How to Reverse Insulin Resistance Through Diet Exercise and Sleep

Insulin Resistance often goes unchecked until blood sugar abnormalities become obvious.

Dr. Ben Bickman and FoundMyFitness

189,673 views Premiered Jul 15, 2025 Interviews
Insulin resistance silently shapes the trajectory of nearly every major chronic disease, yet it’s often overlooked until blood sugar abnormalities become obvious. In this episode, Dr. Ben Bikman exposes the dietary culprits that drive metabolic dysfunction and highlights actionable, evidence-based tactics for improving metabolic health. Ben also addresses pressing questions about popular weight loss medications like Ozempic and other GLP-1 agonists: Are they groundbreaking solutions, or shortcuts with hidden metabolic consequences?

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CHAPTERS:
00:00:00 Introduction
00:01:33 Can you be insulin resistant with normal glucose levels?
00:05:13 Can glucose monitors detect hidden insulin resistance?
00:06:43 What your skin reveals about insulin resistance
00:08:07 Why is insulin resistance behind so many chronic diseases?
00:12:28 Does obesity cause insulin resistance—or vice versa?
00:19:20 Insulin’s surprising roles beyond blood sugar control
00:20:18 What’s driving weight gain—insulin or calories?
00:27:12 Do saturated fats cause insulin resistance?
00:33:44 Why refined carbs amplify risks from saturated fat
00:36:46 Fructose vs. refined sugar—which spikes insulin more?
00:37:43 High-carb vs. keto—which diet controls hunger better?
00:42:09 Why low-carb diets might provide a metabolic advantage
00:44:18 Does exercise give you metabolic ‘wiggle room’?
00:48:42 Why strength training beats cardio for insulin sensitivity
00:50:45 Should you lower insulin before cutting calories?
00:53:54 Does meal frequency drive insulin resistance?
00:57:14 Is nighttime snacking giving you insomnia?
00:59:06 Can a sugary breakfast lead to overeating later?
01:04:01 Does late-night eating disrupt sleep more than blue light?
01:05:41 Can one bad night’s sleep trigger insulin resistance?
01:09:31 Can air pollution cause weight gain?
01:13:23 Vaping vs. smoking—which is worse for metabolic health?
01:14:45 Can statins and antidepressants trigger weight gain?
01:17:30 How to reverse insulin resistance in 90 days
01:24:07 Does apple cider vinegar really lower blood sugar?
01:28:01 Ketone supplements—are the metabolic benefits real?
01:33:42 Why some ethnicities get diabetes without obesity
01:41:36 How oversized fat cells trigger metabolic chaos
01:46:36 Do seed oils silently promote insulin resistance?
01:49:52 Seed oils—always harmful or only when heated?
01:55:43 Fat, muscle, or liver—where does insulin resistance start?
02:01:29 Do fat cells shrink or disappear with weight loss?
02:04:13 Are shrunken fat cells still insulin resistant?
02:05:23 Can exercise and cold therapy specifically shrink visceral fat?
02:06:48 Injecting insulin for muscle—are the risks worth it?
02:09:53 Are drugs like Ozempic a shortcut or solution for obesity?
02:16:20 Are current GLP-1 agonist doses too high?
02:17:10 Microdosing GLP-1 drugs—a solution for carb cravings?
02:23:08 Do these medications cause muscle loss—or is it poor nutrition?
02:25:38 Do GLP-1 agonist benefits extend beyond weight loss?
02:27:49 Could these treatments actually promote longevity?
02:33:20 The dark side of GLP-1 drugs—can they trigger depression?
02:36:39 Insulin vs. glucose—what really drives accelerated aging?
02:41:42 How high glucose levels damage cells—from glycolysis to sorbitol
02:43:48 How insulin shuts down your body’s stress defenses
02:48:23 Which biomarkers best predict biological aging?
02:52:13 One simple breakfast change to lower insulin
02:54:27 Does eating dinner early improve insulin sensitivity?

Ben Bikman, PhD
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Website: https://www.benbikman.com

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Transcript

Time Text
0:00 Introduction
0:05 I unapologetically embrace the view that to some degree insulin resistance is a
0:11 common root cause for most chronic diseases. Obviously, type two diabetes, obesity is
0:17 in there, Alzheimer’s, fatty liver disease, infertility. So, why is that?
0:23 Insulin is one of the few peptide hormones that will literally affect every single cell of the body. For
0:28 example, the connection between insulin resistance and breast and prostate cancers. I’m not saying insulin
0:34 resistance is the singular contributor, not at all. But it is absolutely a contributor. I kind of wanted to start out with
0:40 something a little provocative. Right now, there’s a big trend in weight loss
0:46 that’s made very easy um by taking GLP-1 agonist drugs, things like Ozic and Wego
0:52 V. GLP-1 is a naturally produced hormone. My concern is that the dose of GLP1 that
0:58 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
1:03 really make a difference? The one I like to talk about the most because the evidence is so compelling
1:09 and it’s so easy to get. My one thing would be welcome back to the podcast. I’m very
1:16 excited to be sitting here with Dr. Ben Bickman who is a professor of cell biology at Brigham Young University and
1:23 uh he specializes in all things metabolic disorders and metabolism. So, I’m pretty excited to have a very
1:28 well-rounded discussion today, Ben. This is this has been a while. I’ve been following your research for some time
1:30 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
1:34 Can you be insulin resistant with normal glucose levels?
1:42 something a little provocative and I don’t and I want to say surprising. Uh this this question for you is a lot of
1:48 people that have normal blood glucose levels quote unquote
1:55 can actually be insulin resistant, right? Why is that? And what what is this state
2:01 of like pre pre-diabetes and why is it something that is not caught soon?
2:06 Yeah. And yet so common, right? Right. I mean that that adds an extra layer of
2:14 reason to talk about this because it is it’s become the most common problem. People much of modern clinical care has
2:19 what I call a glucosecentric paradigm when it comes to monitoring metabolic health or even cardioabolic health given
2:26 how relevant diabetes and metabolic problems are to cardiovascular disease. But the the consequence of the
2:33 glucosecentric paradigm and there’s reasons for it. So I don’t mean to s to state this in any kind of incriminating
2:40 way. They they have their own justification for the glucosecentric paradigm, but it’s increasingly harder
2:46 to overlook because of what we know with regards to insulin. So insulin
2:51 resistance is the state where insulin levels are higher. The body’s having to
2:57 use more and more insulin in order to keep glucose in in check. Uh but because
3:04 it is able to keep glucose at that normal range, it flies under the clinical radar because of our glucose
3:09 centric paradigm that the the conventional clinician is only measuring glucose every time the patient’s coming
3:15 in for an annual visit with no regard uh to the patient’s insulin levels. If we
3:21 were able to broaden the paradigm a little bit and include insulin, then all
3:28 of a sudden we are measuring the earliest signs of insulin resistance because it is insulin itself that ought
3:35 to be measured when we’re trying to get that view of the patient’s not only metabolic health but insulin resistance.
3:40 So to say all that another way, type 2 diabetes is when both insulin is high
3:46 but it’s starting to really lose the war and now glucose rises as well. Then the
3:53 conventionally trained clinician says a glucose is elevated so you have diabetes or pre-diabetes. But in its earliest
3:58 stages the glucose is still normal but there’s this cold war happening in the
4:04 body where the insulin levels are still two or three or four times higher than they used to be. it needs to be that
4:10 high but and it’s working well enough to keep the glucose in check and so the
4:15 glucosentric paradigm has us miss the earliest
4:21 metabolic canary in the coal mine which is insulin. So the sooner our paradigm
4:27 with modern medicine includes insulin, then the earlier we can detect these metabolic problems in a person who’s
4:32 progressing towards type 2 diabetes. But also it changes the treatment protocol
4:38 too because not to go off on a tangent too soon off the very first question
4:45 here, but if the longer we ignore the insulin, the more the clinician may be tempted to push the insulin up even
4:51 higher by giving say a type 2 diabetic an insulin therapy. Now they’re pushing
4:57 the insulin from high to super physiological all in an effort to control the glucose
5:04 little realizing that in the process you’re actually killing them faster because so much of what kills the type
5:11 two diabetic is not the hypoglycemia it’s the in the hyperinsulinemia and the insulin resistance.
5:13 Oh I definitely want to get into that. Just just sort of as a follow-up question in this world we live in now
5:17 Can glucose monitors detect hidden insulin resistance?
5:23 where gl continuous glucose monitors are so becoming very popular many people have them without a prescription you can
5:29 get them. Y is there any signs or tests using those
5:36 that people can do to kind of look for this potential problem with you know having perhaps high insulin. In fact
5:42 they’re not measuring insulin but glucose. Yeah. Right. Yeah. So to answer the first uh the question very directly, I’m
5:49 an enormous advocate of CGM use. The more we democratize access to CGMs, I
5:54 think the better we put individuals in a position to be their own coach, you
6:01 know, they don’t need to have someone like me or you berating them and telling them to change their habits and eat a
6:06 little better. when you see how your body is responding to what you’re eating and the CGM enables that, you end up
6:13 making your own lifestyle changes. So, with the with the use of the CGM, fasting glucose isn’t going to be the
6:19 best indicator. It’s going to be the dynamic glucose. So, if you’ve eaten a carbohydrate heavy meal or or a simple
6:26 carbohydrate, I shouldn’t call it a big meal, but a simple carbohydrate like two pieces of bread, if your glucose levels
6:31 aren’t back down to normal by about two hours, that suggests a problem. So in my
6:38 mind, the greatest utility of the CGM is to monitor the dynamic changes rather than the static where am I at every
6:40 morning. That has less value. The dynamic changes are what has value. But
6:43 What your skin reveals about insulin resistance
6:48 beyond the use of the CGM, if a person’s curious about their insulin resistance,
6:55 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
7:00 there are two things you can observe just on your skin and they’re both generally going to be right around the
7:06 neck. One of them is a a condition called aanthosis nigricans which is when
7:14 around the little skin fold that most people have around their neck. The skin will get darker pigmented which can be
7:21 harder to tell depending on the pigment of the person’s skin. But what is obvious regardless of pigment is the
7:27 kind of crinkled tissue paper texture of the skin. So the skin will be very sort
7:33 of roughed like crinkled tissue paper. So that’s echanthosis nigricans around the neck. And then the other one people
7:38 know is called skin tags. And that is those little it’s not like a rounded
7:45 little mole but rather a distinct little kind of mushroom stock column of skin.
7:51 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
7:59 little like a little mushroom stock almost of skin. Skin tags. Both of those are very very strong evidence of insulin
8:05 resistance. And the nice thing is as the insulin sensitivity improves, those problems go away just like everything
8:09 else will. So many researchers, including yourself, do view insulin
8:11 Why is insulin resistance behind so many chronic diseases?
8:16 resistance as a sort of root of causing
8:23 many different types of chronic diseases, age related diseases, obviously type two diabetes, obesity is in there, cardiovascular disease,
8:29 Alzheimer’s, fatty liver disease, infertility. So, so why why why is that
8:36 Yeah. some something that people think as the root cause of so many chronic diseases? And again, you know, why do you you’re
8:41 talking about insulin resistance being common and certainly like this pre pre-diabetic state being pretty common.
8:48 Uh what do you think the reason for that is? Yeah. Yeah. So the first part of the question I unapologetically embrace the
8:55 view that to some degree that’s italicized wording there to some degree insulin resistance is a common root
9:01 cause for most chronic diseases. Uh so I’m not claiming that it’s the singular
9:06 cause. For example, the connection between insulin resistance and breast and prostate cancers, the two most
9:12 common cancers in men, in women and men respectively. I’m not saying insulin resistance is the singular contributor.
9:19 Not at all. But it is absolutely a contributor. With regards to Alzheimer’s disease, insulin is not probably the
9:26 singular contributor, but it is one undeniably. And the same goes for polycystic ovary
9:31 syndrome uh the most common uh infertility in women or erectile dysfunction in men and fatty liver
9:38 disease and hypertension. So when I in fact this question is the question I
9:45 asked myself as an academic in in at my university when I got tenure I thought I
9:50 looked at the rest at at my future career and I thought do I want my career to be defined by the number of
9:56 peer-reviewed papers I publish in science journals and I thought no that’s not enough because most people will
10:02 never read those articles no one will ever get a direct benefit from them and I thought what would be the one message
10:11 as a biomedical metabolic scientist that I would want to convey to people and it was this one. It was that to some degree
10:18 most of chronic disease can be attributed to one common origin. And so rather than trimming at the branches of
10:24 this sick tree where we are giving the patient a a drug for their Alzheimer’s
10:30 disease, we’re giving them a patient for a drug for their hypertension, we’re giving them a drug for their infertility.
10:36 What if all of those were actually just branches coming off of one tree? Let’s
10:41 just cut down the tree. So when we can acknowledge a sort of common soil hypothesis,
10:47 it starts to simplify the clinical approach. So
10:53 all of this in my mind is a reflection of just how powerful the hormone insulin is. Most individuals only think about
11:00 insulin as being a hormone that controls blood sugar, which is fantastically unfair. Insulin is one of the few
11:08 peptide hormones that will literally affect every single cell of the body from from brain cells to bone cells,
11:14 lung cells to liver cells, and every cell in between. There’s no exception. Insulin will have an effect at every
11:21 cell of the body. And the the particular pathology with insulin resistance is unique because you have some cells that
11:28 aren’t responding very well to insulin. Like in the case of erectile dysfunction, insulin is less capable at
11:34 producing nitric oxide in the endothelium of the blood vessels. So there’s less vasoddilation. Less
11:40 vasoddilation means compromised erectile function. So on one hand, you have some cells that suffer because they’re not
11:46 responding. But on the other hand, you have some cells that are overstimulated
11:51 because insulin resistance is insulin not working the same at all cells of the
11:56 body and blood insulin levels are higher. So there’s too much insulin.
12:02 Some cells are responding too much to that insulin. So with polycystic ovary syndrome, for example, that’s not a
12:09 problem of the insulin signal not working well. That’s a problem of there being too much insulin stimulating the
12:15 ovary to inhibit the conversion of testosterone into estrogens and thus she
12:21 manifests with polycystic ovaries. So to to some degree most chronic diseases can
12:27 be connected back to insulin resistance and to me that has a a tremendous power. That’s a reason to focus on that
12:30 disorder. So some researchers think that the high insulin is more of a response to ectopic
12:34 Does obesity cause insulin resistance—or vice versa?
12:40 fat accumulation, obesity sort of being the underlying cause of the high
12:46 insulin. So how do you kind of differentiate between this cause and effect? What what
12:51 role does ectopic fat accumulation have in insulin resistance causing high insulin?
12:56 Yeah, that’s a great question. In fact, that’s a big question. Uh, and I already am too longwinded with my answers, so
13:04 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
13:09 two origins where you have what I call fast insulin resistance and then slow insulin resistance. And what you’re
13:16 touching on is the slow insulin resistance, which I’ll come to in just a second. Within the fast insulin
13:22 resistance side, there are three what I call primary stimuli that in humans have been confirmed and in rodents and in
13:28 isolated cell cultures that can cause insulin resistance quickly like within
13:35 hours but at the same time if the stimulus is removed the insulin resistance is resolved in short order
13:42 and that is stress. So elevated stress hormones whether it’s cortisol or epinephrine adrenaline will cause acute
13:47 insulin resistance in humans. As that stimulus goes away the problem resolves.
13:52 Next is inflammation. If you increase the levels of inflammatory cytoines in
14:00 cells or rodents or humans, they will be insulin resistant very quickly. In fact, people wearing CGMs may notice this,
14:06 that the CGM may reveal that they’re starting to get a cold or a flu because they notice that their glucose levels,
14:11 they’re having a much harder time controlling them even though their habits haven’t changed. That’s often a
14:18 sign of inflammation. But even with autoimmune diseases, uh, where you have people where the autoimmune disease will
14:25 eb and flow, so too will the insulin resistance. It will track very well with the how active the disease is. And then
14:30 lastly of the primary fast causes of insulin resistance is too much insulin
14:36 itself. So we know in humans, rodents and cells, I’ve published my own work on
14:41 this topic that too much insulin will result in a resistance to the stimulus.
14:47 So too much insulin can cause insulin resistance. Now none of those touch on what you had mentioned which is the
14:52 ectopic idea. That idea is very important be uh and there’s a lot of
14:59 nuance to it where we have to define the the fat first of all and by that I mean
15:05 what of the many of the hundreds of thousands of types of molecules that we call a lipid or a fat within a cell
15:11 which are the ones that actually matter to insulin resistance. Some people will think of just triglycerides which is the
15:18 main form of storing fat and yet triglycerides are totally inert metabolically. There was some a case in
15:23 point. Brett Good Pastor and David Kelly 30 years ago described this phenomenon
15:30 of the the athletes paradox where they noted that in obesity with type two
15:37 diabetes and insulin resistance, if you pull a muscle biopsy, there’s really high levels of fat in the muscle of triglycerides
15:42 and they’re very insulin resistant. And so some people would say and did at the time, well, high muscle triglycerides
15:48 causes insulin resistance. And yet when they did muscle biopsies from very lean,
15:53 exceptionally insulin sensitive marathon runners, they had just as much fat in
16:00 their muscle in the form of triglycerides as the obese type 2 diabetics did. And and again, they were
16:06 very insulin sensitive. So it couldn’t be the fat that was being stored in the muscle. The same could be said of the
16:14 liver. If the liver has triglycerides, it’s not the triglycerides that are causing insulin resistance. So
16:20 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
16:26 the same across these say these the lean marathon runner and the obese type two diabetic. When you start measuring
16:33 levels of tissue ceramides or its precursor dihydroamides, there’s still some debate as which of the two matters
16:39 most. I’m very strongly just saying it’s one of them. And so I’ll just say ceramides as a family.
