600 the perfect metab metabolic millu to promote insulin resistance and it all started because the fat cells got too
01:45:53.199 big and not to mention the the with the cytoine signaling you’re talking about now the chronic inflammation I mean
01:45:59.440 there’s studies now linking visceral fat to cancer you know and so it’s the brain
01:46:05.040 the cancer incidents it’s allosis cactive protein is a better predictor of heart disease and LDL cholesterol is
01:46:11.840 and and and the fat cell is the main source of a protein called plasmminogen
01:46:17.280 activator inhibitor one P AI1 whose main job is to erode clots as they form. So
01:46:23.440 why is it that bigger fat cells relate so well with stroke and and cardiovascular disease? Because you are
01:46:30.480 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
01:46:36.000 No text
01:46:37.840 and you know someone’s sex in terms of like male or female and how that affects
01:46:42.880 whether or not they’re going to have this you know predispos predisposition to forming more more fat cells or taking
01:46:49.040 that fat cell and just expanding it. What what other factors play a role because I mean you know is there a
01:46:56.719 dietary is there you know some other some other factors that are that are also contributing to that. There is yeah
01:47:02.480 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
01:47:09.840 they can contribute to insulin resistance through a secondary route by influencing the dynamics of the fat
01:47:16.320 cell. Specifically, when linoleic acid is taken into the cell, one of its
01:47:22.320 peroxide metabolites that it can turn into is a molecule called 4 H&H
01:47:28.400 has been shown to inhibit the fat cells potential for hyperplasia, thus forcing
01:47:34.560 the fat cell to only go down hypertrophy. So if there is some nutritional link that can drive fat cell
01:47:41.840 storage into one versus the other um linoleic acid does have that effect.
01:47:46.880 Linoleic acid being converted to 4H and E will inhibit the atypogenic uh
01:47:52.159 hyperlastic signaling and only enable the hypertrophic signal.
01:47:57.199 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.
01:48:02.960 Yeah I for sure it would be. I don’t know. I can’t quantify the dose but yeah in general my view you and I were
01:48:09.440 chatting earlier linoleic acid is ubiquitous in nature you need it
01:48:15.199 remembering yes you have to have it so as much as I’m talking about it and invoking it as a problem
01:48:21.040 I’m I think it’s very appropriate for you to say yeah but it also like it’s in mother’s milk for goodness sakes it’s in every meat
01:48:28.000 source you’re and I’m a huge defender of meat I think meat is very healthy and yet you’re going to have linoleic acid
01:48:33.679 in I would maybe counter or not counter by just stating that those also in nature
01:48:39.360 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
01:48:47.280 you’re con and often it’ll have some degree even minuscule levels of vitamin
01:48:52.480 E. Vitamin E will help that linoleic acid not go down the pathway of
01:48:58.159 peroxidation. It’ll help it just go down the pathway of oxidation. Even Dr.
01:49:04.159 Steven Kunain, this incredible man, just a delightful individual, he’s done a lot
01:49:09.360 of work documenting the fact that linoleic acid when it’s allowed to just be burned for fuel burns so high and so
01:49:17.600 rapid that it create it allows the brain to create its own ketones. He has a fascinating area of research on this.
01:49:23.679 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
01:49:30.639 it in nature, it’ll come with an omega-3 and it’ll come with some amount of often vitamin E, which will help prevent the
01:49:38.080 linoleic acid from going down the pathway of becoming a villain, which it can. Um, linoleic acid will undergo
01:49:44.480 peroxidation very readily and become a very harmful series of metabolites that are harmful to cell membranes and
01:49:50.719 mitochondrial membranes. Is that is that though more because I you know I’ve looked a lot at the literature here and
01:49:52.000 No text
01:49:56.239 I remember I first was I was submitting a paper and I was going off about how
01:50:01.360 terrible omega6 high omega6 and you know it wasn’t necessarily from seed oil but
01:50:06.880 it was kind of going that way and um and a reviewer just kind of just got me hard
01:50:12.800 and I started to really have to look at this with a different perspective and go into the literature and
01:50:18.320 um I really was shocked by how much of the literature is showing with these,
01:50:25.360 you know, lenolic acid and even, you know, switching saturated fat with these polyunsaturated fat seed oils, um, were
01:50:32.080 either neutral or beneficial, um, with the exception of like maybe one study, but like the bulk of them were
01:50:38.080 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
01:50:45.119 oils and when you start to heat them especially if you’re like heating them very very high temperatures or you’re
01:50:50.159 heating them over again where they’re becoming problematic at least at least with respect to some of the biomarkers
01:50:56.239 that were being looked at like inflammatory biomarkers. Um, so I’m wondering like is is the heating the
01:51:02.159 seed oils the bigger problem? The consuming them in this really concentrated form and heating them and
01:51:08.080 the whole package that they’re, you know, the friends that they’re they’re bringing along, right? People are consuming these seed oils in
01:51:14.159 processed foods, right? They’re all in processed foods um versus eating some, like you said, meats, you know, walnut.
01:51:20.239 I I mentioned nuts because they have a higher ratio, but they also, you know, have omega-3s as well. So, I do think
01:51:26.239 it’s a nuanced topic as well, but I don’t want people to like be so scared of just anything with linoleic acid,
01:51:32.480 right? No, and I totally agree. I would also just say I’m also not the person to tackle the seed oil topic. There would
01:51:39.760 be other people who would be way more articulate on both sides, attacking and defending. I’ve only tried to view that.
01:51:47.199 I’ve tried to kind of stay in my lane, which is I’m an insulin mitochondria guy. And in that that’s why I’ve tried
01:51:54.560 to be a little cautious because as much as people will invoke linoleic acid for causing all heart disease, all fatty
01:52:01.280 liver disease, etc. I just sort of say, okay, great. That’s not my forte. I’m looking at it in the context here. Uh,
01:52:08.159 of I’m looking at metabolic outcomes. So having said all of that, I think what
01:52:14.719 you just said is what I would agree with in that I think it’s appropriate to
01:52:20.239 scrutinize seed oils because of how we eat them. Um, we eat them from refined seed oil sources. Dr.
01:52:27.199 Christopher Ramston at the NIH a number of years ago published a report finding that soybean oil has become the number
01:52:33.119 one consumed source of fat calories in the human diet. That’s not good. And so I think it’s appropriate for us to call
01:52:39.920 them seed oils rather than linoleic acid coming from all natural animal sourced
01:52:46.320 foods, which I’m always an advocate of. Dairy has linoleic acid in it. Meat has linoleic acid in it. They all do. Seeds
01:52:52.560 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.
01:53:00.239 And those help to varying degrees reduce the pathogenicity. Even if the linoleic acid was had the potential to be
01:53:06.960 harmful, which it does through peroxidation more than the other fats do, these other characters that are
01:53:12.159 coming along with it help it behave and act in a way that we want it to act because it is everywhere. It is
01:53:19.199 ubiquitous. And so I think where you and I would agree and maybe others would disagree, I don’t have a fear of
01:53:26.080 linoleic acid per se as an omega-6 in so far as it’s going to come in every natural
01:53:31.599 source of fat that I’m eating. But where earlier I’d said control carbs. If
01:53:37.280 you’re controlling your carbs by, and pardon me for repeating again, not getting your carbs from bags and boxes
01:53:42.800 with barcodes, you’ve also eliminated essentially all of those refined seed oils from your diet, too. And that’s why
01:53:49.440 I also don’t like getting caught up in the is it seed oil or carbs. They always these refined carbs, they always come
01:53:55.920 together. So as much as I am the guy who’s saying, “Well, refined starches and sugars are a real problem.” And ever
01:54:01.840 someone else would say, “No, it’s the seed oils.” And I’d say, “You know what? Fine. They’re coming together anyway.”
01:54:08.000 Uh because it’s it’s in that it’s you opening up that pack of chips or treats or some refined snack that’s going to
01:54:15.840 have the first ingredient is going to be a starch that’s it’s the potato chip, you know, as it’s been fried, but what’s
01:54:22.000 it been fried in? It’s been fried in corn oil or whatever. So you not only have a concentrated source of omega-6,
01:54:27.920 but it’s undergone this superheating and now it’s absolutely gone through some peroxidation. So, if the person’s just
01:54:34.800 eating whole fruits and vegetables and natural sources of fats and proteins, you’re going to get linoleic acid. And I
01:54:41.520 would say there’s no reason to fear it. Um, yeah. I I think also it it can be a
01:54:46.719 distraction if you’re if you’re not focusing on like avoiding avoiding the refined carbohydrates, avoiding the
01:54:52.080 refined sugars, making sure you’re getting exercise, making sure you’re not overeating, like all those things. And
01:54:57.199 then like I look, full disclosure, I don’t cook with seed oils. I don’t cook with them. I don’t use
01:55:03.040 them. Um, but I will say that an unbiased look at the literature, I still
01:55:09.199 think uh I don’t I think cooking them I think heating them I I would stay away from that for sure. But um if someone
01:55:15.360 wants to put a little bit of, you know, of this uncooked oil on their salad, do
01:55:21.040 I think it’s like the worst thing in the world? I’m not sure that it is. I don’t either based on the current evidence. But, you know, at the end of
01:55:28.000 the day, I think that that person’s probably already doing things right, and that’s really what matters. So, that’s
01:55:33.760 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.