16:46 You can in any biological model cause very strong robust insulin resistance
16:52 just by increasing the ceramides because ceramides will block the insulin signal. When serum when insulin binds to its
17:00 receptor then you have a series of of of phosphorilation events. Ceramides block that very well. It’s a very well-defined
17:07 pathway. And if you can just do one thing and just resolve the ceramides, you correct the insulin signaling. So
17:13 when it comes to ectopic fat, it’s not a matter of how much triglycerides you’re storing, but rather what is the entire
17:20 metabolic millu to be promoting ceramides in various tissues throughout the body. Interestingly, all of those
17:27 primary stimuli, the quick insulin resistance, all induce ceramide biosynthesis and acrruel. But with the
17:33 slow insulin resistance, I still think it’s appropriate to invoke fat. Um, but
17:39 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
17:45 level insulin resistance is it starting in the muscle or the liver or the fat. I’m very much an advocate of the fat
17:52 first focus when it comes to insulin resistance from that slow progressive. It settles in over years and it may
17:58 take, you know, weeks to months in order to reverse. Yeah. Well, this is we we’ve got a lot
18:08 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
18:15 insulin resistance like like free fatty acids and and and can you make like a little nematode worm insulin resistant
18:21 and you know it it it from my understanding had to do with the atyposite cell and
18:28 this sort of spillover of ceramides that are then attack it all had to do with the AKT signaling pathway which you know
18:33 stopping basically the insulin receptor That’s exactly and that’s where in that’s where ceramides act. You
18:40 mentioned AKT that’s what we would measure and you must have too. We would measure a particular protein in AKT for
18:45 or an amino acid residue for phosphorilation and then look at one other downstream signal and then we
18:50 could do some other more complicated metrics but that was always the absolute baseline. In fact, I’ve run so many
18:55 western blots measuring phosphoic that next time I if I have to have if I ever
19:00 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
19:08 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
19:13 nutrition, you know, later on down the line and it’s like, well, it always stuck with me like there’s
19:18 there’s a role for fatty acids in causing insulin resistance. Oh, there is. So, so that was something that kind
19:20 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
19:23 Insulin’s surprising roles beyond blood sugar control
19:31 a minute, but like um beyond you know we’re talking about you kind of hinted at this earlier. Insulin has many roles
19:38 and oftent times the general public thinks about its role in just regulating blood glucose levels
19:43 but maybe you could just talk about some of the other roles insulin plays for example in fat accumulation.
19:49 Oh yeah for sure. Yeah. Uh, in fact, we’ve I’ve already touched on a few. Like, for example, who would have
19:54 imagined that insulin regulates the enzyme that’s responsible for the conversion of testosterone to estrogens
20:01 for goodness sake. And yet, it does. Insulin has a direct inhibitory role on aromatase, that enzyme that mediates the
20:07 conversion and the synthesis of estrogens in men and women. It also regulates nitric oxide production,
20:14 regulating dilation of blood vessels and other hormones throughout the body that affect water retention, salt signaling,
20:18 neuron conductant of of signals and and more. But when the at the fat cell insulin probably has its most um
20:22 What’s driving weight gain—insulin or calories?
20:28 powerful effect where the you cannot under now we’re touching on a broader
20:34 topic of why do we get fat here and I I welcome that topic. Uh in fact of all
20:41 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
20:48 my lab a few years ago and that’s the tissue we study the most. So I’m very comfortable talking about atapost tissue
20:54 physiology. There is as much as there is the debate in two camps of what makes fat cells
21:00 grow. It’s just purely a matter of thermodynamics or no it’s purely a matter of endocrinology. The truth is of
21:08 course you actually have to have both. You cannot under any circumstance make a fat cell get big unless you have both.
21:13 Just to make a put a fine point on that. If you have all the calories in the
21:20 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
21:25 incubator. Um they are swimming in a culture medium filled with calories.
21:32 Everything the fat cell needs is all the calories that fat cell could ever want are around it right now. And yet they’re
21:39 teeny little cells. They’re not getting big at all until we add one thing. And the moment
21:44 we add insulin into that culture, now the fat cells start to get big. If we check them six hours later, there’s a
21:50 big lipid droplet. 6 hours still later, it’s even bigger. So in other words, the
21:55 fat cell knows what to do with the energy that it has access to. A cell doesn’t have any kind of intuitive
22:01 intellect to think, okay, there’s calories here, or more accurately, carbons that I can turn into
22:08 triglycerides, and I’m going to take them in and store them. But in the context of the body, the fat cell needs
22:13 to know, am I playing nice with the rest of the body? How stupid would it be if
22:18 we got up and went extra, we go out on a jog outside, our fat cells are breaking
22:24 down triglycerides as free fatty acids by activating lipolysis. and yet at the same time they’re pulling them right
22:31 back in to store them. That would be stupid. The fat cell wants to cooperate well and be part of the orchestra of the
22:39 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
22:46 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
22:52 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
22:58 say, “Well, Ben, that’s just uh in fat cells.” What about humans? In fact, humans provide the most convincing
23:04 evidence of all that you cannot get fat unless insulin is elevated. Because one of the more common eating disorders
23:12 among young people with type 1 diabetes is a condition called diabelmia, which is this terrible tragic scenario where
23:18 the person feels such pressure to be lean. And they have learned that that little
23:23 syringe of insulin is the absolute gatekeeper of the fat cell. So they will
23:31 deliberately underdose their insulin in order to stay as thin as they want. They can eat as much as they want. And as
23:36 long as they underdose their insulin, and it’s not even at zero. They’re just doing a deliberately lower dose. They
23:41 will be as skinny as they want. Now there’s metabolic hell to pay, right? They’re hypoglycemic. They’re getting
23:47 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
23:54 just calories.” We have a human case study that absolutely proves that wrong. That it’s not just calories. Now, having
24:01:00 said all that, I’m not claiming calories don’t matter. Because on the other hand, if you just have high insulin in the
24:08:00 absence of sufficient calories coming in, that’s also incompatible with life and the person will die. Because if you
24:14:00 if you and I were fasting, in fact, Dr. George Cahill did these studies about 40 years ago. You could never get IRB
24:19:00 approval to do it now. He would fast men for days and then give them an insulin
24:27:00 dose and drive their glucose levels down to about 20 milligrams per deciliter just to see how low could the glucose
24:33:00 get and the person maintains consciousness. And they did. But suffice it to say, if you spike insulin, which
24:39:00 is telling the body to store energy, but there’s not energy coming in, then the total energy available in the blood
24:46:00 drops to essentially zero. Glucose goes down to zero. Ketones go to zero. Fatty acids go to zero because you’re you’re
24:52:00 inhibiting lipolysis. You’re inhibiting ketogenesis. You’re stimulating glucose uptake. Now, the brain has no energy
24:57:00 because it doesn’t have a reserve of energy like the liver or the fat cells or the muscle. And so as blood energy
25:04:00 goes to essentially zero, the brain shuts off. So coming back to the fat cell, you have to have both. You have to
25:10:00 have elevated insulin sufficient to tell the fat cell to store that energy, but
25:15:00 then you have to have the energy to store. So calories matter, but so too
25:21:00 does the insulin stimulus because in the absence of the insulin stimulus, there is no such thing as fat storage. And
25:28:00 indeed, the body can’t stop breaking down the fat. And in fact, that’s what ketones are. Ketones are nothing more
25:34:00 than sign a a sign of the liver burning a lot of fat where it’s burning so much
25:40:00 fat. It has such an abundance of acetal COA that it can’t it can no longer feed
25:47:00 the acetal COA into the citrate cycle because it’s too full. It cannot divert it to lipogenesis because insulin’s low.
25:54:00 So that pathway is inhibited or not activated. Then the only other option of all that acetal COA is ketogenesis. So
26:00:00 ketones are simply sort of this overflow, this metabolic release valve
26:05:00 of of fat burning, but they go one step further if you’ll allow me where how do
26:11:00 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
26:17:00 break the laws of thermodynamics. In fact, my PhD is bioenergetics. I have a unique appreciation for energy in
26:24:00 organisms. So that those carbons need to be accounted for. But the more insulin
26:30:00 is low, uh, you have two adaptations that allow the body to stay lean or to
26:36:00 not store that excess as excess that they’re eating as fat, which is one, a
26:41:00 higher metabolic rate by several hundred calories a day when insulin goes down as
26:46:00 so the body’s just burning a little hotter. The the engine is revving higher. So the overall energy
26:53:00 expenditure is up again by 2 to 500 calories a day. And when you’re in ketosis, you’re eliminating ketones
27:00:00 through the breath and the urine. And every ketone that a person’s breathing out or urinating out has a caloric value
27:05:00 roughly similar to glucose. So you’re just excreting calories from the body.
27:10:00 So the net effect of all of that can be up to 800 or so calories a day that the person’s just wasting.
27:12:00 Do saturated fats cause insulin resistance?
27:19:00 Okay. Um well it’s not we’re we’re really getting into this sort of underlying cause of what you know what’s
27:24:00 causing the insulin resistance what I mean obviously the what’s causing the
27:31:00 high insulin as well. Yeah. And then ultimately obesity is in in that mixture as well. And I think you
27:36:00 know refined carbohydrates is something that you’ve mentioned and I think a lot of people think that refined
27:41:00 carbohydrates definitely play a role in insulin resistance perhaps the a primary
27:46:00 role but um aside from the obesity as you’re talking about obesity being that slow
27:53:00 forming insulin resistance um what role can we talk a little bit deeper about carbohydrates refined
27:59:00 carbohydrates saturated fats is also something you touched on the camide y you know as well we know palmitate
28:07:00 yep kind of plays into that pathway. And so what role do dietary carbs, refined
28:14:00 versus maybe complex saturated fats play? And then is this all in the the
28:21:00 background of caloric excess or or you know being in a deficit? Does that matter as well? The mixture of the two
28:26:00 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
28:32:00 calories. And this is where I need to be careful because the the degree of studies that have looked at these
28:38:00 interventions that you’re alluding to and I’ll touch on more now in low calorie or hyperc calorie, it’s not been
28:43:00 fully fleshed out, but I would think it’s safe to say if there is a caloric
28:50:00 deficit, then it becomes less relevant um which of the the balance of saturated
28:55:00 fats to refined carbs. Now then someone would say, “Well, then let’s just always live in a caloric deficit.” Yeah, good
29:01:00 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
29:09:00 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
29:15:00 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
29:21:00 to counter that by saying that’s not really feasible long term. You know, people get hungry. Hunger always wins.
29:26:00 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
29:32:00 chronic low calorie state. So my view on so saturated fats is one of the more
29:38:00 polarizing topics and I’m very comfortable talking about it because my entire post-doal fellowship was looking
29:45:00 at I shouldn’t say entire my biggest paper ever published was looking at the degree to which different fatty acids
29:53:00 are capable of causing insulin resistance through the conversion into ceramides. And I’m going to upset some
29:59:00 people, but in cell cultures and if you treat cells with saturated fat,
30:05:00 pulmitate, which is the main saturated fat in the body, you get insulin resistance very quickly. Now, if you
30:11:00 block ceramides, you resolve that insulin resistance. If you treat those cells with monounsaturated fatty acid,
30:18:00 no insulin resistance. If you treat those cells with polyunsaturated fatty acid, no insulin resistance. So, as much
30:26:00 as there is, and I believe it’s justified, a very heavy focus on seed oils, I I approve of that focus, I think
30:31:00 they’re pathogenic, but I grimace when people invoke them as a primary cause of
30:39:00 insulin resistance because the data do not support it. Again, I think they’re very harmful. Um, but not when it comes
30:44:00 to insulin resistance because you can in fact we would treat cells with palmitate
30:51:00 cause insulin resistance, co- treat them, co-incubate the cells with either oleic acid or linoleic acid and we would
30:57:00 reverse the insulin resistance. Now, I do not mean to give seed oils a pass. I
31:03:00 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
31:10:00 them really. Yeah. Yeah. And and meat, I mean, literally any animal source of of fat, any animal food has some linoleic
31:17:00 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
31:22:00 saturated fat, that my own work when I published that paper in
31:30:00 uh 2010 maybe, um I I left that project with this idea that saturated fats are
31:35:00 thus a cause of insulin resistance. And I had to challenge my own assumptions
31:40:00 when I saw the work of Dr. Jeff Volic, a friend and a legend in the realm of low
31:46:00 carbohydrate studies because he published some incredibly compelling papers
31:52:00 over a few papers. He found that I I had to sort of challenge the model
31:57:00 where I thought all right I was treating cells with saturated fat. Is that the same as a human eating it? And of course
32:04:00 it’s not. And now to touch on his work, you can have uh humans that if if the
32:11:00 carbohydrate levels are going down, they can eat two or three or four times more saturated fat than a high carb group.
32:18:00 And then they’re circulating levels of saturated fat. So the saturated fat in some in the plasma is significantly
32:24:00 lower. That’s because most of the saturated fat that’s flowing through our veins is
32:30:00 coming from the liver. When the liver is told to make fat through denovo lipogenesis, the fat that it makes is
32:36:00 palmitate. So most of the fat, most of the saturated fat we have flowing through our blood that’s going to get to
32:42:00 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
32:48:00 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
32:55:00 clear. So, the lower carbs are getting, the more you can eat saturated fat and appear to have no deficit.
33:00:00 I’m very comfortable with that. No deficit in no problem with insulin resistance. Insulin resistance. Okay. And indeed,
33:06:00 but calories aren’t an issue in that in that context. I don’t recall whether they had it in a
33:11:00 low calorie context or not. I would suspect because insulin is low. Once again, you probably have a little more
33:17:00 of that metabolic wiggle room um with the higher metabolic rate and then the ketone wasting. So, it starts
33:24:00 to get a little cloudy as to because the saturated fat scenario is they that there is definitely a pathway
33:31:00 to insulin resistance. Um, however, it seems as though if you’re more of a ketogenic type of
33:36:00 eater, low carb, ketogenic type of eater, that pathway doesn’t seem to be
33:41:00 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
33:45:00 are getting, the less the dietary saturated fat matters. Now, in the context of a higher carb diet, as much
33:48:00 Why refined carbs amplify risks from saturated fat
33:54:00 as it pains me to admit because I’m such a defender of saturated fats, there are a couple studies that are very well
34:00:00 done. If I recall, it was some groups in Europe um in the European Journal of Clinical Nutrition where they had in the
34:07:00 context of a high carb diet and then manipulating the saturation of fats, the high carb and highsaturated fat was the
34:14:00 worst for insulin resistance and insulin signaling. And so when it comes to again
34:21:00 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
34:26:00 from natural sources I I which is where they come from that begins to be problematic.
34:33:00 I I think it’s problematic and not just you know for for for metabolic health but cardioabolic health. I mean that’s
34:39:00 where you get small dense LDL particles. Again it’s the combination of the saturated fat and the refined
34:46:00 carbohydrates. Are we talking about when you’re having, you know, a high saturated fat diet in combination with
34:53:00 what you call carbohydrate, high carb? I mean, is this what if you’re eating, you know, fruits and vegetables and, you
34:59:00 know, maybe some oats? Is that the same as eating cookies and
35:04:00 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
35:11:00 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
35:17:00 effect of those carbs. So if these are low glycemic load type carbs where the insulin response is going to be very
35:25:00 modest, right? Insulin itself causes insulin resistance and again rapidly and and so what I
35:30:00 think is if you take the context of an insulin spike with a saturated fat load,
35:37:00 that’s uniquely harmful with regards to insulin resistance. So, back to the idea of what are the carbs. I think if you’re
35:43:00 talking about the low glycemic load carbs like cruciferous vegetables and berries and citrus fruits, for example,
35:49:00 now there’s almost nothing and then you chase that down with a tablespoon of coconut oil, the most sat the most
35:56:00 concentrated form of saturated fat on the planet. I think you’re fine. Well, coconut oil is a bit of a an outlier
36:03:00 because so much of it’s MCT which doesn’t follow which is not a substrate for ceramides. So, it doesn’t quite fit.
36:10:00 But in that case, no, I think that’s would be perfectly fine. But you are touching on what is to me the obvious
36:16:00 villain. As much as we have increasingly two camps of people saying no, it’s the seed oils and I’m generally more just
36:22:00 because I’m an insulin resistance guy in the notes refined starches and sugars. The fact is they always come together.
36:29:00 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
36:35:00 get your food from bags and boxes with barcodes, you’re getting rid of both the refined starches and sugars and the
36:40:00 refined oils. Anything else is going to be fine for the average for most people.
36:45:00 Just less bags and boxes with barcodes, mole more whole foods, you’re fine. And but what about like fructose versus
36:47:00 Fructose vs. refined sugar—which spikes insulin more?
36:53:00 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.
36:59:00 No, it absolutely is not. No, fructose itself will not elicit an insulin response whatsoever. Now, the body will
37:04:00 convert some of that fructose to glucose, which is why the diabetic who’s gone hypoglycemic can just drink a cup
37:10:00 of orange juice and within minutes it’ll start to, you know, that’s such a concentrated load of fructose that they
37:15:00 will see a glycemic excursion. But no, fructose isn’t the same. But even still,
37:20:00 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
37:27:00 to an overweight type two diabetic, then I say, “All right, well, the most sugary of the fruits, just be more careful with
37:32:00 like say mango or a banana.” Um, then I would say, “All right, you maybe want to
37:38:00 be a little more careful because your disorder is you don’t burn glucose. You don’t burn sugar very well. And so you
37:40:00 just be careful with the most sugary of the fruits, but then everything else enjoy liberally.
37:44:00 High-carb vs. keto—which diet controls hunger better?
37:50:00 Um, so with respect to insulin resistance and
37:55:00 weight loss and obesity and what’s causing like the cause of these things, right? I mean, this is where we get into
38:03:00 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
38:08:00 the other better? And that’s where Kevin Hall’s study was kind of interesting. I’d love to get your thoughts because
38:14:00 so he’s published a study back in 2021 NAH did a pretty well-controlled study
38:20:00 where people were on a high higher carb diet or they were on a ketogenic diet and they were isocaloric so same
38:26:00 calories but if I recall the no in fact they were they were able it was ad limitum
38:32:00 and then they found they found that the plant-based group just spontaneously ate less
38:38:00 so yeah so the 2021 study they one of The powers of that study and it’s not a
38:44:00 perfect one which I can articulate was that they allowed them to just eat freely but you got to follow these kinds
38:52:00 of balance and you follow this pattern you follow that pattern and if I recall the plant-based he he um rejoiced in the
38:57:00 fact that it challenged the carbohydrate insulin theory of obesity which I can
39:03:00 articulate in a moment because they found that the higher carb group spontaneously ate about 700 calories a
39:09:00 day less. Does that sound right? I think that’s right. So they they just spontaneously were eating less because
39:15:00 they could eat freely. They just ate and 700 calories a day is a meaningful amount
39:21:00 to just spontaneously eat less of. That did challenge the idea because one view
39:29:00 I actually don’t like. But they lose more fat as well. Yeah, they did. They did. Yeah. But it was this is modest. I mean to to to to
39:36:00 be fair to the study they did a good job controlling it. to be a little critical of the study. The findings were
39:42:00 exceptionally modest. This is the kind of thing where it was like one pound versus two pounds and it was two weeks
39:48:00 and it was a very small study and and a lot of what Kevin has done is a lot of these kind of mathematical modeling
39:54:00 outcomes where they sort of speculate or extrapolate beyond the data that they get. So they they found that they
40:00:00 spontaneously ate 700 calories a day less. that challenged one of the central
40:07:00 ideas of the carbohydrate insulin model, which is if you spike insulin, you get hungry. And he was saying, well, they
40:13:00 ate all these carbs. Mind you, it was mostly plant-based complex carbs. Exactly. So, that’s right. And so, it’s
40:18:00 almost it’s a little unfair because that’s not how most people are getting their carbs these days. And and just to
40:24:00 put a fine point on that point, 70% of all calories consumed globally, it’s
40:31:00 about 60% in the US, are carbohydrates. And they’re not coming from leafy greens and berries and and you know, citrus
40:38:00 fruits. It’s coming from bags and boxes with barcodes. But nevertheless, that’s an interesting finding. My my
40:46:00 criticism of that is one, it’s an extremely short-term study, and there are longer studies that we ought to
40:51:00 highlight just to offset this very short study, but at the same time, when you’re
40:57:00 eating so much fruits and vegetables, you’re putting a lot of bulk in your stomach. And it didn’t surprise me that
41:02:00 these may be people who within just two weeks on this diet were just probably
41:09:00 having a lot of bloating and gas um from eating a lot of plants when they probably weren’t eating that many plants
41:15:00 before they started the diet. So it didn’t entirely surprise me that they were spontaneously eating less. I would
41:21:00 personally enjoy eating more meat than I would big leafy greens and and other
41:28:00 fruits and vegetables. So I would probably eat more calories. the fact at the end of the two weeks. In fact, what’s funny is I looked at the outcome
41:33:00 and thought, “Okay, the low carb group was eating 700 calories more per day and
41:40:00 you’re telling me they only gained like one more they only had one more pound of fat.” If anything, you could have looked
41:46:00 at all that data and said, “Wow, there is a metabolic advantage to a low carb diet.” And in fact, some of the studies
41:52:00 Kevin Hall of his own work that he’s tried to distance himself from is finding that in a ketogenic state,
41:58:00 people have a significantly higher metabolic rate. And so perhaps one outcome of that study is that when a
42:03:00 person gets to ketosis, they were able to eat 700 calories more
42:08:00 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
42:11:00 Why low-carb diets might provide a metabolic advantage
42:17:00 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
42:23:00 very good at that, but um uh over a hundred years ago, two famous legendary
42:28:00 scientists um Francis Benedict, who you and I may recall wrote, uh created
42:34:00 what’s called the Benedict equation, which is an equation that is still used to this day to try to assess metabolic
42:42:00 rate based on someone’s body size. So the Benedict equation this legend of energy expenditure he collaborated with
42:48:00 Elliot P. Joselyn the who the most famous endocrinology clinic in the world
42:54:00 the Joslyn diabetes centers named after him. So you had these two legends in their own realm who tried to understand
43:00:00 the metabolism of people in what they called severe diabetes which we would call type one. They found that their
43:06:00 metabolic rate was about 20% too high. And then years later when insulin began
43:13:00 to be a therapy, a group at Minnesota uh the first author is N Share N AIR they
43:20:00 not only confirmed the findings from 60 or 70 years earlier that in type 1 diabetes the metabolic rate is too high
43:26:00 like something’s broken they’re burning too hot but when you gave them insulin within minutes the metabolic rate began
43:32:00 to slow down and so all of this back to that study from 2021 the reason I even
43:38:00 brought all of this up is to me That’s further evidence of the lower insulin gets like with a low carb diet, the more
43:43:00 metabolic wiggle room a person has where energy expenditures up by several
43:49:00 hundred calories a day. And and we found in human work that part of it is because
43:54:00 the fat tissue starts having a much higher metabolic rate when insulin comes down. There’s much more mitochondrial
44:00:00 uncoupling. So the engine is just revving and revving and burning energy just to create heat. But at the same
44:07:00 time, the more you’re making ketones, the more you’re expelling those ketones. And ketones are calories. And so maybe
44:13:00 those 700 calories a day that the low carb group was eating in excess, the fact that they only had one other pound
44:15:00 of fat could be that they were just burning the rest off because of these metabolic advantages.
44:18:00 Does exercise give you metabolic ‘wiggle room’?
44:24:00 Well, speaking of wiggle room, I mean, we’re talking about a variety of scenarios here where people can have
44:30:00 wiggle room. We talked about, you know, being in caloric deficit gives you a little more wiggle room. Yep. being in a ketogenic or, you know, close to a
44:36:00 ketogenic state seems to give you more wiggle room. Um, but what about being like highly physically active?
44:42:00 Absolutely. Yeah. Good. I love how you’re framing that with this context, these themes of wiggle room. Where do
44:48:00 you have a little bit of margin to work with? Yeah. Absolutely. Exercise is one of those other
44:54:00 uh outlet, if you will, where if you have energy that you need to account for, exercise is going to be a wonderful
45:02:00 way to do it. Um I I often don’t focus so much on ins on exercise because I
45:09:00 don’t want to convey to people that it can outdo the diet. There there was a paper published in women where they
45:14:00 looked at a very structured and intense exercise program with just it was I
45:23:00 think it was just low carb diet and the low carb diet had better metabolic improvements than the strength training did. And so diet is going to generally
45:29:00 smart smartly done diet. So changing nutrition is going to yield better long-term benefits with metabolic
45:38:00 health. However, the I’m an enormous advocate of exercise. Uh and to me, you are not
45:44:00 going to go it’s one thing to be metabolically healthy and lean, but then
45:51:00 it’s something else to be lean and sick or or or or weak or frail. And that’s where to me the exercise comes in. So my
45:57:00 my view is you eat smart to be lean and metabolically sound. You exercise to be
46:02:00 strong and capable and metabolically sound. So muscle of course is the great
46:09:00 glucose consumer. When if someone’s wearing their CGM and they see the glucose come up and down, 80% of that
46:16:00 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
46:22:00 muscle you have, the more you’re going to have this big buffer or what we’re calling wiggle room where you’re going
46:29:00 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
46:34:00 having more fat and one having more muscle, but otherwise the same, and that’s a big difference, though, I know
46:39:00 they eat the same amount of carbs, the guy with more muscle is going to have his glucose curve come up and down, and
46:46:00 it’ll be back down to normal in an hour, maybe 90 minutes. the person who has less muscle,
46:52:00 even more fat, so same body mass, they’re it’s going to take much much longer for that glucose to come down and
46:57:00 thus it take longer for the insulin to come down because muscle is the main place where insulin is going to escort
47:03:00 the glucose to. And it does so very well if so the more muscle mass a person has,
47:08:00 the more sort of metabolic wiggle room they have to clear that glucose and then
47:15:00 the more carbs they can eat. As much as I really point the finger at carbs as a primary problem, the more they can eat
47:20:00 and even to the point where if a person’s very active, I knew a guy who was training for a marathon, he would
47:26:00 eat over 200 grams of carbs per day and still be in deep ketosis the next morning.
47:31:00 You’d think, well, no, normally a ketogenic diet is no more than 50 grams. Well, unless you’re just burning that
47:38:00 glucose, right? And and also you you mentioned this the study that was comparing strength training to to the you know low
47:45:00 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
47:53:00 we’re talking about how exercise can improve metabolic health and I think it is a really important um le lever to
47:59:00 pull here because you you’re you’re activating these glute for transporters and it does that like that activation
48:05:00 happens through lactate the generation of lactate which is happening when you’re really pushing yourself hard and
48:10:00 and so at that point, you know, you’re you’re becoming insulin sensitive, too, right? So, you’re you’re really kind of
48:16:00 changing the the the scenario in some ways. It doesn’t I don’t personally think it should give people the um
48:23:00 justification to go and eat tons of pizzas and, you know, ice cream and all all that stuff. Um, all you know,
48:31:00 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
48:39:00 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
48:42:00 extremely important especially like there’s different types of exercises that that was kind of another question you know the strength training versus
48:45:00 Why strength training beats cardio for insulin sensitivity
48:51:00 like really going hard or or the long endurance training right so high intensity interval training you can kind
48:56:00 of get away with doing less time but you’re going really hard right you’re pushing that and I am unapologetically an advocate of
49:04:00 that as much as people may look at their day and say I have one hour I would say everyone man old young strength train
49:10:00 strength train Um, maybe someone I I sometimes question my own motivations
49:16:00 where I just think if I were in a crisis situation, would my ability to run away from the challenge be better than my
49:22:00 ability to face the challenge? No, I don’t think so. Because I’m going to be with my wife and kids and the fact that I can outrun them isn’t going to solve
49:30:00 the problem. And so, I want to be ready to do something if I need to. But even beyond that silly dramatic scenario,
49:36:00 the bigger the muscle, the hungrier the muscle. And given the time constraints that most people have, but even then
49:41:00 there are studies to show that minute form minute at that shorter end if a person’s spending I think it was like 30
49:46:00 minutes a day the strength training group had better improvements in insulin sensitivity than the aerobic training
49:52:00 group. So if you have constrained time and let’s face it everybody does default
49:57:00 to strength training. whatever degree of strength training you can get. And just your to touch on your point about
50:03:00 intensity, just try to go to failure at least at some point during that overall
50:09:00 muscle or that movement. Get to it doesn’t have to be a high weight, low
50:15:00 rep. Even if you’re doing a lower weight, higher rep, just get to failure. Fatigue yourself. Yeah. Fatigue yourself. Yeah.
50:20:00 Yeah. And that’s where like if you’re in the context of aerobic training, I think that’s also like there’s a spectrum,
50:26:00 right? Like what were they doing? They were they able to talk? You know, if they’re really going hard, which zone are they in,
50:32:00 right? You know, it really it does make a difference with respect to your how you’re pushing that lever for for you
50:38:00 know, insulin sensitivity and your glute transporters and them sort of transllocating up to the muscle and
50:40:00 opening the floodgates. And so, um, yeah, it’s it’s nice to know. In other words, there’s there’s many roads to
50:45:00 Should you lower insulin before cutting calories?
50:50:00 Rome and and so I do I I’m just trying to, you know, there’s there’s definitely
50:55:00 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
51:02:00 lot of things going on here. And yes, having a low carb diet can be very beneficial for insulin sensitivity, for
51:08:00 staving off insulin resistance, but there’s also people that are not going to eat a low carb diet and they can
51:14:00 still be very metabolically healthy, particularly if they’re avoiding refined carbohydrates. they’re exercising, they’re not overeating, they’re not in a
51:20:00 caloric surplus. Um, and then there’s people that hear saturated fats okay and
51:27:00 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
51:33:00 scenario where you’re combining the two. Yeah. Well, anytime Yeah. To me, highfat, high carb is the worst
51:40:00 combination for every outcome. You’d mentioned cardioabolic with regards to adverse changes in lipoprotein profile.
51:46:00 Absolutely. I agree with that. But high carb and highfat just bringing it back to the fat cell. You are now giving it a
51:52:00 stimulus of insulin which is telling the fat cell to get big and the fat cell wants to get big most easily just by
51:59:00 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
52:05:00 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
52:10:00 but then having touched on what causes the growth of the fat. Well, naturally, it begs the question, what shrinks the
52:17:00 fat cell? Well, you look at those two levers, the the high insulin and the high calorie, you have to pick one. My
52:24:00 only worry is, as much as people are so ardently defending the caloric view, which they have for a century now. Um,
52:29:00 if you just cut calories without addressing someone’s underlying high insulin, you’re going to make them
52:34:00 hungry very quickly. And that’s one of the reasons why I speak to the insulin
52:39:00 side. As much as I acknowledge the calorie side, I think that is a step to take. It just shouldn’t be the first
52:45:00 step. What I like to see as the first step is control your insulin. Okay, how
52:50:00 do I do that? Well, reduce your consumption of refined carbs. So, make sure you’re getting a lot of good
52:56:00 protein and fat and then fruits and vegetables. That’s going to help your
53:01:00 insulin come down. Don’t worry about your calories yet. We’ll get there later. And just by focusing on the
53:06:00 lowering insulin aspect, you have the metabolic advantages come into place, which is metabolic rate goes up, calorie
53:12:00 wasting through ketone excretion goes up. And so you’re going to start to lose weight. And then if you get when you get
53:18:00 to that next sort of plateau, all right, now we can look at that calorie side because with lower insulin, your brain
53:24:00 is more accustomed to using ketones now and you’re more accustomed to you mobilizing fat. You have more
53:31:00 mitochondria because you’ve been burning more fat with low insulin. Now you can start cutting calories and
53:37:00 not have to worry about hunger kicking you out. The most obvious example of the
53:44:00 problem with just going after calories without addressing a high insulin would be perhaps like The Biggest Loser where
53:49:00 you never see a reunion tour with those poor contestants because they gain
55:52:00 everything back, right? Hunger always wins. It’s true. Um, I definitely we’re going
53:55:00 Does meal frequency drive insulin resistance?
54:00:00 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
54:06:00 about a little bit more about what’s the underlying cause of insulin resistance. We’ve talked about diet composition.
54:12:00 Um, that’s a big one. What about meal frequency? So, how often
54:18:00 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
54:24:00 worker, how does that play a role? Yeah. Oh well, we pity the the shift workers and bless them for everything
54:31:00 they’re doing for community, but that’s the worst way to do it. So, um, with regards to meal frequency, I think that
54:37:00 our the advice that we’ve been giving since the 19 unofficially since the
54:42:00 1960s, officially since the late 1970s of high carb diet and then what
54:48:00 transitioned into with the food guide pyramid and then what transitioned into eating multiple small meals per day. I
54:54:00 think the proof is in the pudding, which is that’s how most people eat. They eat a starchy, sugary, terrible breakfast,
55:01:00 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
55:07:00 consequences, which is insulin resistance and obesity are the most common problems. Even where obesity is
55:14:00 not common, insulin resistance is still common. Um, not to go on a tangent too much, but even countries like Japan or
55:20:00 Singapore, my second home, one of my kids was born there. I did my fellowship in Singapore. Why would the beautiful
55:26:00 little island of Singapore care so much about diabetes when the average Singaporean is incredibly lean? Because
55:32:00 their rates of diabetes are higher than ours by a lot. We’re not even close to the most diabetic country. And that
55:38:00 actually comes back to how we store fat. So with regards to meal frequency and
55:45:00 what we eat, I think high carb diet with abundant calories and eating multiple
55:50:00 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
55:58:00 day where you are controlling carbs. So whole fruits and vegetables, enjoy them. And then good proteins and fats, enjoy
56:04:00 them liberally. But this isn’t convenient in social or
56:10:00 family situations. But the more you can stack your meals to be earlier in the day, the better. So studies that have
56:15:00 looked at humans finding where they do the kind of intermittent fasting or timerestricted eating of you have one
56:23:00 group eat breakfast and lunch, one group eat lunch and supper, the lunch and supper group has worse outcomes. Not
56:28:00 that they’re not better. I mean, any one of those is better than the standard, but when you compare the two, the
56:35:00 outcomes are better for the meals being earlier in the day. Now, you and I are parents. How awkward would it be for me
56:42:00 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
56:48:00 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
56:55:00 lunch and fast through later part of the day, including supper, I’m not going to do that because I care more about being
57:02:00 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
57:09:00 maybe I without I don’t need to explain my own situation but I think that intermittent finding one meal of the day
57:12:00 or at a minimum just have three meals a day and try to have about four hours between those meals and then the most
57:15:00 Is nighttime snacking giving you insomnia?