01:55:39.440 Yeah. If there’s if there’s a a researcher doing that, I’ll look into that. Um, but kind of going back to this
01:55:43.000 No text
01:55:44.639 fat cells and shrinking. And you you were talking about the the adiposites kind of becoming insulin resistance
01:55:50.560 first. Insulin resistant first. And and that kind of leads into something that I I forgot I wanted to ask you about as we
01:55:57.199 were talking about some of this before and that is, you know, insulin resistance doesn’t happen at the same
01:56:02.880 time in all tissues and and so it’d be kind of nice to just talk about that briefly while we continue on in terms of
01:56:10.080 like the muscle, the atapost tissue, the liver. Um what happens when each of
01:56:15.360 those become insulin resistance? Um insulin resistant and you also talked about atapost tissue. Yeah. Yeah.
01:56:20.719 Maybe first is that then contributing to the other ones then becoming insulin resistant. Yeah. Yeah. So I absolutely so there are
01:56:27.119 people who would say no the fat is first when it becomes so what what is the first domino if if
01:56:32.639 it’s a sequence of tissues which is the first to fall when it comes to here’s the person healthy here they’re
01:56:38.719 progressing through insulin resistance with type two diabetes being the most obvious outcome at the end of it. What’s
01:56:44.719 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 uh in my view
01:56:52.400 very strongly it’s the fat tissue. Um so insulin resistance in its earliest
01:56:58.560 stages is high insulin but normal glucose. The problem with invoking a fat
01:57:04.639 a muscle centric view or a liver centric view or I need to add one an alpha cell
01:57:10.320 centric view because that’s also relevant of the pancreas for a reason I’ll I’ll touch on in a moment. The
01:57:15.520 moment those become insulin resistant, glucose is not going to be controlled anymore. And and so then you skip a step
01:57:22.080 because insulin resistance, if you look at the progression of the person towards type two diabetes, the insulin has come
01:57:27.920 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
01:57:34.800 view is the fat cell falls first. It’s the first tissue to become insulin resistant as it starts to experience
01:57:41.280 some degree of hypertrophy. that then starts to
01:57:47.599 facilitate the other tissues becoming insulin resistant. And at that point, there’s no order in my mind. It’d be
01:57:53.280 hard to distinguish if there’s another order. But I actually when I teach this very idea to my students, I one of my
01:57:59.679 undergraduate assignments is a class called pathophysiology. And these kids are fortunate enough to learn the true
01:58:05.119 origins of type two diabetes from an expert. But I actually show the fat cell first and then the next step I say I
01:58:12.880 teach it in this concept of all right well what flips the switch from pre-diabetes insulin resistance to type
01:58:18.560 2 diabetes. What is it that makes the glucose go up? That is then when the muscle becomes insulin resistant. You
01:58:24.800 have lost access of the main glucose consumer. So you are you’re clearing the
01:58:30.239 glucose out far of the blood far worse less readily than you were before resulting in a hypoglycemia. When the
01:58:36.800 liver becomes insulin resistant, insulin can no longer inhibit glycogenolysis.
01:58:42.480 So normally one of the mechanisms whereby the liver works with insulin is
01:58:47.679 by storing glucose as glycogen. Insulin inhibits the breakdown of that glycogen
01:58:53.840 unless the liver has become insulin resistant. Now the liver is breaking down glycogen and releasing it as
01:58:59.199 glucose even when insulin is attempting to tell it not to thereby further compounding the hypoglycemia. Then the
01:59:06.400 last one is the most overlooked but absolutely relevant which is the alpha cell. The alpha cell is the yin to the
01:59:14.400 beta cell’s yang where the beta cell releases insulin and insulin’s most
01:59:19.440 famous job is to lower blood glucose. The alpha cell releases glucagon and its
01:59:24.560 most famous job is to increase blood glucose. So it’s very important for fasting and exercise. The opposite of
01:59:30.400 when insulin would be up basically. But the alpha cell knows when to not release
01:59:36.320 glucagon when the beta cell is releasing a lot of insulin because insulin and their nextoor neighbors within the
01:59:42.480 eyelets of the pancreas. Insulin will flood the beta cell with rather ins the
01:59:48.480 beta cell will flood the alpha cell with insulin and insulin will inhibit the production of glucagon which is good
01:59:55.199 because then that helps insulin overall affect blood glucose to bring it down. But the alpha cell can become insulin
02:00:01.119 resistant. Dr. Roger Unger at UT Southwestern over years published a series of mind-blowingly cool papers
02:00:08.960 finding that in type 1 diabetes if you just control the glucagon excess you
02:00:14.800 don’t even need to give the patient insulin that you could correct all hypoglycemia by just inhibiting the
02:00:20.320 glucagon. So that’s just a weird little feature of the fact that when the alpha cell becomes insulin resistant and it
02:00:27.119 does it starts releasing uncontrolled glucagon which comes to the liver and
02:00:32.480 once again is telling the liver to make glucose and release it into the bloodstream. So the fat tissue becomes
02:00:39.520 insulin resistant first that facilitates the insulin resistance of the glucose
02:00:45.040 controlling tissues muscle, liver and the alpha cells. And when those start to become insulin resistant in any
02:00:51.199 particular order, that’s when you start to see the gl the glucose start to climb. But we know decades potentially
02:00:58.880 before the person ever starts to have hypoglycemia, they have hyperinsulinemia.
02:01:04.159 That’s why I think the fat cell is subtle enough in its metabolic demands that it doesn’t really need a lot of
02:01:10.159 glucose. Its metabolic rate is so modest. So it can become insulin resistant without really affecting
02:01:17.040 fasting glucose levels. So the person’s fasting glucose levels can stay normal. But once the glucose handling tissues
02:01:23.440 like the three I’ve already articulated become insulin resistant now glucose is uncontrolled.
02:01:29.000 No text
02:01:29.040 Going back to the this fat cell hyperplasia like a lot of you know forming lots of different fat cells
02:01:35.520 versus this you know swelling of it the hypertrophy. If a person loses weight, like let’s let’s say they’re they’re on
02:01:42.960 a weight loss diet. They’re, you know, doing restricting their calories, they’re doing low carb, they’re exercising, any of the combination of
02:01:49.920 those. What happens to the fat cells? Do they shrink? They shrink.
02:01:55.360 They shrink. Do you ever do they ever die? They do. Yeah, they do. Yeah. But they shrink. So, I actually say when I talk
02:02:01.520 about this in my class, I say the patient’s on a fat cell shrinking journey. That’s exactly how I describe
02:02:06.719 it because that is weight loss. All weight loss is shrinking of the fat cells.
02:02:12.400 Now, however, a fat cell has a lifespan of about 10 years. And so, depending on the utility of that fat cell, it may not
02:02:19.199 be replaced or it may be replaced. And so, you can over time lose fat cell number. And indeed, you do. At around 60
02:02:26.719 years old, 60 to 70 a person. So, during infancy, childhood, puberty, we’re
02:02:32.480 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
02:02:39.520 I said earlier but even then you could have a person who gains a hundred more pounds or 200 more pounds in adulthood.