57:22:00 important thing I would say and this is where we pity the shift workers and thank them it would be evening. Do not
57:28:00 snack in the evening. Especially one of the things I think that people don’t appreciate is as much as they’re
57:34:00 monitoring their sleep and they’re wondering why they have night after night terrible sleep habits, the most
57:39:00 common cause of insomnia is elevated body temperature. So they’re too hot.
57:45:00 And one of the most common causes of being too hot is hypoglycemia. Most people don’t appreciate that. When your
57:52:00 blood glucose levels spike, you you activate your sympathetic nervous system. And of all the times of the day
57:57:00 when your sympathetic nervous system is activated, you don’t want it to be turned on when you’re trying to go to
58:03:00 bed. That’s when you want the parasympathetic to dominate. So when someone eats that evening snack of
58:09:00 spiking their blood sugar, then they go to bed in a hypoglycemic state. They’re going to have all of the signs and
58:16:00 symptoms of anxiety. They’re going to be laying there hot. their heart is going to be beating hard and fast and they’re
58:21:00 going to feel that pulse pounding and wonder what am I anxious about? Why can’t I just sleep? Well, it’s not
58:27:00 because you have anxiety. It’s because you went to bed hypoglycemic. But unfortunately, that is the one time of
58:32:00 day where people are at their weakest. And I’m very sympathetic to that because I feel the same thing. People can walk
58:38:00 past treats and junk food all day and and and deny themselves that knowing
58:43:00 that it’s not good for them. But the moment 6 o’clock comes around or 7:00
58:50:00 then all of a sudden the temptation starts to take on a new form and they can’t they indulge and that is the worst
58:56:00 time. It would be better for them to indulge in that at lunch for example than it would be at that point of the day. Not only metabolically and in
59:02:00 maintaining good insulin sensitivity but not to mention sleep then the compounding consequences of poor sleep
59:05:00 just creates this vicious cycle. Yeah. Okay. So the meal frequency it
59:09:00 Can a sugary breakfast lead to overeating later?
59:14:00 sounds like you know the more you’re each time you’re elevating each time you’re having an insulin response that
59:20:00 insulin is then you’re you’re getting into the fat storage. Yeah. And you will get hungry. Yeah. So so as much as we highlighted
59:27:00 that 2021 study what I ought to have done is highlight the work of Dr. Dr. David Lewig um Cara Ebling and others
59:33:00 and shy at all in New England Journal of Medicine in 2012 where there are there’s so many decades worth of evidence
59:39:00 showing that as much as we had that one study suggesting well the insulin higher insulin group didn’t had less hunger.
59:46:00 Yeah. There’s a lot of evidence showing the opposite. So where you you end up creating this roller coaster of glycemia
59:52:00 and hunger where the person eats a starchy sugary breakfast which let’s face it most breakfasts are these days.
59:59:00 they have this big spike and then when you go high you inevitably go low and then when you go low hunger comes again
1:00:04 even though you may still literally have food in your stomach and yet your brain is starting to sense well I’m hungry
1:00:11 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
1:00:17 David Lewig’s main contributions so anyway it puts the person on this roller coaster of glycemia and every time it
1:00:23 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
1:00:29 to eat six or seven times a day. And if they’re not eating, they’re drinking something sugary, either a soda or a
1:00:35 sugary fruit juice, right? And and the difference between, you know, this sugary type of like
1:00:42 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
1:00:48 and and causing some satiety as well. Um, so that would be something that you would contrast. Not to mention even
1:00:53 in that study in 2021, they probably were doing more complex carbohydrates and not they were Yeah. And it was it was
1:00:59 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
1:01:06 appreciate it, but at the same time, I think we need to um elaborate on the limitations, which is most people aren’t
1:01:12 starting with a breakfast of a big leafy green salad. Um but there is an a group
1:01:17 uh that found that when you have a breakfast and they looked at breakfast and the name of the article was
1:01:23 something like more rapid return of hunger. They it was something like return to hunger was in the title and if
1:01:29 the breakfast isocaloric breakfast so same number of calories protein was clamped and it just differed in the
1:01:34 ratio of fats to carbs. The high carb group was hungrier much sooner and then
1:01:39 ate more for their next meal than the low carb group. And and so I would say
1:01:47 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
1:01:52 and fats, that’s going to be a winning combination of satiety. And then have a
1:01:59 nice lunch and then my view for me personally, I don’t eat breakfast as much as I said I wouldn’t elaborate on
1:02:05 my own uh approach. I eat a big lunch. um that’s my main meal of the day
1:02:12 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
1:02:19 not snack in the evening. But as much as I know, one of the great ironies of being a metabolic scientist and yet a
1:02:24 fallible human um with bad habits sometimes is that evening time is still
1:02:30 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
1:02:35 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
1:02:41 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
1:02:46 little darling babies, but I do it because I don’t want cereal in the home because if there’s cereal in the home,
1:02:52 daddy is a meth addict when it comes to cereal. And if it’s there, as much as I
1:02:58 know, I will like go through this like I can almost script it out where
1:03:05 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
1:03:11 right now. And so then I will eat myself sick. And like a true addict, I will
1:03:17 tell myself, I’ll just have one bowl. What’s the problem with one bowl? And then yet there’s this little shoulder
1:03:23 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
1:03:29 just gonna have one bowl. I never My wife can, though. My wife has this
1:03:36 uncanny alien-like ability to eat something like this, something sweet like an ice cream or a cereal, and just
1:03:41 have a little bit of it and be done. I can’t do that. She is a moderator and I
1:03:47 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
1:03:52 modern the most popular modern mantra when it
1:03:59 comes to nutrition is moderation and all things. What if you can’t moderate? then it would be better not to even start,
1:14:02 right? Um I want to talk about you talked you sort of alluded to this and
1:04:04 Does late-night eating disrupt sleep more than blue light?
1:04:10 this has to do with the other contributing factors to insulin resistance and you were talking about
1:04:15 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
1:04:22 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
1:04:28 systems are all activated thermic effective food you’re hot. So I mean it makes it makes perfect sense and um in
1:04:37 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
1:04:42 people were you know uploading pictures of their meals and it was timestamped and they’re putting comments and like
1:04:48 the most one of the most common comments he was getting was um is disrupting sleep. Eating later was disrupting
1:04:54 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
1:04:59 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
1:05:05 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
1:05:11 thing. I’m convinced I’m convinced that given that the natural uh temptation and inclination people have to indulge
1:05:16 before bed. I’m and and the sleep epidemic, the poor sleep epidemic, I’m
1:05:21 convinced that more of it isn’t blue light. It isn’t evening light exposure or evening activities. It’s you’re going
1:05:27 to bed hypoglycemic and and full. And you’re full. And so, like you said, your your stomach, you’re bubbling, you’re
1:05:34 digesting when No, you ought to have you give yourself at least a few hours before from your last meal. Yep. Before
1:05:40 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,
1:05:41 Can one bad night’s sleep trigger insulin resistance?
1:05:47 that’s the one thing, sleep. So you you were talking about these fast causes of insulin resistance, inflammation, the
1:05:52 the chronic stress, high cortisol, um and then the last one, insulin,
1:05:58 right? Too much insulin. Where where does lack of sleep come into that? Because I have seen I’ve read
1:06:06 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
1:06:11 sleep was entirely wrecked. I mean just entirely wrecked. I mean I aged like 10
1:06:18 years and like but for a good cause but for a good cause. I would do it all over again in a heartbeat. Um
1:06:24 my my postprandial glucose which is what I was monitoring at the time with my continuous glucose monitor was
1:06:31 I mean it was not my normal I mean I was pre-diabetic. It was unreal. Um and so I started looking into
1:06:37 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
1:06:43 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
1:06:49 sleep and everything else. Nothing mattered anymore. I was like, this is real. Like this is the real deal here.
1:06:54 Um and I started looking into the literature where sleep, you know, sleep deprivation after one night,
1:07:00 like half you’re getting four hours of sleep instead of eight. You can be insulin resistant the next day. And I’m
1:07:06 like, what? Oh yeah. So I’d love to hear about that and how that’s contributing to this, you know,
1:07:12 fast cause of insulin. Yes. Well, everything you just said I am nodding to because I I can relate. Um uh
1:07:19 where I when I’ve worn CGMs, I absolutely see that the single most predictive variable of my glycemia in
1:07:26 any given day is how did I sleep? Nothing and that I’ve played around with nothing has even come close.
1:07:33 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
1:07:40 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
1:07:47 result in a much higher and disrupted rhythm of cortisol. And and so cortisol
1:07:55 is will cause insulin resistance in every biological model very quickly. So too will epinephrine. And epinephrine is
1:08:00 another stress hormone, sort of the faster stress hormone, the cortisol being a little more delayed. But both of
1:08:05 them are higher um with regards to sleep deprivation. And even even epinephrine,
1:08:11 even adrenaline can cause insulin resistance in humans. If you do a steady little drip in a human of adrenaline,
1:08:17 they’re going to be insulin resistant with demonstrabably insulin resistant within just an hour or two. To make so
1:08:22 that’s how sleep deprivation causes uh insulin resistance. And to make matters
1:08:28 even worse, what is the most common intervention to try to offset the negative consequences of sleep
1:08:34 deprivation? Well, it’s more caffeine. Well, more caffeine is going to increase epinephrine even more. Epinephrine
1:08:41 causes insulin resistance. So, even the solution to the sleep deprivation ends up inadvertently compounding the
1:08:47 metabolic consequences of the sleep deprivation. Now, that’s not to say epinephrine uh it’s not to say caffeine
1:08:53 doesn’t have some metabolic benefits. It can when used correctly, like I would say when used in the context of
1:08:59 performance. But for someone who’s trying to offset the consequences of their sleep deprivation, you may have
1:09:05 some increased alertness. Yes, but the metabolic consequences of the sleep have now just been added on. Before we
1:09:10 continue, I just want to mention something important. If you’re finding these episodes valuable, please consider
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1:09:30 it. Now, back to the episode. Um, what about So, we’re talking about um other
1:09:36 Can air pollution cause weight gain?
1:09:41 causes of insulin resistance. You’ve also kind of looked into some of this other stuff that’s very interesting with
1:09:48 respect to environmental toxins. Yeah. and how air particulate matter from air pollution perhaps even
1:09:54 plastic associated chemicals or microplastics how those those can contribute is that something that’s
1:10:00 meaningful like the sleep deprivation the cortisol sounds pretty meaningful um are these other talk about it and
1:10:05 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
1:10:11 because as much as I found that work and still do really really cool and we’re
1:10:18 doing more of it so so to articulate what we’ve done So far we’ve published reports looking at PM2.5 diesel exhaust
1:10:23 particles and we published another report looking at cigarette smoke with
1:10:28 the cigarette smoke particles that was purely in the context of ceramides
1:10:34 forced mitochondrial fision and insulin resistance and the cigarette smoke did all of those things. The newer paper
1:10:42 that we published about a year or two ago was I think the first to find that if you just have increased diesel
1:10:48 exhaust particles even when we calorie clamped these we pair fed these animals and the animals that were inhaling more
1:10:55 of the diesel particles at physiological levels like at a level that a human could be exposed to they had much fatter
1:11:01 fat cells. So they had much more atyposite hypertrophy um which accounted for a higher body fat
1:11:08 mass even though they were eating the exact same amount of calories. Again we pair fed them. We only let them eat as
1:11:13 much calories as the other group was eating and they still had more fat. So it does suggest that there are
1:11:19 non-nutritive stimuli. You’d mentioned some others. We’ve not done work on microplastics or
1:11:26 the plasticizers those like dethyl stillbsterol and and BPA but those also
1:11:34 have been shown to promote greater fat expansion in the absence of calorie changes. That’s another reason why I I
1:11:40 think that it’s we don’t do ourselves any favors when we only have a calorie centric view of obesity because there
1:11:45 are more variables that come into play here. Now, to answer the last part of your question, which is to what degree
1:11:50 should the average person be worried about that I pains me to say this
1:11:55 because it’s my own work. I think that’s a that’s a lower tier concern. It’s also
1:12:01 one that some people may not literally be able to do anything about. You know, like if you are simply living in an
1:12:08 inner city area and there’s just pollution, there’s nothing you can really do. Maybe you can replace your intern your inhome
1:12:14 air filter more frequently and get one and but those aren’t cheap either. So I’m very mindful of the financial
1:12:20 constraints of the person who we may be fictionally talking about. But I guess other than that would be the only thing
1:12:26 you could do if you could have a better in-home purifier, great. But for the vast majority of people who couldn’t
1:12:33 even quantify their their pollution exposure, let alone afford an intervention to reduce it, the good news
1:12:39 is that’s going to have a much lower effect than just changing your nutritional and exercise habits.
1:12:45 Yeah, there are there are some more affordable hepailters now that do seem to kind of u make a dent in reducing
1:12:51 particulate matter. And um but it’s interesting that this this air pollution is really
1:12:58 it seems like pretty pervasive like it’s not just metabolic health but it’s Alzheimer’s disease. I mean it seems
1:13:04 like it’s a cardiovascular disease. I mean it’s really affecting lungs of course you know respiratory health. It’s
1:13:10 affecting so many different chronic diseases as well. And so um it is it is important to keep the context in
1:13:18 perspective right obviously diet you know exercise these things are the most important when it comes to metabolic health but But but matter they
1:13:20 do and not just for metabolic health for a variety just our overall health right and
1:13:23 Vaping vs. smoking—which is worse for metabolic health?
1:13:29 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
1:13:36 preliminary data now when we look at the superheated particles which is what you’re inhaling we’ve we finding we
1:13:41 haven’t published this yet so this is unpublished my master student is this is her thesis project right now so the data
1:13:46 is forthcoming but the early data suggests that it’s it actually at at a
1:13:54 relatively controlled um dose matching it for the cigarette smoke dose that we used previously it’s worse so with now I
1:14:00 can’t speak to the consequences of the tumor agenesis effects like maybe the person’s going to have slightly better
1:14:06 outcomes with cancer but when we’re looking at forced the outcome we’ve measured so far is mitochondrial um
1:14:12 outcomes looking at the degree to which the mitochondria can take in oxygen and convert it to ATP rather than the oxygen
1:14:19 being converted into super oxide radical It’s worse with the superheated particles from the vaping than from the
1:14:24 cigarette smoke. Do you think this is coming down to nicotine or other things in the vape?
1:14:30 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
1:14:37 which culprit if one culprit is more uh to blame with regards to the EIG
1:14:42 exposure versus the cigarette because it is different chemicals. Yeah. Right. No, I’d be I’m going to you
1:14:45 have to let me know. I’m in that. Um I before we get into some solutions here,
1:14:48 Can statins and antidepressants trigger weight gain?
1:14:55 I’d also love to touch on one more thing that I you know you’ve you’ve also looked at with respect to other causes
1:15:01 of insulin resistance and and metabolic health and that is you know commonly prescribed medications. M
1:15:08 and this is something, you know, that I’ve I’ve witnessed firsthand and and friends where they’re, you know,
1:15:15 metabolically healthy, lean, lean and metabolically healthy, and they get on an antid-depressant, for example,
1:15:21 and all of a sudden gain a bunch of weight. I mean, unbelievable amount of weight, you know, 30 to 40 lbs,
1:15:28 and are no longer metabolically healthy. So, um, there’s a there’s a whole host of commonly prescribed medications out
1:15:34 there from lipid lowering medications like statins to antid-depressants and other neuroscychiatric, you know,
1:15:40 disorders and medications that help with those disorders. What what what is that something to be concerned about?
1:15:45 Oh, for sure. Yeah, it absolutely is. And I’ll just mention one that you just mentioned, which is statins, just
1:15:52 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
1:15:58 consequences to messing with cholesterol, lest people forget, cholesterol is a precursor to an
1:16:04 essential component of the electron transport system. And so, it’s no surprise that if people are waging war
1:16:09 on cholesterol synthesis, the mitochondria may suffer. And in women,
1:16:15 uh, middle-aged and older women have a 50% greater risk of developing type 2 diabetes when they get on a statin.