02:02:46.880 For the the for the average individual that’s hypertrophy not a result of hyperplasia. But then when we get to
02:02:52.880 older age then the number of fat cells stop turning over. So as they start dying at their 10year lifespan we don’t
02:02:59.840 replace them. And so at the end of life we have a little drop off in the number of fat cells. Uh um so no so weight loss
02:03:06.960 is shrinking the size not changing the number. And in fact if you force
02:03:12.080 artificial weight loss by sucking out fat cells where you are just sucking out
02:03:17.360 the fat cells and reducing fat cell number then you don’t improve any cardioabolic outcome whatsoever. So
02:03:23.840 there’s many studies that show that you can have people lose a significant amount of fat through liposuction and
02:03:29.679 there not a single outcome has improved. Whereas if that same person had lost that 20 pounds of fat through normal
02:03:35.920 lifestyle interventions like you’d mentioned, they would have had improvements in every cardabolic outcome. But you don’t do that with
02:03:42.400 liposuction because you haven’t changed the size of the fat cell. The size of your fat cells is the same. You’ve just
02:03:48.080 sucked out a lot, but the remaining ones are still there. And now in fact you’ve
02:03:53.199 put a greater pressure on them because a person an adult doesn’t make new fat cells very readily. So what will happen
02:03:59.760 is the remaining fat cells will be forced to grow through size because they can’t share the burden with their other
02:04:05.599 neighbors that you’ve sucked out already. So when a person starts to regain weight the cardioabolic outcomes
02:04:11.840 are amplified. When when people do um lose weight and they’re shrinking their
02:04:13.000 No text
02:04:17.199 fat cell size, are those fat cells like let’s say someone was even insulin resistant, right? And there’s a
02:04:23.440 problematic fat cell and it shrinks in size. They lose weight, it shrinks in size. I mean, is
02:04:29.199 it still problematic? No. No. No. In fact, that’s why with the slow insulin resistance, the reversal of that
02:04:36.159 like over the 90 days in the type 2 diabetic patients that we had in our published case series, uh that would
02:04:43.119 have been not that we measured this, but it would have been because of a shrinking of the fat cell. Now, let’s
02:04:48.480 say they grow those fat cells again, the same problems will come back. So
02:04:54.000 whatever intervention, one of the problems I have with diet, whatever the intervention is, low carb or, you know,
02:04:59.679 calorie restricted, whatever, people will complain and they’ll say, “Well, but it’s only short term.” Yeah, of
02:05:05.440 course it is. Um, whatever a person has done to reverse their metabolic problems
02:05:10.800 will only persist as long as they adhere to those changes. Uh, the more they go
02:05:15.920 back to their old habits, the more the same consequences will return because it was those old habits that caused it.
02:05:23.000 No text
02:05:23.119 with respect to the visceral fat and I mean I particularly the visceral fat since it’s the fat that’s really got
02:05:29.040 that expansion of the fat cells it can only go through hypertrophy right only going through hypertrophy
02:05:34.560 what what sort of targeted diet lifestyle interventions would be
02:05:40.719 suggested or evidence-based to to actually decrease the visceral fat yeah that’s a great question so visceral
02:05:47.199 atyposites are more responsive to the lipolytic signal the fat breakdown signal of epinephrine. So, anything that
02:05:54.560 increases epinephrine will have sort of poundfor-pound or sight for sight visceral versus subcutaneous is going to
02:06:02.320 have a better visceral response. Um, so the more the epinephrine is being targeted, so that’s going to be things
02:06:07.599 like exercise and like cold therapy, for example, cold immersion, talked about an epinephrine spike. So anytime you’re
02:06:15.119 really activating the sympathetic nervous system, you’re going to be sort of molecule for molecule, cell for cell,
02:06:21.760 targeting the visceral more than the subcutaneous. So it is more responsive to that sympathetic tone than
02:06:28.400 subcutaneous fat is. Interesting. So epinephrine, high-intensity interval training is really like more intense exercise.
02:06:34.719 Again, back to that and then yeah, deliberate cold exposure. Another one. Great. And I’m a big advocate of cold
02:06:40.079 immersion. Great. Yeah. Okay. Well, that’s interesting. Um, I didn’t know about the ep the the fact that epinephrine was was
02:06:45.920 linked to that as a as a mechanism. Okay. So, uh, a little bit about we talked a little bit about the the muscle
02:06:48.000 No text
02:06:52.000 mass and I think just the the the one thing that was kind of on my mind was that sort of
02:06:58.239 anabolic paradox of insulin. Yeah. And and kind of what your thoughts are with respect to like you know some
02:07:03.280 bodybuilders are injecting insulin, right? Um, so how Yeah. like let’s let’s talk about a
02:07:09.199 little bit like reconciling insulin’s role as being this you know anabolic versus you know storing fat being
02:07:15.520 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. Um
02:07:23.119 but because I’m familiar with insulin I’m comfortable enough answering this question. So there was a group in fact I
02:07:30.239 think it was the same guy I mentioned earlier Shrinire NI at Minnesota at the time. They published a paper finding
02:07:37.840 that insulin wasn’t necessary for muscle protein synthesis. So, so you have the
02:07:43.920 here we have the muscle and we have the protein formed giving the the bulk of the muscle. There’s you have to look at
02:07:49.679 both the stimulus building it and the signals that are breaking it down. They
02:07:55.119 documented that insulin was not necessary for muscle protein synthesis but it was very helpful for inhibiting
02:08:01.599 the breakdown. So it they suggested that insulin’s main effect on muscle is an anti-p proteolytic effect rather than a
02:08:09.760 stimulating effect. So that my general view is that that’s where insulin is going to be favorable. But it also
02:08:15.679 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
02:08:23.679 intervention to try to promote muscle growth. And in fact, just as a very
02:08:29.040 unscientific observer, when I compared the physiques of Arnold and Lou from the old 1980s bodybuilders to the modern-day
02:08:35.920 bodybuilders and the almost bizarre phenotype of this like bubble belly, do
02:08:42.000 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
02:08:47.679 can all agree that there’s an odd physique. You know, whereas Arnold and Lou were extremely tapered, very, very
02:08:54.880 narrow waist. Modern bodybuilders, yes, they’re more jacked, but they’re also
02:09:00.480 oddly distended with their abdomen. I can’t help but wonder whether insulin
02:09:05.840 has been somehow facilitative to promoting some degree of visceral growth because insulin wants to promote fat
02:09:12.159 growth. It wants to, no matter, it’s like a fertilizer for fat cells. And so someone who’s who’s wanting to overdose
02:09:19.520 on insulin in an effort to promote muscle when you’re just maybe enhancing some proteolytic antipolytic effect, I’d
02:09:26.800 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
02:09:32.560 focusing on growth hormone than you would injecting yourself with insulin. So I am not a fan. Now I appreciate some
02:09:38.400 big yolked bodybuilder looking at relatively spelty small Ben Bickman and saying, “Well, what do you know? Maybe I
02:09:43.840 don’t know a lot.” Um, no, I I think I think that was a that’s a really good
02:09:48.960 those are great points that you made. For sure. For sure. Um, I think we covered a lot of the muscle effects on
02:09:53.000 No text
02:09:55.280 insulin and, you know, how exercise is so important, growing muscle tissue and exercise is important for, you know,
02:10:01.040 allowing the muscle to be that, you know, site of glucose disposal. Um, but let’s kind of then shift gears and talk
02:10:07.599 about this weight loss. And obviously I think right now there’s a big trend in
02:10:14.800 rapid weight loss and and weight loss that’s made very easy um by taking GLP1
02:10:20.639 agonist drugs like Ozic and Wiggov. And I I’d love to to know what your thoughts
02:10:27.840 are on maybe first you can explain just you know generally how these GLP1
02:10:33.280 agonists work and why they’re causing weight loss and how they affect metabolic health but
02:10:40.000 also whether they’re addressing the underlying root cause of obesity.
02:10:45.760 Yeah. And you know if if or if there’s sort of shortcutting around that. Right. Well, there’s no no no question.
02:10:51.840 It’s it’s a bit of a shortcut and I am I’m worried about the long-term effects.
02:10:56.880 So, with GLP1, I have had my finger on the pulse of GLP-1 probably since well,
02:11:03.199 not since the its inception, but since the late 90s, early 2000s. My PhD lab
02:11:08.560 was one of the first labs funded in the US looking at the study of incrretins by
02:11:14.079 a drug company. And so I’ve I’ve long been familiar with GLP-1 and the other incrretins. Incrretin being a word to
02:11:21.040 describe these gut derived hormones that have metabolic effects. But it’s been interesting for me to note
02:11:27.599 the evolution in their use because originally they were only used as antid-diabetic drugs
02:11:35.040 and then the what was considered kind of an offtarget effect of controlling satiety is now the mechanism of action
02:11:43.040 at these much higher doses as the dose has been multiplied up to the kind of current WGO weight loss dose. So it’s
02:11:49.520 really just been an evolution in the dose of this of semiglutide for the most part although there are other glutides
02:11:56.000 that fit in this as well but semiglutide is the main one. So at the lower dose
02:12:02.320 originally used these GLP1 activators worked actually by inhibiting glucagon.
02:12:08.159 So back to the alpha cell that I mentioned earlier, it’s we come back to them now where in type two diabetes, the
02:12:14.800 insulin resistance of the alpha cell results in a chronic elevation of glucagon chronically then telling the
02:12:21.840 liver to be releasing glucose leading to the hypoglycemia that defines the diabetic state. At this low dose,
02:12:28.480 semiglutide inhibits the alpha cell. It inhibits glucagon and by inhibiting glucagon, you’re helping correct blood
02:12:35.119 glucose. So it was an effective anti-diabetic. Now some people have the very mistaken
02:12:41.360 view that semiglutide or GLP-1 activators also release insulin. That is not true. That has been shown to happen
02:12:49.360 in isolated cell cultures. But in humans there’s no evidence. And the authority on the subject is a guy named Arie. A r
02:12:57.360 nestrop. A s t rup p. Arie ostrop in uh in Denmark. He’s one of the absolute
02:13:04.719 authorities on this topic. He’s published multiple papers in humans showing that no amount of GLP-1 elicits
02:13:10.800 an insulin release. So that we need to put that idea to bed. In humans, that does not happen. GLP-1 does not act as
02:13:17.599 what’s called an insulin secret or a hormone that a drug that forces the beta cell to make insulin. GLP-1 inhibits
02:13:25.119 glucagon, which helps correct blood glucose. Now as the dose starts to go up higher just I guess just for the sake of
02:13:32.800 time I’d mention two effects which is one in the guts and then one central
02:13:37.920 within the intestines GLP-1 will act to delay gastric emptying and slow
02:13:43.599 paristalsis. So that has the effect of a person eating and having that bulk sit in their
02:13:50.719 stomach much longer which is going to generally discourage them from wanting to eat more. At the same time, it’s
02:13:56.880 going to take a lot longer to get through the intestines. Now, that is good for weight loss because it forces
02:14:03.440 them to eat less. A consequence of that is it ranges from the uncomfortable to
02:14:09.679 the problematic. So, on the uncomfortable side, the person will have food that’s sitting in their stomach for
02:14:15.440 up to 20 hours. And so, they will start burping a lot. And they will have like people who go through general surgery
02:14:22.560 and have to be put under for general anesthesia. They found that normally you tell the person don’t eat for 24 hours
02:14:29.040 and their stomach’s empty. So they’re not going to vomit food up while they’re um asleep. But when they found that if
02:14:34.719 people were on these were on semiglutide the food was still there and they would still have food in their stomach even
02:14:40.239 though they hadn’t eaten for 24 hours. So this results in what people colloquially just call ompic burps where
02:14:46.320 they just have putrid breath and burping and just stomach nausea. But because of
02:14:51.760 the change in gastric emptying even some medications like birth control
02:14:57.440 medications don’t work anymore for example because you’ve so changed how long it takes that drug to get from the
02:15:04.560 stomach into the the small intestine where it would have been absorbed. So it starts to change the absorption of
02:15:10.320 certain compounds and drugs as well as potentially affecting the absorption of nutrients which may be part of what the
02:15:18.480 person is observing with regards to other changes in say muscle mass. Maybe that’s a result of just poor nutrition
02:15:24.960 because even though they’re eating they might not be getting they might not be digesting and absorbing everything
02:15:30.000 they’re eating anymore because of how the the rate of the the paristalsis has
02:15:35.119 changed so much. So anyway, numerous changes of the guts and then there’s a central nervous system effect to
02:15:41.520 activate satiety centers. Now the combination of those two is powerful where you have the I’m full signal here
02:15:49.440 and I have a lot of stuff in my stomach here resulting in a person who has a much better control over their appetite.
02:15:57.119 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.
02:16:04.639 So that’s the main mechanism of action and and GLP-1 is a normal hormone. I didn’t mention this. GLP1 is a naturally
02:16:10.560 produced hormone from the gut. We have it. We know that we can change its levels based on what we eat. And that
02:16:17.119 might explain why some people eat more and some people eat less. But still, my
02:16:20.000 No text
02:16:22.480 concern is that the dose of GLP-1 that we’re using now has gone. It’s just a little too much of a good thing.
02:16:28.960 What is the dose range that you were referring to talking about? Yeah. Yeah. So I think that the commonly
02:16:36.320 used doses are going to be in the order of actually in this case it’s I know it
02:16:41.599 in milligrams I think it’s about five milligrams or so 2 and a half plus
02:16:46.879 milligrams and a once weekly injection and if people are thinking of that in
02:16:52.320 units I think that’s going to correspond to units of about 25 to 30 units of of
02:16:58.638 GLP-1. So that to me is is too high and and two and a half milligrams being
02:17:03.760 the low dose. That is the Yeah, that that’s the low dose of what is used now, right?
02:17:09.840 And and the underlying the the addressing obviously this was these were used for
02:17:10.000 No text
02:17:15.840 like you mentioned this was a you know diabetes drug, right? I mean this wasn’t
02:17:20.959 necessarily meant to treat obesity. Yeah. Right. Um but I guess that it all depends on
02:17:26.478 you know the cause of obesity. Overeating is partly partly a cause of obesity. So, oh no, for sure it is. Yeah. In fact, I
02:17:33.200 am as as much as people will hear me describe this and think that I’m being just universally opposed, I actually do
02:17:38.879 think there’s a place for these GLP-1 drugs, a paper was published in 1996
02:17:44.000 that looked at the changes in GLP-1 in two populations. They took otherwise healthy humans and split them up in and
02:17:51.599 they noticed changes in the obese group and the lean group. So when they gave both groups a highfat meal, they looked
02:17:59.200 at the GLP-1 response and it was roughly similar in both groups that whether they were obese or lean, they ate a highfat
02:18:06.240 meal and GLP1 was the same a heavy overlap suggesting that the satiety
02:18:12.160 effect of that meal would be roughly equal. Now I’m speculating a little bit there. I’m adding that last part in. So
02:18:18.320 if you look at the GLP-1 response, given GLP-1’s effects on satiety, which is very meaningful, the highfat meal
02:18:24.320 elicited a similar response regardless of body fat mass. However, when they
02:18:29.599 gave them a high carb meal, the lean group had a huge increase in GLP1. The
02:18:35.281 obese group had no statistically significant response whatsoever. There was a little noise, but the error bars
02:18:41.120 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 a significant
02:18:48.080 increase suggesting that you may now have two people who sit down to eat a
02:18:53.360 meal. One person eats that carbohydrate heavy meal and they have a big GLP1 response. They pat their tummy and slide
02:19:00.879 the plate away. The other person eats that same amount and asks for seconds or
02:19:07.440 even thirds because they aren’t getting that GLP-1 response. So to me, the best
02:19:12.638 use of these drugs in the context of weight loss isn’t for weight loss per se, but it’s rather to acknowledge some
02:19:20.558 people aren’t going to get that off switch when they eat carbs in particular that apparently people responded the
02:19:26.638 same way to fat, but they are not. There are differences in how people respond to carbohydrates with GLP-1. This study
02:19:32.558 made it very, very clear. It was published in the journal Gut in 1996.
02:19:37.679 To me, that’s the best use of the drug to say the physician or the clinician,
02:19:44.000 the expert would be talking with the overweight patient and they would say, “You know what? You need to control
02:19:50.240 carbs. These refined sugars and starches. You got to eat less of them.” And the person says, “Yeah, but that’s the problem. I can’t eat less of them.
02:19:56.880 I’m addicted to them.” All right, let’s use a low dose. And this gets into that range of, you know,
02:20:03.920 5 to 10 units or uh 0.05 005 to one gram milligram
02:20:09.200 milligram that yeah milligram per week that is going to be like kind of a micro dose level to me that’s the best use
02:20:17.200 where the physician the expert the clinician is saying let’s just give you a low low dose of this drug and it’s
02:20:23.040 going to and I want you to think of it as helping you control your cravings because what do people crave people
02:20:29.120 don’t crave a plate of bacon and eggs they don’t crave a handful of of walnuts they crave something sweet and gooey or
02:20:35.920 salty and crunchy. And usually it’s going to be potato chips, crackers, cereal, ice cream. And that’s what we
02:20:42.479 want to help them control. So rather than saying this is a weight loss drug, let’s what if we changed the
02:20:47.840 conversation and said this is a drug that is designed to help you change your eating habits. While you’re on this low
02:20:53.520 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
02:21:00.000 cravings and these these refined foods that you’re always eating and then you
02:21:05.840 get them back three months later. Ideally, they say, “Boy, for the first time, I can control my cravings and I’m
02:21:12.479 doing better and I’m losing weight.” Then I would say, “Let’s see what happens when you cycle them off and say,
02:21:18.319 “All right, you’ve learned how to what it looks like and what it feels like to eat differently. Let’s see whether you need to still be on this micro dose.”