1:16:21 That’s a meaningful increased risk. Women appear to be much more susceptible to the consequences of statins,
1:16:26 metabolic consequences of statins. Not to mention the increased risk of Alzheimer’s and even certain cancers
1:16:32 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
1:16:38 I do think they’re overprescribed. Now, more heavily metabolic, any steroid uh
1:16:44 that’s been prescribed to control inflammation is going to be deeply problematic for weight gain. So if a
1:16:50 person has an autoimmune disease or a chronic inflammatory condition and the clinician has prescribed a
1:16:57 corticosteroid, they’re going to gain weight very very quickly because that starts to play on that stress pathway
1:17:02 where the more cortisol is that pathway is being activated, which is what that’s doing, the more you’re going to make the
1:17:08 body insulin resistant. Higher insulin promotes fat gain. And then just for the sake of time perhaps I just mention the
1:17:13 atypical antiscychotics. The any drug that ends with an apne
1:17:20 um at the end of it the suffix being apne is generally going to promote weight gain. That’s probably through a
1:17:26 central insulin resistance of the hypothalamus. When the hypothalamus becomes insulin resistant, you have a
1:17:20 reduced satiety signal and the person’s just going to start eating more. All right. So, let’s kind of shift gears and
1:17:31 How to reverse insulin resistance in 90 days
1:17:38 talk about some solutions here, protocols to maybe enhance some sensitivity. People that are, you know,
1:17:44 we talked, we started this conversation talking about people who are a large population of people that are actually
1:17:49 pre pre-diabetic. They might be, you know, on their way to insulin resistance or already insulin resistant
1:17:55 and not even really know it. Um what what are some of the best strategies
1:18:00 people can do now to really make a difference and you know dietary
1:18:07 strategies, you know, stress reduction, physical activity, but but also how how
1:18:13 soon can they expect to see changes and what should they look at? Yeah. To see and monitor those changes.
1:18:18 Yeah. Well, in fact, I’ll I’ll start with that last part of your question, which is how quickly can it turn around.
1:18:26 We published a a clinical report. So working collaborating with a local clinic in Utah, we took 11 women with
1:18:31 newly diagnosed type 2 diabetes and their A1C was 8.9%. So very much
1:18:39 diabetic range. And the physician who’s very much on board had given these patients two options. And he said, “You
1:18:44 can leave the office with a prescription for an anti-diabetic drug like metformin
1:18:52 or you can meet with the nutritionist and go through this lifestyle nutrition counseling.” And in just 90 days, their
1:18:58 A1C went down. The average A1C, the average was 8.9 and it went to 5.6. So
1:19:05 no sign of diabetes whatsoever after just 90 days without a pill popped or a
1:19:11 needle injected. So, I have often taken that 90day span as a very reasonable
1:19:16 amount of time to reverse insulin resistance. Now, depending on the scope of the problem, it may take a little
1:19:23 longer to get rid of all of the consequences of the insulin resistance, but I think 90 days is a very reasonable
1:19:28 justified timeline. Again, I say justified based on our own evidence.
1:19:34 Now, what did we tell them? That could sort of segue into the first part of your question. We gave them in fact just
1:19:40 three pieces of advice based on the three macronutrients and I’ve actually kind of already alluded to this which
1:19:46 the first one is control carbs and that was simply this admonition to eat whole
1:19:52 fruits and vegetables. You don’t even need to count it just whole fruits and vegetables but in the case of these type
1:20:00 2 diabetics we said try to be mindful of the most sugary fruits and ve or the starchy fruits and vegetables. So um the
1:20:08 tropical fruits we said please be careful with like b bananas, pineapples, mangoes and then the starchy
1:20:14 if the vegetable grows in the ground eat less of it relatively but all other fruits and vegetables and that’s still a
1:20:20 lot enjoy liberally and then prioritize protein and don’t fear the fat that
1:20:26 comes with that protein. And that was an important caveat because we didn’t want them to be drinking fat, but we wanted
1:20:32 them to acknowledge that in nature all protein comes with fat. Don’t be afraid
1:20:37 of that fat. Um, when humans eat fat with the protein, we digest the protein
1:20:44 better and it’s more anabolic. There’s there’s studies in humans to show that people work out, give them protein,
1:20:50 they’ll have a certain degree of muscle protein synthesis. If you give them protein and fat, it’s even higher than
1:20:56 it was with just the protein alone. Yeah. And that’s most people don’t appreciate that bile when when the
1:21:02 gallbladder from the liver releases the bile into the intestines, we always just think of that as being relevant to fat
1:21:08 digestion and it’s critical for that. But it also enhances proteolytic enzymes. It makes the proteolytic
1:21:13 enzymes more active uh better. They work better. So we digest the protein better
1:21:19 and that may be the mechanism that explains the enhanced muscle protein synthesis from the combination. So that
1:21:26 was the dietary advice we gave them and I would just say that for people that manage your macros, control carbs,
1:21:32 prioritize protein, don’t fear fat. And then when it comes to eating time, I
1:21:38 mentioned it earlier, the more you can stack your meals earlier in the day or at least the bulk of the calories coming
1:21:46 earlier in the day, the better so that you can taper off through evening. And by all means, or please don’t eat within
1:21:52 that 3 to four hour window before bed. As much as you can, don’t don’t eat. And
1:21:57 then exercise. And my view on exercise, as much as we both are, I am an enormous
1:22:02 advocate of exercise. I was a personal trainer back in the day during my master’s degree, and I hated every
1:22:10 minute of it, but I did it. And I appreciate the role of exercise, and I enjoy exercising every day. If people
1:22:18 are wondering what’s the best exercise, my somewhat pathy answer is the one you’ll do. Just do something. If you can
1:22:25 do the sort of higher intense strength training that we were talking about, then please do it. But if this is like
1:22:30 some 80-year-old grandma who just likes walking around with her girlfriends, just walk around with your girlfriends.
1:22:37 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
1:22:43 said for timing it where perhaps you can do your exercise session, if it is a walk around the block a few times with
1:22:50 the gals, do that after your biggest meal. where if you just do 10 to 15 minutes of
1:22:57 physical activity after your biggest glucose spiking meal, you will blunt that glucose excursion by half if not
1:23:02 even better. So what would have been a huge big long glucose spike and a and a
1:23:09 commensurate insulin dose as well, you’re going to cut that down substantially if you did if you do time
1:23:14 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
1:23:19 exercise snack where you had your big meal, maybe hopefully it was lunch, go
1:23:26 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
1:23:33 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.
1:23:39 And so just find a way to get up and do something in little bits, little bits of activity throughout the day, but then
1:23:46 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
1:23:52 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.
1:23:59 Um that’s something that I’ll, you know, try to do after a meal, particularly when I’m on vacation and uh get the
1:24:06 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,
1:24:10 many people ask about these supplements and you know, are there these supplements that can improve insulin
1:24:12 Does apple cider vinegar really lower blood sugar?
1:24:18 sensitivity? So, they you know, you hear everything from magnesium to alphaic acid to bourberine, apple cider vinegar,
1:24:23 and if if there’s any merit to that or taking it before a meal or or is this
1:24:29 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
1:24:36 mentioned works. Um, frankly, the one I like to talk about the most because the evidence is so compelling and it’s so
1:24:43 easy to get. So, bourberine is undoubtedly effective. No doubt it works. Bourberine absolutely works. I
1:24:49 love apple cider vinegar as a personal favorite. Maybe it’s because of my old man palette where I like really tart
1:24:55 things the older I’m getting. So, I just love the taste when I dilute it in water or sparkling water. But apple cider
1:25:03 vinegar that really that that’s the shortest of all short chain fats that acetic acid and the short chain in the
1:25:10 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
1:25:15 spectrum of fats because we don’t really eat a lot of fermented foods anymore. So we don’t get the mediumchain fats and
1:25:21 because we don’t eat any much fermentation fermented foods, we don’t get any short- chain fats for the most
1:25:26 part. So short- chain fatty acids, which is what apple cider vinegar is, is a
1:25:33 really it it that’s a small little molecule that punches well above its its weight, where the acetic acid will
1:25:38 reduce hippatic um gluconogenesis to help control glucose. Um which is very
1:25:45 relevant in a person with diabetes with especially type two. There’s so much glucagon always in their bloodstream,
1:25:50 it’s constantly pushing the liver to make more glucose. Apple cider vinegar
1:25:57 will inhibit that and so it it helps the blood glucose by just having the liver dump less glucose into the blood but it
1:26:03 also stimulates and you’d mentioned glute 4 at the muscle. The reason
1:26:08 exercise is able to open glute 4 or transllocate it and get the glucose in
1:26:14 without insulin is because of EMPK. Uh so it’s that interesting paradox of
1:26:20 exercise where insulin comes down and yet glucose is taking in more the muscle taking in more glucose than it ever was.
1:26:25 It’s because of this kind of backdoor of the muscle exercising. AMPK gets turned
1:26:32 on through a series of events that moves glute 4. Well, apple cider vinegar will do the same thing in the absence of
1:26:38 exercise, albeit to a more modest degree. So, that’s a couple mechanisms among others, including mitochondrial
1:26:44 biogenesis and a little bit of uncoupling, where apple cider vinegar is one of my favorites where if you take a
1:26:49 couple tablespoons before your most starchy meal, you absolutely could
1:26:56 compare the glucose curve from one day to the next and you’ll see that it’s significantly lower with just that tart
1:27:02 little bit of drinking. That’s fascinating because when you’re talking about the short- chain fatty acid, you
1:27:08 know, and I’m thinking, you know, acetate. Yep. So, acetate, acetic acid, we’re going
1:27:13 from acid base. Um, I’m thinking of lactate, lactic acid, lactate, lact, and
1:27:19 that’s when you’re generating with exercise and lactate signaling is to amkin is it’s it’s it’s very much
1:27:27 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
1:27:33 is there something that would be so interesting to look at to see if there’s something going on with lactate acetate
1:27:40 malate, right? Like that’s in like a Granny Smith apple or something like the more sour apple, right? Yep. I mean all these different short
1:27:46 chain fatty acid well the short chain fatty acids that you’re getting from foods and then there’s another mallet’s also in like blueberries
1:27:51 malic acid malic acids in them and then so so I just my my sort of wheels are
1:27:57 turning here when you were mentioning that because it would be so fascinating to see if there’s a common mechanism like why is the
1:28:01 acetic acid work working we know lactate works too um and so I think acetic acid I know beta
1:28:02 Ketone supplements—are the metabolic benefits real?
1:28:10 hydroxybutyrate one of the one of the ways that main ketone not that we’ve talked about ketones Some of my work is on ketones.
1:28:16 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 calorie to
1:28:22 be burned but at the other hand it’s a signaling molecule and it is known to elicit some of its signaling like
1:28:28 anti-inflammatory effects and antioxidant effects. Part of it is through changes elicited because of a
1:28:35 groin coupled receptor where it does have a cell surface receptor that it will activate. I don’t know the degree
1:28:41 to which acetic acid may do the same thing but with regards to beta hydroxybutyrate
1:28:47 even exogenous ketones um that wasn’t one you mentioned but there are increasingly increasing studies showing
1:28:53 that you can have there was just a a study in women with PCOS the only
1:29:00 intervention was to give them exogenous ketones and every outcome related to
1:29:06 metabolic markers and PCOS got better and the only change was the supplementation with exogenous ketones.
1:29:12 I don’t know that that was an effect of the bioenergetics of the ketone. It was probably more of the signaling effect.
1:29:18 And so that would be another thing if a person’s becoming increasingly curious about ketones. And that’s not without
1:29:24 justification. The evidence supporting the the value of ketones is growing uh
1:29:29 and and growing quickly and it ought to. I have never in the past wanted to be
1:29:36 seen as a drum beating advocate of a ketogenic diet. simply knowing that that’s not everyone’s cup of tea. But
1:29:41 increasingly, I will vigorously defend ketones as very beneficial, viable
1:29:46 signaling molecules in the body. So even when it comes to uh controlling the
1:29:53 metabolic response, you’re probably going to eat less because ketones have a very satiating effect um more so than
1:30:00 say glucose does. Um but then they also will impact uh mitochondrial uncoupling
1:30:06 and help the body burn through that glucose faster. No, it’s it’s it’s it’s interesting. Ketone ketones are definitely signaling
1:30:12 molecules and I also think there’s a lot of overlap between lactate and beta hydroxybutyrate as well. I mean, they’re
1:30:17 activating a lot of the same like brain drive neurotrophic factor being one that you know
1:30:24 um and and the you know, I’ve had Dom Dagustinino on the podcast twice. We talked a lot about ketogenic diets and
1:30:29 uh you know, Eric, Dr. Eric Berden talked about them as well. Um, I do
1:30:35 think they’re not the easiest diet for people to follow for for several reasons. Um, including, you know, social
1:30:42 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
1:30:47 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
1:30:53 to do as well, but I’m interested in the brain benefits of ketones. Yep. Um, and
1:30:58 this is where exogenous ketones, I think, become so helpful. Where if you have someone who just says, “I just
1:31:04 don’t want to do the ketogenic diet, but I still would like some of the benefits.” Um, there are so many good
1:31:09 options nowadays that I think I think it becomes a viable approach for someone to say, “I want the ketones, but I want I
1:31:15 don’t want ketogenic, so I’m just going to drink them.” Do you think the dose matters? So like
1:31:22 not only in respect to wanting the right dose of ketones to activate, you know, these beneficial signaling pathways,
1:31:28 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
1:31:34 like, what’s going on here? A little bit anxious, a little bit Yeah. Like you can get I can get, you know,
1:31:40 when 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
1:31:45 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
1:31:52 actually even the earlier in our discussion I mentioned on one of my many tangents Dr. George Cahill’s work and he
1:31:57 was really one of the more more famous prominent what they called at the time
1:32:05 starvation scientists we would call fasting scientists but that same study I mentioned where he they it made you
1:32:11 wonder why was it that these patients who got down to 20 milligrams per deciliter of glucose many people will
1:32:17 say that’s lethal like it’ll kill you and yet they not only didn’t die they had no cognitive deficit whatsoever the
1:32:24 speculation I don’t know whether it was him or maybe Richard Vch in a sort of follow-up commentary, a ketone scientist
1:32:29 who’s also passed away now, where uh if if the brain has adapted to
1:32:35 ketones, it may be more resilient to tolerate a low glucose,
1:32:40 but most people one haven’t adapted to ketones and two don’t even have any
1:32:46 ketones. That’s the problem is because the same intervention for the most part that’s going to drop the glucose in
1:32:51 someone like someone who eats a really sugary meal or drinks it their glucose
1:32:56 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
1:33:02 hypoglycemia. You would say well I should be able to weather that drop because I have
1:33:10 ketones. No, because the same thing that’s that’s helping you reser reverse your glucose, the high insulin is going
1:33:15 to inhibit ketogenesis. And so you’ve deprived your brain in that acute moment
1:33:20 of its primary fuels, uh, glucose and ketones. Although the brain does use lactate
1:33:26 um, as a fuel as well, albeit to lower levels. But if glucose and ketones have
1:33:31 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
1:33:38 earlier, the brain doesn’t have a reservoir of stored energy, a very very modest amount, but its metabolic rate is
1:33:40 so high that it it needs constant supply. Right. Okay. Well, let’s talk a little
1:33:43 Why some ethnicities get diabetes without obesity
1:33:49 bit more about, you know, fat. And we kind of talked about this a little earlier about, you know, not all fat
1:33:55 being equal and a lot of people are thinking about fat as just stored calories, but I mean, there’s much more
1:34:01 to this picture, right? So there’s there there are different ways we store fat and there’s the subcutaneous way,
1:34:07 there’s visceral fat. Um these fats are not the same. Yeah, I know when you were talking you were talking about liver
1:34:13 biopsies, you kept pointing to the abdominal reg region. I was wondering if you were talking about you were getting visceral fat biopsies or probably not.
1:34:18 But um can you talk a little bit about these different types of fat and
1:34:26 what determines whether or not you’re going to store fat subcutaneously versus viscerally? Yeah. why visceral fat is so
1:34:32 dangerous. Yeah. Yeah. So, a lot of that conversation, there’s so many topics I could take with this and perhaps just
1:34:40 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.
1:34:45 So earlier I’d mentioned and it’s a perfect opportunity to bring in different ethnicities because different
1:34:50 ethnicities will store fat differently. And this all is underlying the earlier
1:34:56 conversation of the slow insulin resistance where I said it starts in the fat cell and I very much advocate that
1:35:04 view. So why is it that Singapore 15 years ago was recruiting young scientists to come do diabetes research
1:35:10 where you look at the average body weight in Singapore and by American US standards they’re very lean people and
1:35:16 that’s reflective of all East Asians and and most and many South Asians as well.
1:35:21 So India up through Japan and the Koreas. Um why is it that these are
1:35:28 people with such low body weights and even low body fat levels and yet their diabetes rates are way higher than we
1:35:35 have in the US and that is the difference in how people store fat. So if a human body is gaining fat mass, it
1:35:42 will gain that fat mass through two different mechanisms. It will either be a function of multiplying the fat cells.
1:35:48 So the person will have the ability to make new fat cells. That’s called hyperplasia. And when the fat is
1:35:54 undergoing hyperplasia, the size of the fat cell is staying very modest. So the size of the each individual fat cell is
1:36:00 small, there are just a lot more of them. On the other hand, you could have someone who’s storing more of their fat
1:36:08 through hypertrophy where the number of fat cells is not changing, but the size is the hypertrophic fat cell is a very
1:36:14 sick fat cell for two reasons. And then I’ll explain the ethnic predisposition
1:36:19 predisposition predispositions because of it. So firstly, the fatter the fat
1:36:24 cell gets, the more insulin resistant it becomes to prevent further fat growth.