02:21:24.640 Maybe they need maybe they’re done. I know people who have done this and they say it changed me and I’ve it’s been a year and I’ve not gone back to my old
02:21:30.720 habits. It just helps them rewire their habits. In 90 days is a good length of time to change your habits. So at 90
02:21:37.600 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 one or
02:21:44.800 something. But basically, my view without having it outlined as a specific protocol would be micro dose and
02:21:52.720 cycling. Let’s put you on it with the intention of helping you change your habits. Let’s take you off it to see
02:21:58.640 whether the habits have stuck. If they haven’t, let’s cycle you back on. But always using these very, very low doses,
02:22:05.680 not for weight loss, but for changing habits. That’s interesting that um in your
02:22:10.880 experience, people can do this micro dose and after about 90 days, they can
02:22:17.040 keep the the appetite regulation under control. Because when you look at studies with people using you know the
02:22:23.600 clinical clinically relevant doses that they’re using now um of of these different GLP1 agonist um a lot of most
02:22:31.600 of the people end up gaining weight back because it you know they go back to their old habits. Yeah. And I think that’s because they’re
02:22:37.520 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
02:22:43.040 helping you change your dietary habits rather than this is just a magic bullet and you’re going to lose weight. I think
02:22:48.479 in that instance the person’s changed the way they’re eating, but maybe they’re not. This is I know kind of
02:22:53.600 getting into this hokey pseudo area of science perhaps, but when the conversation is focused on the habit, I
02:22:59.359 think it helps change habits. Oh, I mean, absolutely. The the the way you’re thinking about something
02:23:05.760 can change the outcome. Yeah, for sure. Um, I want to kind of go back to something that you mentioned that was
02:23:08.000 No text
02:23:10.880 very interesting to me and it has to do with the way, you know, this this food is sitting in your gut and the and the
02:23:17.040 way digestion’s kind of changed um, and perhaps, you know, nutrient absorption. I hadn’t really thought about it in that
02:23:23.680 way because I’m what I’m sort of alluding to is, you know, the I guess it’s pretty well known now is that when
02:23:29.359 people are rapidly losing weight, whether it’s on a GLP-1 agonist or it’s from caloric restriction,
02:23:36.960 they can lose a lot of muscle along with the fat. It’s not just all fat. um
02:23:42.000 particularly if people are not getting enough dietary protein which is a big signal for muscle protein synthesis and
02:23:47.760 if they’re not engaging in resistance training which is the other very important signal for growing muscle
02:23:53.760 mass. So um my question to you was going to be
02:24:00.319 you know is there kind of a way around this muscle loss by increasing dietary
02:24:06.640 protein? Obviously, the resistance training would be key. Um, perhaps even more key now because
02:24:12.240 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 depending on
02:24:18.080 the person and what their side effects and stuff are, but um, eating the protein and then like are they absorbing all the protein? I don’t
02:24:23.680 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
02:24:28.800 the use of sem. So, it’s very real. The evidence is very real showing one of the best looked papers in the New England
02:24:36.000 Journal of Medicine about 2 three years ago found that about almost 40% of the weight loss that a person was losing was
02:24:42.800 fat-ree 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
02:24:50.880 has determined whether it is a direct effect of the semiglutide. In other words, is the drug actually harming
02:24:56.479 muscle and bone or is it just an artifact of the poor nutrition? Um, it
02:25:01.840 might be a little bit of both, but it also might matter in the dose where I’ve heard reports. Um, in fact, my lab is
02:25:08.080 doing a muscle cell culture now looking at varying doses of the drug where it’s possible at a lower dose it’s
02:25:14.640 facilitative and at a higher dose it may be more catabolic when it comes to muscle um, muscle mass and the dynamics
02:25:21.840 of muscle protein synthesis. But even still, I’m as far as I’m aware, it’s unknown. Is it a direct effect of the
02:25:27.439 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.
02:25:34.000 They’re certainly not eating enough protein. Yeah. Um this is this kind of there’s another
02:25:38.000 No text
02:25:39.600 interesting point here and that is like GLP-1 receptors and I mean they’re all over
02:25:45.920 many different organs. The muscle has them and so does bone. Bone, right? Yeah. So that is that is an
02:25:51.359 interesting neurons do. Yeah. Yeah. I mean, and and it also starts to touch on the broader use of GLP-1 drugs where you and I both
02:25:57.200 know people are using them uh well beyond the as much as I bemoone the fact
02:26:02.720 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,
02:26:09.520 it’s a fertility drug. I I I just don’t know. In fact, as far as I am aware,
02:26:14.880 there’s very few studies to touch on that broader on the mechanism. And even
02:26:20.560 all of that could simply be an outcome of improving metabolic health because back to the origins or the beginning of
02:26:26.479 our conversation because metabolic health is so foundational to chronic disease. All of this could just be a
02:26:33.200 consequence of improving metabolic health. Um but it still is worth the pursuit of determining well maybe it is
02:26:39.680 a direct effect. Maybe there is the direct effect of the drug at the neuron or at the muscle cell um etc.
02:26:46.960 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
02:26:53.680 studies that have looked at, you know, people on, you know, various forms of
02:26:58.880 the GLP1 agonist. Yeah. And a reduced incidence of cardiovascular disease, obviously, type
02:27:04.319 two diabetes, Alzheimer’s disease. now and and you have to wonder like is is
02:27:09.680 this a is there a direct effect of you know agonizing these GLP-1 receptors on different tissues or is this just an
02:27:16.479 indirect effect of weight loss and improved metabolic health? Right. Yeah. Yeah. So I I don’t know but we
02:27:21.920 what I can speak to is our unpublished results right now in muscle cells we’re treating them with varying doses of semiglutide at the higher doses there is
02:27:31.040 catabolism of the muscle and they’re far less resilient and far more fragile. So we challenge the muscle with a chemical
02:27:37.439 challenge and they die way more readily at at used at doses used now at the
02:27:43.200 level you in which you see the dose in the the drug in the plasma. So it’s a physiological dose.
02:27:48.479 Okay. Well then this gets back to the micro doing and this is kind of you know I feel like um you’re talking you were
02:27:49.000 No text
02:27:54.800 talking about micro doing GLP1 agonist for a very different reason than I’m going to ask you about now. and you’re
02:28:00.640 talking about appetite regulation and and that I think that’s it’s super interesting um particularly
02:28:06.640 for people who don’t have real good control of their appetite or perhaps they’re I mean who know their hormones
02:28:12.160 are out out of whack right but there is now this sort of growing budding interest amongst you know many
02:28:19.840 people about this potential GLP1 agonist being a longevity drug because of these
02:28:26.160 different you know outcome studies that have been observational in nature right you’re looking at correlation here. But
02:28:31.760 the question is well like some people are now sort of starting to whisper about we think we think now maybe these
02:28:39.280 drugs are actually affecting they’re actually prolongevity and so micro doing
02:28:44.720 you know these drugs in the in the in the ranges that you’ve been discussing earlier might be a way of
02:28:51.600 getting the benefits and you’re also getting the side effect benefit of appetite regulation. So maybe you’re not
02:28:58.399 going to be eating as much as well. Maybe it’s just easier to not eat as much, right? Yeah. Yeah. So I I appreciate the
02:29:05.280 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
02:29:12.800 correlation because I’m a basic scientist. I want to do one thing and observe a direct effect from that one
02:29:18.000 thing. So one reason I am extremely cautious and even a little chagrined
02:29:23.120 with the entire realm of longevity is that it’s it’s not to disparrage it necessarily but it’s entirely based on
02:29:30.080 correlation when it comes to humans. We can only speculate and predict and model these sorts of things. Now I’m not
02:29:36.560 saying there’s no utility to that. But I also think it behooves us to be mindful of the limitation that comes with that.
02:29:42.880 So with GLP1 it in fact it’s worth noting another paper was just published
02:29:47.920 this week finding that the risk of blindness doubles more than doubles in people on
02:29:54.880 highdose GLP1s. It was just a paper was just published. So you look at the degree of blindness that occurs in
02:30:00.399 adults and those using the drug it was more than twice the risk of developing
02:30:06.479 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 I
02:30:12.960 truly don’t mean to suggest the drug is causing blindness no more than someone could say the drug is promoting
02:30:18.880 longevity. Although you actually can do a hard outcome with blindness. You can’t really do the hard outcome with when
02:30:24.240 does the person die very well. But there’s so many variables that get worked in here that I cannot say it’s
02:30:29.280 because of the drug. But it is worth another reason to have some caution that
02:30:34.479 what’s the point? So, so maybe we just come back to the dose that maybe that’s where we can find a common ground for
02:30:40.560 all the enthusiasts and those who are enthusiastic but also a little skeptical on on my end where I am enthusiastic but
02:30:48.240 I also just want to bring in a note of caution maybe where we do have that common ground is the dose. So with
02:30:55.920 regards to GLP-1 at the risk of seeing everything through a singular lens, one
02:31:01.680 of the most common variables that predicts longevity within families, there’s one paper that
02:31:08.640 actually mentions the word of of familial longevity. And then the longevity studies like the Amore study
02:31:15.120 in Sweden or the Honolulu aging study or the Shanghai aging study, some of the most consistent variables is
02:31:22.720 metabolic health. um optimal glucose levels and insulin sensitivity. In fact, that one study, I think it was in the
02:31:29.520 Mediterranean, that looked at families where you have a high number of centinarians, they found that the most
02:31:35.680 common theme was that they were all very insulin sensitive. And as much as people have a over the years there’s been an
02:31:41.680 ideology of villainizing protein as as a villain of aging because protein activates mTor and when mTor is too
02:31:48.560 activated, it promotes aging. I find that view uh unfortunate because for
02:31:55.760 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
02:32:02.240 have any anabolic, no retention of lean mass, let alone building it. But when you vilify protein because of mTor, you
02:32:10.319 ought to vilify insulin because insulin activates mTor much higher than even the
02:32:15.680 most anabolic amino acids like leucine does. And it keeps it active. One dose
02:32:20.720 of insulin can activate mTor for up to 24 hours. Whereas leucine, the most
02:32:25.760 anabolic of the amino acids, will only activate mTor for about an hour or two. And so if mTor matters for longevity and
02:32:32.560 I I know I’ve sort of contorted the whole thing about longevity here, all the more reason to come back to these
02:32:37.760 kind of metabolic first principles. And so looking at insulin sensitivity and glucose control and I would just say the
02:32:43.840 same thing with GLP-1. While we may find that GLP-1 has a direct effect of say
02:32:49.680 activating autophagy. Maybe it could and that could be a mechanism whereby it promotes longevity. At the same time, I
02:32:57.200 don’t have to go that far because I could just say, “Does it improve insulin sensitivity?” Okay, good. Then it’s
02:33:02.319 probably going to correlate and predict and even cause improved longevity because of the evidence we have in that
02:33:08.560 realm. So, yeah, what you’re saying essentially is that the improved metabolic health is
02:33:13.600 probably what’s driving the longevity benefits. And I would it’s at least low hanging fruit. Yeah, I I would agree that makes the most sense. Yeah.
02:33:19.439 Um, you know, and it is it is important to obviously keep everything in context as well. Obviously, there’s people that
02:33:20.000 No text
02:33:24.720 are obese and metabolically unhealthy that have really just change it’s changed their lives, right? Yep.
02:33:31.040 But the question is, do they have to keep taking it? Yeah. And in fact, 70% in the US, 70% of
02:33:37.840 Americans get off the drug at 2 years either because of cost or nausea or whatever, 70% stop taking it. And like
02:33:45.200 you said, when they stop taking it, if habits haven’t changed, maybe that’s an important caveat, they gain it all back.
02:33:52.080 Not to mention those who stay on the drug, a paper was published within the past six months. I think it was within
02:33:58.240 the past six months, definitely within the past year, the risk of suicidal behavior doubles and the risk of major
02:34:04.479 depression triples in people who were on the drug for up to two years on any dose of it or the high dose
02:34:10.000 on the high on the currently used um wiggoi dose which is the higher dose which is common. Um so not a micro dose.
02:34:16.800 Uhhuh. 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 but
02:34:23.200 as much one way and this is my own kind of philosophical view. We we rejoice in the fact that this drug
02:34:31.840 has helped me it’s reduced my cravings for junk food let’s say and we would say
02:34:36.880 that’s a a wonderful outcome. What if in the midst of reducing the cravings for
02:34:42.640 junk food, it reduces their cravings for everything they enjoyed? Where you hear,
02:34:48.560 this is anecdotal now. People lose interest in their old habits. A gal, the gal who used to like
02:34:55.520 walking around the block with her girlfriends doesn’t really want to go anymore. The guy who used to like
02:35:00.880 getting on and playing video games, he doesn’t want to do that anymore. They don’t want to a couple, they don’t go play pickle ball with their friends
02:35:06.479 anymore. whatever. Maybe what we describe as improved eating control is
02:35:14.080 actually just a reduced joy for life in general. But the regardless of the
02:35:19.359 mechanism or the philosophy behind it, the evidence is extremely clear. The major depression risk, people were three
02:35:26.479 times more likely to have clinically diagnosed major depression. And again, twice more likely for suicidal behavior
02:35:33.040 and twice as likely. It was like 106% increased risk of anxiety. And this is after the weight loss and after being on
02:35:39.680 the drug. And yeah, that’s right. It was two years on the drug. So this is this is part of why I’m
02:35:45.200 cautious where I respect the power of this tool. It is extremely powerful
02:35:51.520 because it’s so powerful. I think we c we should be mindful of going too far
02:35:56.640 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
02:36:03.520 context at a very specific dosing regimen with a cycling protocol where we
02:36:08.560 want them to have in their mind, we don’t want you on this drug indefinitely. This is not a lifetime
02:36:14.800 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
02:36:21.520 is so micro dose cycling with the conversation surrounding eating habits.
02:36:26.880 I I think um I mean that that’s a pretty balanced view. Uh thank
02:36:32.080 I think so too. Yeah. Yeah. I mean there’s there’s definitely more to discuss here, but we’d have to have another three-hour conversation.
02:36:39.000 No text
02:36:39.120 So, I kind of want to just circle back and end on, you know, this. You were talking about metabolic health being a
02:36:46.160 predictor of longevity and, you know, there’s metabolic health and inflammation is another one that I’ve
02:36:52.160 seen where it predicts which they’re linked, right? I mean, they’re very much linked. So
02:36:58.399 if you know if metabolic health is so important for longevity and the opposite
02:37:03.600 is true, right, where you’re metabolically unhealthy and that is essentially accelerating aging.
02:37:09.520 Mhm. Um you mentioned something that kind of surprised me early on and that is we you were kind of talking about mechanisms by
02:37:16.160 which insulin is so damaging independent of glucose. And I was sitting here
02:37:23.120 thinking one of the main reasons why being metabolically unhealthy, being insulin
02:37:29.040 resistant is so unhealthy is because you’re having high levels of glucose which is
02:37:34.399 glycating everything from your endothelial cells lining your blood vessels to your mitoardium
02:37:40.160 heart, your skin, proteins, DNA, lipids, everything’s getting stiffer and damaged. Um what’s what what are the
02:37:48.319 mechanisms that are that are involved here with you know accelerating aging
02:37:53.359 and just the glucose alone? Yeah. Well well what yeah in general is it the glucose alone or what else?