1:36:30 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
1:36:37 of. It can get 20 times bigger than its original volume. And as it starts to reach this point of maximum dimension,
1:36:45 it has to start limiting its growth. And so it becomes insulin resistant to stop growing. But at the same time, it starts
1:36:53 to become hypoxic where the fat cell has become so big that they’ve pushed each other too far from capillaries and now
1:36:59 it can’t get the oxygen from the capillaries. And so it starts releasing a bunch of pro-inflammatory cytoines
1:37:05 because some of them will work like a trail of breadcrumbs resulting in one capillary having a little budding
1:37:11 capillary grow off and follow the cytoines to the hypoxic or suffocating
1:37:16 fat cell. So the hypertrophic fat cell becomes insulin resistant to stop growth
1:37:24 and it becomes pro-inflammatory to try to correct blood flow. All of which results in a very insulin resistant on
1:37:29 the course to cardioabolic disease body. Now back to the various ethnicities.
1:37:35 Some ethnicities like whites and blacks have the ability to make new fat cells.
1:37:40 So these are ethnicities that can be a little fatter than other ethnicities and yet have lower levels of insulin
1:37:47 resistance and type 2 diabetes. And that’s what we see in the US. High rates of obesity but relatively modest rates
1:37:54 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
1:37:59 look at all the countries in the world and how diabetic they are, we’re about number 70. Whereas Singapore, for
1:38:05 example, and Japan is not too far back. Singapore is I think number nine. this and and all the countries of the Middle
1:38:12 East are actually numbers one through eight are like Oman, Dubai, Jordan, these countries in the Middle East and
1:38:18 and then the other countries sort of round out through Southeast Asia and the Middle East are the and the Pacific
1:38:24 Islands the most diabetic places these ethnicities especially so India has
1:38:29 among it is among the highest most diabetic countries on the planet East
1:38:34 Asia, Southeast Asia their fat cells on average are sign
1:38:40 there the one paper I’m recalling where it looked it took Caucasian men and South Asian men and did an atapose
1:38:46 subcutaneous biopsy and it found that the average South Asian man had
1:38:53 atyposytes that were about four times larger volumetrically than the fat cells in the Caucasian at the same body size
1:39:00 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
1:39:06 up what is more problematic about fat storage storage. It’s not the mass of fat that matters most, but the size of
1:39:13 each fat cell when it comes to slow insulin resistance and the consequences of too much fat mass. And this explains
1:39:19 why say an East Asian fellow will just be moderately overweight
1:39:25 compared to his obese Caucasian counterpart and yet he has all of the
1:39:30 complications of insulin resistance and this guy just doesn’t look good in his speedo and is otherwise fine
1:39:36 metabolically. It’s because his fat cells are small because he has so many of them. His fat cells are so few, but
1:39:42 they’re much larger. And so he has a lower body fat mass, but it’s more harmful because his fat cells are
1:39:47 bigger. And that is the problem with visceral fat. The main there’s nothing
1:39:53 inherently pathogenic about visceral fat. Those fat cells aren’t mystically
1:40:00 harmful. It’s just that that visceral cavity is so limited in volume that it
1:40:05 only allows fat growth through hypertrophy because that is a way to limit the total amount of fat you can
1:40:11 grow. If our visceral fat was able to grow through hyperlasia, then it may
1:40:17 expand so much that it starts to compress our our tissues. It starts to squeeze the liver or squeeze the
1:40:24 intestines or squeeze the kidneys. And so by only allowing visceral fat to grow through hypertrophy, you do limit how
1:40:31 much it can grow, but it also becomes much more pro-inflammatory because hypertrophic fat cells release a lot
1:40:36 more pro-inflammatory cytoines than smaller hyperlastic fat cells. So
1:40:42 there’s very much a genetic ethnic component to this that influences how
1:40:47 ethnicities are able to stimulate the growth of new fat cells. And then there
1:40:53 is there’s absolutely a sex component to it as well which of course is still genetic where women because of the
1:41:01 effects of estrogens are able to stimulate a higher degree of hyperplasia than her male counterparts are. And so
1:41:08 women will have that ability to and this explains why the average woman both has higher fat than her male counterpart and
1:41:14 yet is healthier in every single cardabolic metric. If it was just a matter of fat mass, then women should be
1:41:20 dying more from all these cardioabolic diseases. And yet, they’re not. It’s men. Because women will have more fat
1:41:26 cells, but smaller because of estrogens. Men have relatively lower levels of estrogen. So, we don’t have that
1:41:34 hyperplasia as much as the females do. So, if we’re getting fatter, it’s more through hypertrophy relative to the to
1:41:38 the ladies. Um so with respect to these hyperplasia versus like hypertrophy fat
1:41:40 How oversized fat cells trigger metabolic chaos
1:41:46 cells and I probably should have mentioned the visceral fat the fat lining the organs. You mentioned the
1:41:51 visceral cavity is so this this fats usually like the lining the organs and you usually find it around the midsection
1:41:57 as well. But um you mentioned the the fact that the the
1:42:04 the fat in the atapost tissue will become insulin resistant to basically shut down growth like as a response like
1:42:10 an adaptation like okay we got to stop growing. What about spillover of fat? like is
1:42:16 this feeding into that whole ceramide pathway that you started to talk about where is is visceral fat and is this you
1:42:22 know this hypertrophy like swollen fat cell also causing more ceramides to go
1:42:28 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
1:42:34 long-winded, but here you are slow pitching the the ball to me anyway. So yeah, the problem with that hypertrophic
1:42:40 fat cell is that it’s becoming insulin is trying to still force-feed it to
1:42:45 store more fat and insulin’s main mechanism of promoting fat storage is by
1:42:52 inhibiting lipolysis. So insulin will promote the growth of the fat cell. It does enable the feeding to some degree,
1:43:00 but its most powerful effect is blocking the breakdown. And so the fat cell is saying insulin, I can’t keep you keep
1:43:07 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
1:43:13 together. It’s like a balloon that’s being filled too much. And so, it becomes insulin resistant,
1:43:19 which is manifested as insulin not being able to inhibit lipolysis. Now, we have
1:43:24 a metabolic millu that’s quite odd, where you have
1:43:29 high insulin and high free fatty acids. That does not happen unless the fat
1:43:36 cells are insulin resistant. So just to make that clear, in a fasted state or a low carb state, insulin is low and so
1:43:42 you have more lipolysis. So free fatty acids will be higher. That’s a that’s a very common feature. This is the fasted
1:43:49 state. Low insulin, high free fatty acids. In contrast, the fed state, especially if it has some carbs, now
1:43:56 insulin has gone up. It’s inhibited lipolysis and so free fatty acids will be down. This is the normal. It’s one or
1:44:03 the other. Unless the fat cells are insulin resistant. Now you have high insulin reflective of insulin resistance
1:44:08 but it can’t inhibit lipolysis. Thus we have high free fatty acids. This is a
1:44:14 problem back to the ectopic aspect that you’d mentioned earlier where normally if free fatty acids are high the muscle
1:44:21 will just burn it and the muscle will happily burn free fatty acids or any tissue any cell with the mitochondria
1:44:26 would burn it. But if insulin’s elevated you can’t burn fat. um then fat burning
1:44:34 uh beta oxidation has been inhibited at virtually every single step with high insulin. So now we are storing more fat
1:44:41 as triglycerides which is the ectopic fat deposition. So that’s where you start to have fatty liver. In fact the
1:44:46 main cause of fatty liver is spillover from fat from fat cells especially
1:44:52 visceral fat. That’s the main origin of all that fat. As much as we talk about fructose and other nutritional variables
1:44:58 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
1:45:04 burn it. Normally, the liver would take those fatty acids and just say, “Well, I’m going to burn it into ketones.” But
1:45:10 if insulin’s elevated, it can’t happen. The liver has to store it. The pancreas starts to store it. But as I mentioned
1:45:17 earlier, the triglycerides are not the cause of insulin resistance. But now we have the high insulin, which is an acute
1:45:23 cause of insulin resistance. and a lot of free fatty acids and where some of those are going to be palmitate because
1:45:29 palmitate is some of the stored triglycerides you have pulmitate coming out that will directly be activating
1:45:35 TLR4 the receptor that’s going to then drive ceramides bio uh to be synthesized
1:45:41 so you have a lot and not to mention the inflammatory cytoines that are also being released from the hypertrophic fat
1:45:47 cell at the same time also stimulating ceramide acrruel thus we end up having
1:45:53 the perfect metab metabolic millu to promote insulin resistance and it all started because the fat cells got too
1:45:59 big and not to mention the the with the cytoine signaling you’re talking about now the chronic inflammation I mean
1:46:05 there’s studies now linking visceral fat to cancer you know and so it’s the brain
1:46:11 the cancer incidents it’s allosis cactive protein is a better predictor of heart disease and LDL cholesterol is
1:46:17 and and and the fat cell is the main source of a protein called plasmminogen
1:46:23 activator inhibitor one P AI1 whose main job is to erode clots as they form. So
1:46:30 why is it that bigger fat cells relate so well with stroke and and cardiovascular disease? Because you are
1:46:35 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
1:46:37 Do seed oils silently promote insulin resistance?
1:46:42 and you know someone’s sex in terms of like male or female and how that affects
1:46:49 whether or not they’re going to have this you know predispos predisposition to forming more more fat cells or taking
1:46:56 that fat cell and just expanding it. What what other factors play a role because I mean you know is there a
1:47:02 dietary is there you know some other some other factors that are that are also contributing to that. There is yeah
1:47:09 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
1:47:16 they can contribute to insulin resistance through a secondary route by influencing the dynamics of the fat
1:47:22 cell. Specifically, when linoleic acid is taken into the cell, one of its
1:47:28 peroxide metabolites that it can turn into is a molecule called 4 H&H
1:47:34 has been shown to inhibit the fat cells potential for hyperplasia, thus forcing
1:47:41 the fat cell to only go down hypertrophy. So if there is some nutritional link that can drive fat cell
1:47:46 storage into one versus the other um linoleic acid does have that effect.
1:47:52 Linoleic acid being converted to 4H and& will inhibit the atypogenic uh
1:47:57 hyperlastic signaling and only enable the hypertrophic signal.
1:48:02 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.
1:48:09 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
1:48:15 chatting earlier linoleic acid is ubiquitous in nature you need it.
1:48:21 Yes. Yes. You have to have it. So as much as I’m talking about it and invoking it as a problem.
1:48:28 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
1:48:33 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
1:48:38 in it. I would maybe counter or not counter by just stating that those also
1:48:45 in nature when you have the omega-6 linoleic acid you often also have an omega-3 that comes with it. That to me
1:48:51 is key that if you’re con and often it’ll have some degree even minuscule
1:48:57 levels of vitamin E. Vitamin E will help that linoleic acid not go down the
1:49:03 pathway of peroxidation. It’ll help it just go down the pathway of oxidation.
1:49:08 Even Dr. Steven Kunain, this incredible man, just a delightful individual, he’s
1:49:14 done a lot of work documenting the fact that linoleic acid when it’s allowed to
1:49:19 just be burned for fuel burns so high and so rapid that it create it allows
1:49:25 the brain to create its own ketones. He has a fascinating area of research on this. So, I’ve always tried to have a
1:49:30 little bit of a nuanced view of linoleic acid in that it’s everywhere, but when
1:49:37 we get it in nature, it’ll come with an omega-3 and it’ll come with some amount of often vitamin E, which will help
1:49:44 prevent the linoleic acid from going down the pathway of becoming a villain, which it can. Um, linoleic acid will
1:49:50 undergo peroxidation very readily and become a very harmful series of metabolites that are harmful to cell
1:49:54 membranes and mitochondrial membranes. Is that is that though more because I you know I’ve looked a lot at the
1:49:55 Seed oils—always harmful or only when heated?
1:50:03 literature here and I remember I first was I was submitting a paper and I was going off about how terrible omega6 high
1:50:09 omega6 and you know it wasn’t necessarily from seed oil but it was kind of going that way and um and a
1:50:15 reviewer just kind of just got me hard and I started to really have to look at
1:50:22 this with a different perspective and go into the literature and um I really was shocked by how much of
1:50:29 the literature is showing with these, you know, lenolic acid and even, you know, switching saturated fat with these
1:50:34 polyunsaturated fat seed oils, um, were either neutral or beneficial,
1:50:40 um, with the exception of like maybe one study, but like the bulk of them were not showing that. Yeah. And it wasn’t
1:50:47 until I started to really dive deep and see like okay it’s like this heated seed oils and when you start to heat them
1:50:52 especially if you’re like heating them very very high temperatures or you’re heating them over again where they’re
1:50:59 becoming problematic at least at least with respect to some of the biomarkers that were being looked at like inflammatory biomarkers. Um, so I’m
1:51:05 wondering like is is the heating the seed oils the bigger problem the consuming them in this really
1:51:10 concentrated form and heating them and the whole package that they’re you know the friends that they’re they’re
1:51:15 bringing along, right? People are consuming these seed oils in processed foods, right? They’re all in
1:51:21 processed foods um versus eating some like you said meats, you know, walnut. I I mentioned nuts because they have a
1:51:28 higher ratio, but they also, you know, have omega-3s as well. So, I do think it’s a nuanced topic as well, but I
1:51:34 don’t want people to like be so scared of just anything with linoleic acid, right? No, and I totally agree. I would
1:51:39 also just say I’m also not the person to tackle the seed oil topic. There would
1:51:47 be other people who would be way more articulate on both sides, attacking and defending. I’ve only tried to view that.
1:51:54 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
1:52:01 to be a little cautious because as much as people will invoke linoleic acid for causing all heart disease, all fatty
1:52:08 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,
1:52:14 of I’m looking at metabolic outcomes. So having said all of that, I think what
1:52:20 you just said is what I would agree with in that I think it’s appropriate to
1:52:27 scrutinize seed oils because of how we eat them. Um, we eat them from refined seed oil sources. Dr.
1:52:33 Christopher Ramston at the NIH a number of years ago published a report finding that soybean oil has become the number
1:52:39 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
1:52:46 them seed oils rather than linoleic acid coming from all natural animal sourced
1:52:52 foods, which I’m always an advocate of. Dairy has linoleic acid in it. Meat has linoleic acid in it. They all do. Seeds
1:53:00 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.
1:53:06 And those help to varying degrees reduce the pathogenicity. Even if the linoleic acid was had the potential to be
1:53:12 harmful, which it does through peroxidation more than the other fats do, these other characters that are
1:53:19 coming along with it help it behave and act in a way that we want it to act because it is everywhere. It is
1:53:26 ubiquitous. And so I think where you and I would agree and maybe others would disagree, I don’t have a fear of
1:53:31 linoleic acid per se as an omega-6 in so far as it’s going to come in every natural
1:53:37 source of fat that I’m eating. But where earlier I’d said control carbs. If
1:53:42 you’re controlling your carbs by, and pardon me for repeating again, not getting your carbs from bags and boxes
1:53:49 with barcodes, you’ve also eliminated essentially all of those refined seed oils from your diet, too. And that’s why
1:53:55 I also don’t like getting caught up in the is it seed oil or carbs. They always these refined carbs, they always come
1:54:01 together. So as much as I am the guy who’s saying, “Well, refined starches and sugars are a real problem.” And
1:54:08 every someone else would say, “No, it’s the seed oils.” And I’d say, “You know what? Fine. They’re coming together anyway.”
1:54:15 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
1:54:22 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
1:54:27 it been fried in? It’s been fried in corn oil or whatever. So you not only have a concentrated source of omega-6,
1:54:34 but it’s undergone this superheating and now it’s absolutely gone through some peroxidation. So, if the person’s just
1:54:41 eating whole fruits and vegetables and natural sources of fats and proteins, you’re going to get linoleic acid. And I
1:54:46 would say there’s no reason to fear it. Um, yeah. I I think also it it can be a
1:54:52 distraction if you’re if you’re not focusing on like avoiding avoiding the refined carbohydrates, avoiding the
1:54:57 refined sugars, making sure you’re getting exercise, making sure you’re not overeating, like all those things. And
1:55:02 then like I look, full disclosure, I don’t cook with seed oils. I don’t cook
1:55:07 with them. I don’t use them. Um, but I will say that an unbiased look at the
1:55:14 literature, I still think uh I don’t I think cooking them I think heating them I I would stay away from that for sure.
1:55:21 But um if someone wants to put a little bit of, you know, of this uncooked oil on their salad, do
1:55:28 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
1:55:33 the day, I think that that person’s probably already doing things right, and that’s really what matters. So, that’s
1:55:39 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.
1:55:43 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
1:55:44 Fat, muscle, or liver—where does insulin resistance start?