02:37:59.520 Yeah. Yeah. Well so insulin will promote aging by by an a persistent chronic mTor
02:38:06.640 activation. So I mean and insulin inhibits autophagy. If autophagy is a mechanism for aging that we want to
02:38:12.720 leverage. I’m unaware of any signal that will inhibit autophagy stronger than insulin will. It abhores catabolism. It
02:38:19.280 only wants anabolic, which can be favorable when leveraged wisely. But when it comes to aging, if you are
02:38:25.439 inhibiting that catabolic process of autophagy, that’s not going to be facilitative. So I rarely I have the
02:38:32.319 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
02:38:38.800 of it. But when I want to, as much as some people will be here say, “Ben, it’s all seed oils.” I’ll say, “No, you’re
02:38:44.560 you got the seed oils covered. I’m going to stay where I’m at because I’m so familiar with this.” Um, but glucose is
02:38:50.800 a partner in crime. I just sort of say, um, it’s sort of who would be who would
02:38:57.040 be the partner. So, it’s sort of Joker, the main villain is the insulin. And then the glucose would be like Harley
02:39:03.439 Quinn, sort of Joker’s right-hand gal in this case to invoke a comic book reference, which I am delighted to do
02:39:10.720 because of a misspent childhood. So insulin, I believe, matters most, but
02:39:16.160 glucose on its own is pathogenic. But before I even defend glucose, I just
02:39:21.680 want to say because so much of modern medicine is obsessed with glucose at a
02:39:27.439 cost, as I articulated earlier, that obsession not only causes us to miss the
02:39:33.120 metabolic problem as early as we could by focusing on insulin, but it also leads us to unhealthy interventions
02:39:39.920 where you have a hyperglycemic, hyperinsulinemic type 2 diabetic and you’re only caring about lowering the
02:39:46.240 glucose and you do so by pushing the insulin higher. If the glucose were the main pathogenic signal, this should
02:39:53.280 result in improved outcomes and nothing gets better. When you give a type 2 diabetic an insulin therapy, they get
02:39:59.359 fatter and sicker and die faster. All while glucose looks good. This is well documented. Their risk of dying from
02:40:05.359 heart disease triples. Their risk of getting dying from cancer doubles when you give them insulin. So I defend
02:40:11.520 you with a type 1 diabetic. Ah, well that’s different. Yeah, because in a type one diabetic there’s no
02:40:16.800 insulin and so you have to give them insulin therapy just to bring them to normal insulin. In the type two diabetic
02:40:23.439 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
02:40:29.680 diseases of total opposites. The only thing they have in common is that the glucose looks the same in that it goes
02:40:35.280 high. Now glucose is not benign. As much as I have an insulin centric view
02:40:41.200 unapologetically, glucose is a problem uh through multiple mechanisms. You
02:40:46.240 mentioned glycation that is a huge one not only because of the change in the structure of that protein or that
02:40:52.399 molecule itself like skin a lot of like you can induce premature wrinkling by
02:40:57.920 under undergoing by forcing glycation of the skin. you can result in a compromised glycoalix of the endothelium
02:41:04.800 by all that glucose compromising with glycation. So glycation itself is a way
02:41:10.000 to um irreversibly alter a molecule and eliminate its utility. And indeed at the
02:41:17.359 same time when you form an advanced glycation end product, it becomes a a
02:41:23.359 substrate for or a molecule that can b a lian for rage the receptor for advanced
02:41:29.439 glycation end products. And when rage gets activated you have a lot of inflammation. So the glycation goes
02:41:35.600 beyond the altered structure of the molecule itself leading into some chronic subclinical inflammation. But
02:41:42.000 No text
02:41:42.319 there’s another mechanism too where when you elevate glucose substantially you may you will have cells that are taking
02:41:48.720 in that glucose but it’s overwhelming its ability to undergo glycolysis. And
02:41:54.640 if most cells if you if you you know there’s so much glycolysis happening that it starts to inhibit entry into the
02:42:01.280 glycolytic pathway then you divert the glucose into the sorbital pathway. Now you have glucose turning into sorbital
02:42:08.880 which the cell can’t do anything with and so sorbital begins to accumulate in the cell and that starts to increase the
02:42:15.520 osmotic gradient into the cell and now you have basically a water balloon that’s getting overfold and you can have
02:42:21.439 over full and you have this what’s called hydroic degeneration where you basically force water into the cell
02:42:27.120 because of this glucose metabolite and then the cell can burst and this is a large part of the problem with like
02:42:33.359 macular degeneration and retinopathies In the nephropathies of the kidney, the main mechanism whereby the glucose is
02:42:40.000 damaging or one of the main mechanisms is the conversion of the glucose into sorbital. And when sorbital accumulates
02:42:46.399 in the cell, it can’t go anywhere and it starts pulling in water and the cell will burst.
02:42:51.520 Um, wow. I was just started thinking about prunes because prunes are like high in sorbital.
02:42:56.880 Yeah. So, what’s funny though, when I teach this concept to my students, you can tell I’m the I’m an ultimate professor here. I I teach all these
02:43:03.359 ideas. I actually have my students, as a funny little assignment, look up the customer reviews of sugar-free gummy
02:43:11.120 bears. And it’s so funny because these these derivatives of glucose like
02:43:16.800 sorbital or manitol, they can’t move across cell membranes. And so wherever
02:43:22.640 they are in the body, they’re doomed to stay there, including if it just comes into the intestines. So part of the
02:43:28.160 humor for these 18, 19 year olds is finding these people giving customer reviews of how the gastrointestinal
02:43:34.800 distress of these sweetened gummy bears that are like sorbital that all stays in
02:43:40.720 the guts and it pulls a lot of water in the guts anyway creating some socially awkward situations for these poor people
02:43:47.520 to put it politely. I also like how you’re talking about this insulin centric sort of model of how that’s
02:43:48.000 No text
02:43:54.720 really the most damaging and it really is when you think about insulin you know shutting down I mean
02:44:02.319 I guess I should say it another way when you think about like insulin’s role in activating AKT which then is shutting
02:44:08.800 down all these stress response pathways everything from autophagy to you know
02:44:14.240 making stem cells to just just everything being being shut down by the
02:44:19.840 action of this one hormone. Yeah. A humble little peptide. Yeah. I mean, and most people, it’s one thing
02:44:25.200 for like a steroid hormone to have a kind of global effect, but peptide hormones don’t often do that. You know,
02:44:31.200 glucagon, for example, insulin’s opposite. Muscle doesn’t have glucagon receptors. Like, it’s very much tissue
02:44:37.680 specific. But insulin just operates at a different level. And I’m glad to see that you’re a maybe you always have
02:44:43.520 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
02:44:50.000 my first, you know, experiments as a young biologist. I was a chemist before I was a biologist. So, so I previous
02:44:56.319 You had an evolution. Yeah. Yeah. I was like lots and lots of chemistry and peptide synthesis and stuff. And then I was It’s funny as a
02:45:02.479 chemistry major at UCSD, there’s only a little bit of biology requirements. So, I didn’t really have
02:45:09.760 vast experience in biology until I graduated from, you know, UCSD with my
02:45:15.439 degree in chemistry, biochemistry. Then decided I was kind of like, I don’t know that this is really what I want. I’m
02:45:22.319 going to like go work for a little bit and I went to the Sulkq Institute in La Hoya and started working in an aging lab. And again, one of my first
02:45:29.760 experiments was what happens, you know, when you when you shut down the insulin
02:45:35.439 signaling pathway and these little nematode worms that share a lot of homolog homologous
02:45:41.040 genes with humans, including the insulin receptor um and and IGF-1 receptor. And
02:45:48.399 it was so clear to me that when you decrease the insulin signaling in these
02:45:54.080 little worms, they you doubled their life expect. Exactly. Doubled it. 15 days to 30 days. Boom.
02:46:00.720 Like that. And their health span. I mean, you look at these worms and you get to know them
02:46:06.399 after about, you know, 15 days like they’re like, “Hey, yeah, you can you name them.” And you see like, you know,
02:46:11.520 as they’re reaching after a week, they start to like move slower and then like they’re they they get old like we do.
02:46:17.200 They get old, they like move less, they like it. It’s very clear when you shut down insulin going that doesn’t happen.
02:46:25.600 They are youthful. They’re moving around like they’re young worms when they’re supposed to be dead already. Yes.
02:46:30.800 And that was like No, you in fact I love that you mentioned this. So you of most people
02:46:36.560 may be but you I know you’re familiar with Cynthia Kenyon’s work. Yes. Where when I first heard about that kind
02:46:42.560 of pathway I it was further justification of this insulincentric view. Now not to the extent not that
02:46:49.120 either of us I am certainly not suggesting there aren’t other variables. Oxidative stress is a variable. Um,
02:46:57.520 stress is a variable, but there’s one that I know and and the reason I focus on insulin so much is because of these
02:47:03.120 kinds of results where you can just control one single variable and a simple
02:47:08.479 one at that because insulin is a signal that we can control within 24 hours. Like a person listening to this who’s
02:47:14.640 thinking, okay, I have all these signs and symptoms of insulin resistance. What do I do? Control your carbs. That is the
02:47:20.720 main signal. 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
02:47:26.479 about what carbs you are eating and be a little and then focus on these good sources of protein and fat which aren’t
02:47:32.319 going to have an insulin spike. That’s why these other variables people want to invoke the mitochondria. I am extremely
02:47:38.640 familiar with mitochondrial bioenergetics. And yet, why don’t I invoke the mitochondria as a primary
02:47:43.760 source of disease? Because you can’t measure it in the average person. Like someone listening could say, “Well, it’s
02:47:48.800 my mitochondria.” All right. Well, good luck getting any marker of your M. I could do it in my lab if you’re willing
02:47:53.920 to give me a sample of your muscle tissue or something, but it’s not a clinically kind of supported focus. So,
02:48:01.359 I don’t mean to ever suggest other variables don’t matter. We know insulin matters. You saw it in the work with um
02:48:07.760 the worms and aging. I’ve seen it in the context of neuron bioenergetics and fat
02:48:12.880 cell dynamics and everything else we’ve been talking about. And it’s just a variable. It’s a lever. when you
02:48:18.399 mentioned lever earlier that you can grab and immediately start to turn down.
02:48:23.000 No text
02:48:23.439 Okay. So, let’s talk about these key biomarkers for aging like from a metabolic perspective.
02:48:29.040 What do you think would be, you know, most indicative of biological aging and what biomarkers are good to look at?
02:48:35.279 Yeah. Yeah. My first one would be fasting insulin. If I could if I could change um health care policy and
02:48:42.319 practice in the United States, my one thing would be to have insulin be a standard measurement on every blood
02:48:48.479 test. As much as the average individual is going to go in and get their annual checkup, they’re going to get their glucose. They’re going to get their A1C,
02:48:54.640 they’re going to get all their lipids and uric acid, those can be great. And there’s ones there’s some worth
02:49:00.479 revisiting in a moment. But to me, the fact that we don’t include insulin on that panel is an absolute travesty. It
02:49:08.399 is in my mind the best overlooked marker. So fasting insulin, if a person can get their fasting insulin measured,
02:49:14.960 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-
02:49:22.080 teens or high teens, that’s maybe an okay sign because insulin can be dynamic. But then if it’s in the high
02:49:28.000 teens to the 20s, it’s a problem. That’s a warning that you’re metabolically off.
02:49:33.200 Um, and then let’s come back to some of the common ones. The triglyceride to HDL
02:49:38.240 ratio is a great surrogate marker for not only metabolic and like insulin
02:49:43.760 resistance but also cardometabolic where we focus so much on LDL for
02:49:49.680 example but the triglyceride to HDL ratio is a way better predictor for
02:49:54.720 cardiovascular risk than LDL is. So triglyceride to HDL ratio if it is if so
02:50:01.520 you take your triglycerides which you’re always going to get on a blood test and divide it by your HDL cholesterol which you’re always going to get on a blood
02:50:07.760 test. If that number is less than 1.5 that’s a great sign that you’re doing well metabolically.
02:50:14.800 And then I maybe uric acid is is another one although I could go on but uric I did
02:50:21.279 mention uric acid. It’s another one of those that really well done longevity
02:50:26.319 study, the Amortis study from Sweden. It looked it found that uric acid was one of the very few predictors that when
02:50:33.120 they looked retrospectively at these people measuring the same markers for decades, their glucose control was a
02:50:39.279 predictive variable and their uric acid was a predictive variable as to who lived the longest healthiest lives. So
02:50:45.120 lower uric acid is going to be better. And just for general metabolic health, would you add in some of the HBA1C and
02:50:52.960 you know maybe APOB? So L you mentioned LDL I mean they don’t even directly measure LDL. APOB would be obviously a
02:50:59.359 more direct measure but then looking also at particle size which I get I again think is important. It’s the small
02:51:05.120 LDL particles. Yeah. So I do too. Yeah. So LDL as you mentioned and I actually describe this
02:51:10.160 in my book why we get sick. I talk about the the like why is it that we have such conflicting data across LDL? Some
02:51:16.720 studies say it predicts, some studies say it doesn’t at all. Maybe it’s because we’re not accounting for the diameter differences.
02:51:24.000 Even then, most people won’t have had their diameter measured. The triglyceride to HDL ratio is an awesome
02:51:30.640 surrogate. There’s a beautiful figure of a study. I can’t remember the citation, but I can recall the figure perfectly.
02:51:36.880 It actually looks at the difference in population of the big LDL, the buoyant,
02:51:42.720 versus the the small dense LDL. And wouldn’t you know it, right around that triglyceride to HDL ratio on the x-axis
02:51:49.359 of 1.5 is that crossover. So as the triglyceride to HDL ratio was higher, it
02:51:55.200 reflected a higher particle B uh or type pattern B rather LDL. The lower the
02:52:01.520 triglyceride to HDL ratio was, the more it reflected a pattern A, the large buoyant, apparently less aogenic. So
02:52:08.560 once again, we could come back to that pretty reliable surrogate. Okay, great. Um I think if you could
02:52:13.000 No text
02:52:14.399 leave people with just one practical takeaway about insulin, about their metabolic health, uh how they can
02:52:21.120 improve their life, their health span in the long run, what would it be? Yeah. Yeah. So to I would say the
02:52:27.760 simplest strategy would just be change breakfast tomorrow. Overnight fasting is incredibly
02:52:34.560 therapeutic. um insulin will come down during a fasted state and that sort of
02:52:40.880 re sensitizes the body to insulin. So in the morning you’ve finally been fasting
02:52:46.720 overnight, insulin has come down. The last thing you want to do is spike your insulin with a starchy sugary breakfast.
02:52:53.359 And of course, tragically, breakfast is almost just a dessert nowadays all over the world where it is just like pure
02:53:01.120 dessert. It’s pure sugar and starch. I would say change breakfast tomorrow either fast through breakfast um like a
02:53:08.479 drink I like to drink a cup of yerba mate uh fast drink some coffee or tea uh
02:53:14.880 and uh which is not not going to break your fasted state even if you put a little butter I don’t consider that as
02:53:21.200 breaking a fasted state because I define fast as the endocrinology the the nutrients rather than the calories uh
02:53:29.200 but that’s a topic for another time but uh or or Don’t consume anything, but if you do, then if you do want to eat, then
02:53:36.000 let it be the low glycemic load vegetables um and berries and then more
02:53:42.479 protein and fat. So, whatever you can do to keep your insulin in check for as long as possible until say lunch. The
02:53:49.840 longer the insulin is low, the more you’re improving your insulin sensitivity and the more you are allowing that metabolic flexibility
02:53:56.880 where the human hybrid burning glucose or sugar burning or fat burning, it’s insulin that dictates that fuel. And
02:54:03.680 most people are stuck in sugar burning mode because they never bring their insulin down long enough to shift over
02:54:09.040 to fat burning. So you get to get into this fat burning state, enhancing metabolic flexibility, and you’re
02:54:14.800 improving your insulin sensitivity. So my one piece of advice, change breakfast and change it tomorrow.
02:54:21.120 So you want to extend that that that state where you’re you’re basically improving insulin sensitivity.
02:54:26.160 Yes, that’s right. What if you’re what if you eat dinner early? Is it as awesome way to do it, too?
02:54:27.000 No text
02:54:31.200 Yeah. Yep. That would be another way to do it. It’s just I I don’t focus on dinner so much because it’s just so complicated.
02:54:36.399 You know, you and I, we have families. And so sometimes there are for me, for me personally, as a busy dad and
02:54:43.200 husband, my even though I I’m home for breakfast, the fact that I’m not eating breakfast
02:54:48.800 in the midst of the chaos, no, it doesn’t disrupt the family dynamic at all. The kids are eating,
02:54:54.080 we’re talking, and I’m sipping on my cup of yerba mate while we’re helping get lunch ready and everything else. It’s
02:54:59.760 not at all disruptive. and and then lunch. I’m at work. I have whatever lunch I’m going to have and that’ll be
02:55:05.439 my biggest meal of the day. But as much as I am absolutely a fan of of being
02:55:10.479 careful with dinner because the evidence is so supportive of it, I also recognize that it’s the trickiest meal because of
02:55:16.319 social dynamics, family dynamics. But in so far as you can eat earlier, then just
02:55:22.160 stop eating. The very best you can do, whether it’s drinking some apple cider vinegar or having something bitter in
02:55:28.880 your mouth to um reduce the sweet cravings because bitter tastins can reduce sweet cravings, I would say do
02:55:35.120 it. Whatever tool, whatever leveraging you need in the evening to not crave or snack on junk, do it.
02:55:41.680 Great. Yeah. I mean, I I probably should have mentioned this earlier when we were talking about the late late night
02:55:47.520 snacking, but the the fact that melatonin shuts down Yep. insulin production in the the pancreatic ba beta
02:55:54.000 cells is hypoglycemia disrupts melatonin too. So even back to the glucose mechanism. Um
02:55:59.680 another reason to not go to bed hypoglycemic is it disrupts the melatonin rhythm uh at the same time.
02:56:04.960 Oh interesting. So it’s like a two-way thing here. It’s an ugly little battle. Well, this has been a very enlightening
02:56:11.359 conversation. Ben, thank you so much for coming on this show and talking to me about all things and getting
02:56:16.720 uncomfortable at times. I really appreciate it. My pleasure. people. So, you mentioned your book.
02:56:23.040 Yep. Yeah. Why we get sick? Yeah. Why We get sick and then a follow-up companion. How not to get sick. How not to get sick. That’s that to be
02:56:29.359 coming soon. No, it’s out. Both of them are out. Oh, is it out already? Oh, okay. So, you’re writing a third book. I’m writing a third book. I see. Okay.
02:56:35.359 We’ll do that next time. And then um benbickman.com is your website where people can find all
02:56:40.399 things. You have a YouTube channel. Yeah. Yes. Benickman.com is kind of my education. And then I also am a partner
02:56:46.080 with Insulin IQ. So, we provide some coaching at insuliniq.com and then just straight education at benbickman.com.
02:56:52.240 And and you’re on social media, too. You’re active on I am. Yeah. And that’s just benbickmanphd. Yeah. I try to be active
02:56:57.520 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
02:57:02.800 have a bit of a light touch. Same. Same. Well, thank you so much. My pleasure.