1:55:51 fat cells and shrinking and you you were talking about the the atyposites kind of becoming insulin resistance first,
1:55:57 insulin resistant first. And and that kind of leads into something that I I forgot I wanted to ask you about as we
1:56:02 were talking about some of this before. And that is, you know, insulin resistance doesn’t happen at the same
1:56:09 time in all tissues. And and so it’d be kind of nice to just talk about that briefly before we continue on in terms
1:56:15 of like the muscle, the atapost tissue, the liver. Um what happens when each of
1:56:20 those become insulin resistance? Um insulin resistant and you also talked about atapost tissue. Yeah.
1:56:27 Maybe first is that then contributing to the other ones then becoming insulin resistant. Yeah. Yeah. So I absolutely so there are
1:56:33 people who would say no the fat is first when it becomes so what what is the first domino if if it’s a sequence of
1:56:39 tissues which is the first to fall when it comes to here’s the person healthy here they’re progressing through insulin
1:56:46 resistance with type two diabetes being the most obvious outcome at the end of it what’s the progression
1:56:53 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 very strongly
1:56:58 it’s the fat tissue Um so insulin resistance in its earliest
1:57:04 stages is high insulin but normal glucose. The problem with invoking a fat
1:57:10 a muscle centric view or a liver centric view or I need to add one an alpha cell
1:57:15 centric view because that’s also relevant of the pancreas for a reason I’ll I’ll touch on in a moment. The
1:57:22 moment those become insulin resistant glucose is not going to be controlled anymore. and and so then you skip a step
1:57:27 because insulin resistance if you look at the progression of the person towards type two diabetes the insulin has come
1:57:34 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
1:57:41 view is the fat cell falls first. It’s the first tissue to become insulin resistant as it starts to experience
1:57:47 some degree of hypertrophy. That then starts to
1:57:53 facilitate the other tissues becoming insulin resistant. And at that point, there’s no order in my mind. It’d be
1:57:59 hard to distinguish if there’s another order. But I actually when I teach this very idea to my students, I one of my
1:58:05 undergraduate assignments is a class called pathophysiology. And these kids are fortunate enough to learn the true
1:58:12 origins of type two diabetes from an expert. But I actually show the fat cell first and then the next step I say I
1:58:18 teach it in this concept of all right well what flips the switch from pre-diabetes insulin resistance to type
1:58:24 2 diabetes. What is it that makes the glucose go up? That is then when the muscle becomes insulin resistant you
1:58:30 have lost access of the main glucose consumer. So you are you’re clearing the
1:58:36 glucose out far of the blood far worse less readily than you were before resulting in a hypoglycemia. When the
1:58:42 liver becomes insulin resistant insulin can no longer inhibit glycogenolysis.
1:58:47 So normally one of the mechanisms whereby the liver works with insulin is
1:58:53 by storing glucose as glycogen. Insulin inhibits the breakdown of that glycogen
1:58:59 unless the liver has become insulin resistant. Now the liver is breaking down glycogen and releasing it as
1:59:06 glucose even when insulin is attempting to tell it not to thereby further compounding the hypoglycemia. Then the
1:59:14 last one is the most overlooked but absolutely relevant which is the alpha cell. The alpha cell is the yin to the
1:59:21 beta cell’s yang where the beta cell releases insulin and insulin’s most famous job is to lower blood glucose.
1:59:28 The alpha cell releases glucagon and its most famous job is to increase blood glucose. So it’s very important for
1:59:36 fasting and exercise. The opposite of when insulin would be up basically. But the alpha cell knows when to not release
1:59:42 glucagon when the beta cell is releasing a lot of insulin because insulin and their nextoor neighbors within the
1:59:48 eyelets of the pancreas. Insulin will flood the beta cell with or rather ins
1:59:55 the beta cell will flood the alpha cell with insulin and insulin will inhibit the production of glucagon which is good
2:00:01 because then that helps insulin overall affect blood glucose to bring it down. But the alpha cell can become insulin
2:00:08 resistant. Dr. Roger Unger at UT Southwestern over years published a series of mind-blowingly cool papers
2:00:14 finding that in type 1 diabetes if you just control the glucagon excess you
2:00:20 don’t even need to give the patient insulin that you could correct all hypoglycemia by just inhibiting the
2:00:27 glucagon. So that’s just a weird little feature of the fact that when the alpha cell becomes insulin resistant and it
2:00:32 does it starts releasing uncontrolled glucagon which comes to the liver and
2:00:39 once again is telling the liver to make glucose and release it into the bloodstream. So the fat tissue becomes
2:00:45 insulin resistant first that facilitates the insulin resistance of the glucose
2:00:51 controlling tissues muscle, liver and the alpha cells. And when those start to become insulin resistant in any
2:00:58 particular order, that’s when you start to see the gl the glucose start to climb. But we know decades potentially
2:01:04 before the person ever starts to have hypoglycemia, they have hyperinsulinemia.
2:01:10 That’s why I think the fat cell is subtle enough in its metabolic demands that it doesn’t really need a lot of
2:01:17 glucose. Its metabolic rate is so modest. So it can become insulin resistant without really affecting
2:01:23 fasting glucose levels. So the person’s fasting glucose levels can stay normal. But once the glucose handling tissues
2:01:25 like the three I’ve already articulated become insulin resistant now glucose is uncontrolled.
2:01:29 Do fat cells shrink or disappear with weight loss?
2:01:35 Going back to the this fat cell hyperplasia like a lot of you know forming lots of different fat cells
2:01:42 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
2:01:49 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
2:01:55 those. What happens to the fat cells? Do they shrink? They shrink.
2:02:01 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
2:02:06 about this in my class, I say the patient’s on a fat cell shrinking journey. That’s exactly how I describe
2:02:12 it because that is weight loss. All weight loss is shrinking of the fat cells.
2:02:19 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
2:02:26 be replaced or it may be replaced. And so, you can over time lose fat cell number. And indeed, you do. At around 60
2:02:32 years old, 60 to 70 a person. So, during infancy, childhood, puberty, we’re
2:02:39 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
2:02:46 I said earlier but even then you could have a person who gains a hundred more pounds or 200 more pounds in adulthood.
2:02:52 For the the for the average individual that’s hypertrophy not a result of hyperplasia. But then when we get to
2:02:59 older age then the number of fat cells stop turning over. So as they start dying at their 10year lifespan we don’t
2:03:06 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
2:03:12 is shrinking the size not changing the number. And in fact if you force
2:03:17 artificial weight loss by sucking out fat cells where you are just sucking out
2:03:23 the fat cells and reducing fat cell number then you don’t improve any cardioabolic outcome whatsoever. So
2:03:29 there’s many studies that show that you can have people lose a significant amount of fat through liposuction and
2:03:35 there not a single outcome has improved. Whereas if that same person had lost that 20 pounds of fat through normal
2:03:42 lifestyle interventions like you’d mentioned, they would have had improvements in every cardabolic outcome. But you don’t do that with
2:03:48 liposuction because you haven’t changed the size of the fat cell. The size of your fat cells is the same. You’ve just
2:03:53 sucked out a lot, but the remaining ones are still there. And now in fact you’ve
2:03:59 put a greater pressure on them because a person an adult doesn’t make new fat cells very readily. So what will happen
2:04:05 is the remaining fat cells will be forced to grow through size because they can’t share the burden with their other
2:04:11 neighbors that you’ve sucked out already. So when a person starts to regain weight the cardioabolic outcomes
2:04:13 are amplified. When when people do um lose weight and they’re shrinking their
2:04:17 Are shrunken fat cells still insulin resistant?
2:04:23 fat cell size, are those fat cells like let’s say someone was even insulin resistant, right? And there’s a
2:04:29 problematic fat cell and it shrinks in size. They lose weight, it shrinks in size. I mean, is
2:04:36 it still problematic? No. No. No. In fact, that’s why with the slow insulin resistance, the reversal of that
2:04:43 like over the 90 days in the type 2 diabetic patients that we had in our published case series, uh that would
2:04:48 have been not that we measured this, but it would have been because of a shrinking of the fat cell. Now, let’s
2:04:54 say they grow those fat cells again, the same problems will come back. So
2:04:59 whatever intervention, one of the problems I have with diet, whatever the intervention is, low carb or, you know,
2:05:05 calorie restricted, whatever, people will complain and they’ll say, “Well, but it’s only short term.” Yeah, of
2:05:10 course it is. Um, whatever a person has done to reverse their metabolic problems
2:05:15 will only persist as long as they adhere to those changes. Uh, the more they go
2:05:20 back to their old habits, the more the same consequences will return because it was those old habits that caused it.
2:05:23 Can exercise and cold therapy specifically shrink visceral fat?
2:05:29 with respect to the visceral fat and I mean I particularly the visceral fat since it’s the fat that’s really got
2:05:34 that expansion of the fat cells you can only go through hypertrophy right only going through hypertrophy
2:05:40 what what sort of targeted diet lifestyle interventions would be
2:05:47 suggested or evidence-based to to actually decrease the visceral fat yeah that’s a great question so visceral
2:05:54 adiposites are more responsive to the lipolytic signal the fat breakdown signal of epinephrine. So, anything that
2:06:02 increases epinephrine will have sort of poundfor-pound or sight for sight visceral versus subcutaneous is going to
2:06:07 have a better visceral response. Um, so the more the epinephrine is being targeted, so that’s going to be things
2:06:15 like exercise and like cold therapy, for example, cold immersion, talked about an epinephrine spike. So anytime you’re
2:06:21 really activating the sympathetic nervous system, you’re going to be sort of molecule for molecule, cell for cell,
2:06:28 targeting the visceral more than the subcutaneous. So it is more responsive to that sympathetic tone than
2:06:34 subcutaneous fat is. Interesting. So epinephrine, high-intensity interval training is really like more intense exercise.
2:06:40 Again, back to that and then yeah, deliberate cold exposure. Another one. Great. And I’m a big advocate of cold
2:06:45 immersion. Great. Yeah. Okay. Well, that’s interesting. Um, I didn’t know about the ep the the fact that epinephrine was was
2:06:48 linked to that as a as a mechanism. Okay. So, uh, a little bit about we talked a little bit about the the muscle
2:06:52 Injecting insulin for muscle—are the risks worth it?
2:06:58 mass and I think just the the the one thing that was kind of on my mind was that sort of
2:07:03 anabolic paradox of insulin. Yeah. And and kind of what your thoughts are with respect to like you know some
2:07:09 bodybuilders are injecting insulin, right? Um, so how Yeah. like let’s let’s talk about a
2:07:15 little bit like reconciling insulin’s role as being this you know anabolic versus you know storing fat being
2:07:23 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
2:07:30 but because I’m familiar with insulin I’m comfortable enough answering this question. So there was a group in fact I
2:07:37 think it was the same guy I mentioned earlier Shrinire NI at Minnesota at the time. They published a paper finding
2:07:43 that insulin wasn’t necessary for muscle protein synthesis. So, so you have the
2:07:49 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
2:07:55 both the stimulus building it and the signals that are breaking it down. They
2:08:01 documented that insulin was not necessary for muscle protein synthesis but it was very helpful for inhibiting
2:08:09 the breakdown. So it they suggested that insulin’s main effect on muscle is an anti-p proteolytic effect rather than a
2:08:15 stimulating effect. So that my general view is that that’s where insulin is going to be favorable. But it also
2:08:23 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
2:08:29 intervention to try to promote muscle growth. And in fact, just as a very
2:08:35 unscientific observer, when I compared the physiques of Arnold and Lou from the old 1980s bodybuilders to the modern-day
2:08:42 bodybuilders and the almost bizarre phenotype of this like bubble belly, do
2:08:47 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
2:08:54 can all agree that there’s an odd physique. You know, whereas Arnold and Lou were extremely tapered, very, very
2:09:00 narrow waist. Modern bodybuilders, yes, they’re more jacked, but they’re also
2:09:05 oddly distended with their abdomen. I can’t help but wonder whether insulin
2:09:12 has been somehow facilitative to promoting some degree of visceral growth because insulin wants to promote fat
2:09:19 growth. It wants to, no matter, it’s like a fertilizer for fat cells. And so someone who’s who’s wanting to overdose
2:09:26 on insulin in an effort to promote muscle when you’re just maybe enhancing some proteolytic antipolytic effect, I’d
2:09:32 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
2:09:38 focusing on growth hormone than you would injecting yourself with insulin. So I am not a fan. Now I appreciate some
2:09:43 big yolked bodybuilder looking at relatively spelty small Ben Bickman and saying, “Well, what do you know? Maybe I
2:09:48 don’t know a lot.” Um, no, I I think I think that was a that’s a really good
2:09:53 those are great points that you made. For sure. For sure. Um, I think we covered a lot of the muscle effects on
2:09:55 Are drugs like Ozempic a shortcut or solution for obesity?
2:10:01 insulin and, you know, how exercise is so important, growing muscle tissue and exercise is important for, you know,
2:10:07 allowing the muscle to be that, you know, site of glucose disposal. Um, but let’s kind of then shift gears and talk
2:10:14 about this weight loss. And obviously I think right now there’s a big trend in
2:10:20 rapid weight loss and and weight loss that’s made very easy um by taking GLP1
2:10:27 agonist drugs like Ozic and Wiggov. And I I’d love to to know what your thoughts
2:10:33 are on maybe first you can explain just you know generally how these GLP1
2:10:40 agonists work and why they’re causing weight loss and how they affect metabolic health but
2:10:45 also whether they’re addressing the underlying root cause of obesity.
2:10:51 Yeah. And you know if if or if there’s sort of shortcutting around that. Right. Well, there’s no no no question.
2:10:56 It’s it’s a bit of a shortcut and I am I’m worried about the long-term effects.
2:11:03 So, with GLP1, I have had my finger on the pulse of GLP-1 probably since well,
2:11:08 not since the its inception, but since the late 90s, early 2000s. My PhD lab
2:11:14 was one of the first labs funded in the US looking at the study of incrretins by
2:11:21 a drug company. And so I’ve I’ve long been familiar with GLP-1 and the other incrretins. Incrretin being a word to
2:11:27 describe these gut derived hormones that have metabolic effects. But it’s been interesting for me to note
2:11:35 the evolution in their use because originally they were only used as anti-diabetic drugs
2:11:43 and then the what was considered kind of an offtarget effect of controlling satiety is now the mechanism of action
2:11:49 at these much higher doses as the dose has been multiplied up to the kind of current WGO weight loss dose. So it’s
2:11:56 really just been an evolution in the dose of this of semiglutide for the most part although there are other glutides
2:12:02 that fit in this as well but semiglutide is the main one. So at the lower dose
2:12:08 originally used these GLP1 activators worked actually by inhibiting glucagon.
2:12:14 So back to the alpha cell that I mentioned earlier, it’s we come back to them now where in type two diabetes, the
2:12:21 insulin resistance of the alpha cell results in a chronic elevation of glucagon chronically then telling the
2:12:28 liver to be releasing glucose leading to the hypoglycemia that defines the diabetic state. At this low dose,
2:12:35 semiglutide inhibits the alpha cell. It inhibits glucagon and by inhibiting glucagon, you’re helping correct blood
2:12:41 glucose. So it was an effective anti-diabetic. Now some people have the very mistaken
2:12:49 view that semiglutide or GLP-1 activators also release insulin. That is not true. That has been shown to happen
2:12:57 in isolated cell cultures. But in humans there’s no evidence. And the authority on the subject is a guy named Arie. A r
2:13:04 nestrop. A s t rup p. Arie ostrop in uh in Denmark. He’s one of the absolute
2:13:10 authorities on this topic. He’s published multiple papers in humans showing that no amount of GLP-1 elicits
2:13:17 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
2:13:25 what’s called an insulin secret or a hormone that a drug that forces the beta cell to make insulin. GLP-1 inhibits
2:13:32 glucagon, which helps correct blood glucose. Now as the dose starts to go up higher just I guess just for the sake of
2:13:37 time I’d mention two effects which is one in the guts and then one central
2:13:43 within the intestines GLP-1 will act to delay gastric emptying and slow
2:13:50 paristalsis. So that has the effect of a person eating and having that bulk sit in their
2:13:56 stomach much longer which is going to generally discourage them from wanting to eat more. At the same time, it’s
2:14:03 going to take a lot longer to get through the intestines. Now, that is good for weight loss because it forces
2:14:09 them to eat less. A consequence of that is it ranges from the uncomfortable to
2:14:15 the problematic. So, on the uncomfortable side, the person will have food that’s sitting in their stomach for
2:14:22 up to 20 hours. And so, they will start burping a lot. And they will have like people who go through general surgery
2:14:29 and have to be put under for general anesthesia. They found that normally you tell the person don’t eat for 24 hours
2:14:34 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
2:14:40 people were on these were on semiglutide the food was still there and they would still have food in their stomach even
2:14:46 though they hadn’t eaten for 24 hours. So this results in what people colloquially just call ompic burps where
2:14:51 they just have putrid breath and burping and just stomach nausea. But because of
2:14:57 the change in gastric emptying even some medications like birth control
2:15:04 medications don’t work anymore for example because you’ve so changed how long it takes that drug to get from the
2:15:10 stomach into the the small intestine where it would have been absorbed. So it starts to change the absorption of
2:15:18 certain compounds and drugs as well as potentially affecting the absorption of nutrients which may be part of what the
2:15:24 person is observing with regards to other changes in say muscle mass. Maybe that’s a result of just poor nutrition
2:15:30 because even though they’re eating they might not be getting they might not be digesting and absorbing everything
2:15:35 they’re eating anymore because of how the the rate of the the paristalsis has
2:15:41 changed so much. So anyway, numerous changes of the guts and then there’s a central nervous system effect to
2:15:49 activate satiety centers. Now the combination of those two is powerful where you have the I’m full signal here
2:15:57 and I have a lot of stuff in my stomach here resulting in a person who has a much better control over their appetite.
2:16:04 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.
2:16:10 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
2:16:17 produced hormone from the gut. We have it. We know that we can change its levels based on what we eat. And that
2:16:20 might explain why some people eat more and some people eat less. But still, my
2:16:22 Are current GLP-1 agonist doses too high?
2:16:28 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.
2:16:36 What is the dose range that you were referring to talking about? Yeah. Yeah. So I think that the commonly
2:16:41 used doses are going to be in the order of actually in this case it’s I know it
2:16:46 in milligrams I think it’s about five milligrams or so 2 and a half plus
2:16:52 milligrams and a once weekly injection and if people are thinking of that in
2:16:58 units I think that’s going to correspond to units of about 25 to 30 units of of
2:17:03 GLP-1. So that to me is is too high and and two and a half milligrams being
2:17:09 the low dose. That is the Yeah, that that’s the low dose of what is used now, right?
2:17:13 And and the underlying the the addressing obviously this was these were used for
2:17:15 Microdosing GLP-1 drugs—a solution for carb cravings?
2:17:20 like you mentioned this was a you know diabetes drug, right? I mean this wasn’t
2:17:26 necessarily meant to treat obesity. Yeah. Right. Um but I guess that it all depends on
2:17:33 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
2:17:38 am as as much as people will hear me describe this and think that I’m being just universally opposed, I actually do
2:17:44 think there’s a place for these GLP-1 drugs, a paper was published in 1996
2:17:51 that looked at the changes in GLP-1 in two populations. They took otherwise healthy humans and split them up in and
2:17:59 they noticed changes in the obese group and the lean group. So when they gave both groups a highfat meal, they looked
2:18:06 at the GLP-1 response and it was roughly similar in both groups that whether they were obese or lean, they ate a highfat
2:18:12 meal and GLP1 was the same heavy overlap suggesting that the satiety effect of
2:18:18 that meal would be roughly equal. Now I’m speculating a little bit there. I’m adding that last part in. So if you look
2:18:25 at the GLP-1 response, given GLP-1’s effects on satiety, which is very meaningful, the highfat meal elicited a
2:18:30 similar response regardless of body fat mass. However, when they gave them a
2:18:35 high carb meal, the lean group had a huge increase in GLP1. The obese group
2:18:41 had no statistically significant response whatsoever. There was a little noise, but the error bars were big
2:18:46 enough that there was no statistical difference. It again it wiggled around a little bit but at no point did it reach
2:18:52 a a significant increase suggesting that you may now have two people who sit down
2:19:00 to eat a meal. One person eats that carbohydrate heavy meal and they have a big GLP1 response. They pat their tummy
2:19:05 and slide the plate away. The other person eats that same amount and asks
2:19:11 for seconds or even thirds because they aren’t getting that GLP-1 response. So
2:19:16 to me, the best use of these drugs in the context of weight loss isn’t for
2:19:23 weight loss per se, but it’s rather to acknowledge some people aren’t going to get that off switch when they eat carbs
2:19:29 in particular that apparently people responded the same way to fat, but they are not. There are differences in how
2:19:35 people respond to carbohydrates with GLP-1. This study made it very, very clear. It was published in the journal
2:19:44 Gut in 1996. To me, that’s the best use of the drug to say the physician or the clinician,
2:19:50 the expert would be talking with the overweight patient and they would say, “You know what? You need to control
2:19:56 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.
2:20:03 I’m addicted to them.” All right, let’s use a low dose. And this gets into that range of, you know,
2:20:09 5 to 10 units or uh 0.05 005 to one gram milligram
2:20:17 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
2:20:23 where the physician the expert the clinician is saying let’s just give you a low low dose of this drug and it’s
2:20:29 going to and I want you to think of it as helping you control your cravings because what do people crave people
2:20:35 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
2:20:42 salty and crunchy. And usually it’s going to be potato chips, crackers, cereal, ice cream. And that’s what we
2:20:47 want to help them control. So rather than saying this is a weight loss drug, let’s what if we changed the
2:20:53 conversation and said this is a drug that is designed to help you change your eating habits. While you’re on this low
2:21:00 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
2:21:05 cravings and these these refined foods that you’re always eating and then you
2:21:12 get them back three months later. Ideally, they say, “Boy, for the first time, I can control my cravings and I’m
2:21:18 doing better and I’m losing weight.” Then I would say, “Let’s see what happens when you cycle them off and say,
2:21:24 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.” Maybe
2:21:31 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 habits.
2:21:38 It just helps them rewire their habits. In 90 days is a good length of time to change your habits. So at 90 days, let’s
2:21:44 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
2:21:52 something. But basically, my view without having it outlined as a specific protocol would be micro dose and
2:21:58 cycling. Let’s put you on it with the intention of helping you change your habits. Let’s take you off it to see
2:22:05 whether the habits have stuck. If they haven’t, let’s cycle you back on. But always using these very, very low doses,
2:22:10 not for weight loss, but for changing habits. That’s interesting that um in your
2:22:17 experience, people can do this micro dose and after about 90 days, they can
2:22:23 keep the the appetite regulation under control. Because when you look at studies with people using, you know, the
2:22:31 clinical clinically relevant doses that they’re using now, um, of of these different GLP1 agonists, um, a lot of
2:22:37 most 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
2:22:43 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
2:22:48 helping you change your dietary habits rather than this is just a magic bullet and you’re going to lose weight. I think
2:22:53 in that instance the person’s changed the way they’re eating but maybe they’re not this is I know kind of getting into
2:22:59 this hokey pseudo area of science perhaps but when the conversation is focused on the habit I think it helps
2:23:05 change habits. Oh I mean absolutely the the the way you’re thinking about something
2:23:08 can change the outcome for sure. Um, I want to kind of go back to something that you mentioned that was very
2:23:11 Do these medications cause muscle loss—or is it poor nutrition?
2:23:17 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 way
2:23:23 digestion’s kind of changed um, and perhaps, you know, nutrient absorption. I hadn’t really thought about it in that
2:23:29 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
2:23:37 people are rapidly losing weight, whether it’s on a GLP-1 agonist or it’s from caloric restriction,
2:23:43 they can lose a lot of muscle along with the fat. It’s not just all fat. um particularly if people are not getting
2:23:49 enough dietary protein which is a big signal for muscle protein synthesis and if they’re not engaging in resistance
2:23:55 training which is the other very important signal for growing muscle mass. So
2:24:03 um my question to you was going to be you know is there kind of a way around
2:24:08 this muscle loss by increasing dietary protein? Obviously, the resistance
2:24:13 training would be key. Um, perhaps even more key now because you know, for one, if people aren’t
2:24:19 eating, I mean, I don’t know how many meals a day people are eating. It probably varies depending depending on the person and what their side effects
2:24:24 and stuff are, but um, eating the protein and then like are they absorbing all the protein? I don’t know if anyone’s even looked at that,
2:24:31 but that’s interesting. Yeah, I haven’t seen it either. Yeah, but it does beg the question is it is the use of sem. So, it’s very real. The
2:24:37 evidence is very real showing one of the best looked papers in the New England Journal of Medicine about 2 three years
2:24:42 ago found that about almost 40% of the weight loss that a person was losing was
2:24:50 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
2:24:56 has determined whether it is a direct effect of the semiglutide. In other words, is the drug actually harming
2:25:01 muscle and bone or is it just an artifact of the poor nutrition? Um, it
2:25:08 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
2:25:14 doing a muscle cell culture now looking at varying doses of the drug where it’s possible at a lower dose it’s
2:25:21 facilitative and at a higher dose it may be more catabolic when it comes to muscle um, muscle mass and the dynamics
2:25:27 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
2:25:34 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.
2:25:38 They’re certainly not eating enough protein. Yeah. Um this is this kind of there’s another
2:25:39 Do GLP-1 agonist benefits extend beyond weight loss?
2:25:45 interesting point here and that is like GLP-1 receptors and I mean they’re all over
2:25:51 many different organs. The muscle has them and so does bone. Bone, right? Yeah. So that is that is an
2:25:57 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
2:26:02 know people are using them uh well beyond the as much as I bemoone the fact
2:26:09 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,
2:26:14 it’s a fertility drug. I I I just don’t know. In fact, as far as I am aware,
2:26:20 there’s very few studies to touch on that broader on the mechanism. And even
2:26:26 all of that could simply be an outcome of improving metabolic health because back to the origins or the beginning of
2:26:33 our conversation because metabolic health is so foundational to chronic disease. All of this could just be a
2:26:39 consequence of improving metabolic health. Um but it still is worth the pursuit of determining well maybe it is
2:26:46 a direct effect. Maybe there is the direct effect of the drug at the neuron or at the muscle cell um etc.
2:26:53 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
2:26:58 studies that have looked at, you know, people on, you know, various forms of
2:27:04 the GLP1 agonist. Yeah. And a reduced incidence of cardiovascular disease, obviously, type
2:27:09 two diabetes, Alzheimer’s disease. now and and you have to wonder like is is
2:27:16 this a is there a direct effect of you know agonizing these GLP-1 receptors on different tissues or is this just an
2:27:21 indirect effect of weight loss and improved metabolic health? Right. Yeah. Yeah. So I I don’t know but we
2:27:31 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
2:27:37 catabolism of the muscle and they’re far less resilient and far more fragile. So we challenge the muscle with a chemical
2:27:43 challenge and they die way more readily at at used at doses used now at the
2:27:48 level you in which you see the dose in the the drug in the plasma. So it’s a physiological dose.
2:27:50 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
2:27:54 Could these treatments actually promote longevity?
2:28:00 talking about micro doing GLP1 agonist for a very different reason than I’m going to ask you about now. and you’re
2:28:06 talking about appetite regulation and and that I think that’s it’s super interesting um particularly
2:28:12 for people who don’t have real good control of their appetite or perhaps they’re I mean who know their hormones
2:28:19 are out out of whack right but there is now this sort of growing budding interest amongst you know many
2:28:26 people about this potential GLP1 agonist being a longevity drug because of these
2:28:31 different you know outcome studies that have been observational in nature right you’re looking at correlation here. But
2:28:39 the question is well like some people are now sort of starting to whisper about we think we think now maybe these
2:28:44 drugs are actually affecting they’re actually prolongevity and so micro doing
2:28:51 you know these drugs in the in the in the ranges that you’ve been discussing earlier might be a way of
2:28:58 getting the benefits and you’re also getting the side effect benefit of appetite regulation. So maybe you’re not
2:29:05 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
2:29:12 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
2:29:18 correlation because I’m a basic scientist. I want to do one thing and observe a direct effect from that one
2:29:23 thing. So, one reason I am extremely cautious and even a little chagrined
2:29:30 with the entire realm of longevity is that it’s it’s not to disparrage it necessarily, but it’s entirely based on
2:29:36 correlation when it comes to humans. We can only speculate and predict and model these sorts of things. Now, I’m not
2:29:42 saying there’s no utility to that. But I also think it behooves us to be mindful of the limitation that comes with that.
2:29:47 So with GLP1 it in fact it’s worth noting another paper was just published
2:29:54 this week finding that the risk of blindness doubles more than doubles in people on
2:30:00 highdose GLP-1s. It was just a paper was just published. So you look at the degree of blindness that occurs in
2:30:06 adults and those using the drug it was more than twice the risk of developing
2:30:12 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
2:30:18 truly don’t mean to suggest the drug is causing blindness no more than someone could say the drug is promoting
2:30:24 longevity. Although you actually can do a hard outcome with blindness. You can’t really do the hard outcome with when
2:30:29 does the person die very well. But there’s so many variables that get worked in here that I cannot say it’s
2:30:34 because of the drug. But it is worth another reason to have some caution that
2:30:40 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
2:30:48 all the enthusiasts and those who are enthusiastic but also a little skeptical on on my end where I am enthusiastic but
2:30:55 I also just want to bring in a note of caution maybe where we do have that common ground is the dose. So with
2:31:01 regards to GLP-1 at the risk of seeing everything through a singular lens, one
2:31:08 of the most common variables that predicts longevity within families, there’s one paper that
2:31:15 actually mentions the word of of familial longevity. And then the longevity studies like the Amorus study
2:31:22 in Sweden or the Honolulu aging study or the Shanghai aging study, some of the most consistent variables is
2:31:29 metabolic health. um optimal glucose levels and insulin sensitivity. In fact, that one study, I think it was in the
2:31:35 Mediterranean, that looked at families where you have a high number of centinarians, they found that the most
2:31:41 common theme was that they were all very insulin sensitive. And as much as people have a over the years there’s been an
2:31:48 ideology of villainizing protein as as a villain of aging because protein activates mTor and when mTor is too
2:31:55 activated, it promotes aging. I find that view uh unfortunate because for
2:32:02 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
2:32:10 have any anabolic, no retention of lean mass, let alone building it. But when you vilify protein because of mTor, you
2:32:15 ought to vilify insulin because insulin activates mTor much higher than even the
2:32:20 most anabolic amino acids like leucine does. And it keeps it active. One dose
2:32:25 of insulin can activate mTor for up to 24 hours. Whereas leucine, the most
2:32:32 anabolic of the amino acids, will only activate mTor for about an hour or two. And so if mTor matters for longevity and
2:32:37 I I know I’ve sort of contorted the whole thing about longevity here, all the more reason to come back to these
2:32:43 kind of metabolic first principles. And so looking at insulin sensitivity and glucose control and I would just say the
2:32:49 same thing with GLP-1. While we may find that GLP-1 has a direct effect of say
2:32:57 activating autophagy. Maybe it could and that could be a mechanism whereby it promotes longevity. At the same time, I
2:33:02 don’t have to go that far because I could just say, “Does it improve insulin sensitivity?” Okay, good. Then it’s
2:33:08 probably going to correlate and predict and even cause improved longevity because of the evidence we have in that
2:33:13 realm. So, yeah, what you’re saying essentially is that the improved metabolic health is
2:33:19 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.
2:33:20 Um, you know, and it is it is important to obviously keep everything in context as well. Obviously, there’s people that
2:33:24 The dark side of GLP-1 drugs—can they trigger depression?
2:33:31 are obese and metabolically unhealthy that have really just change it’s changed their lives, right? Yep.
2:33:37 But the question is, do they have to keep taking it? Yeah. And in fact, 70% in the US, 70% of
2:33:45 Americans get off the drug at 2 years either because of cost or nausea or whatever, 70% stop taking it. And like
2:33:52 you said, when they stop taking it, if habits haven’t changed, maybe that’s an important caveat, they gain it all back.
2:33:58 Not to mention those who stay on the drug, a paper was published within the past six months. I think it was within
2:34:04 the past six months, definitely within the past year, the risk of suicidal behavior doubles and the risk of major
2:34:10 depression triples in people who were on the drug for up to two years on any dose of it or the high dose
2:34:16 on the high on the currently used um wiggoi dose which is the higher dose which is common. Um so not a micro dose.
2:34:23 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
2:34:31 as much one way and this is my own kind of philosophical view. We we rejoice in the fact that this drug
2:34:36 has helped me it’s reduced my cravings for junk food let’s say and we would say
2:34:42 that’s a a wonderful outcome. What if in the midst of reducing the cravings for
2:34:48 junk food, it reduces their cravings for everything they enjoyed? Where you hear,
2:34:55 this is anecdotal now. People lose interest in their old habits. A gal, the gal who used to like
2:35:00 walking around the block with her girlfriends doesn’t really want to go anymore. The guy who used to like
2:35:06 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
2:35:14 anymore. whatever. Maybe what we describe as improved eating control is
2:35:19 actually just a reduced joy for life in general. But the regardless of the
2:35:26 mechanism or the philosophy behind it, the evidence is extremely clear. The major depression risk, people were three
2:35:33 times more likely to have clinically diagnosed major depression. And again, twice more likely for suicidal behavior
2:35:39 and twice as likely. It was like 106% increased risk of anxiety. And this is after the weight loss and after being on
2:35:45 the drug. And yeah, that’s right. It was two years on the drug. So this is this is part of why I’m
2:35:51 cautious where I respect the power of this tool. It is extremely powerful
2:35:56 because it’s so powerful. I think we c we should be mindful of going too far
2:36:03 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
2:36:08 context at a very specific dosing regimen with a cycling protocol where we
2:36:14 want them to have in their mind, we don’t want you on this drug indefinitely. This is not a lifetime
2:36:21 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
2:36:26 is so micro dose cycling with the conversation surrounding eating habits.
2:36:32 I I think um I mean that that’s a pretty balanced view. Uh thank
2:36:35 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.
2:36:39 Insulin vs. glucose—what really drives accelerated aging?
2:36:46 So, I kind of want to just circle back and end on, you know, this. You were talking about metabolic health being a
2:36:52 predictor of longevity and, you know, there’s metabolic health and inflammation is another one that I’ve
2:36:58 seen where it predicts which they’re linked, right? I mean, they’re very much linked. So
2:37:03 if you know if metabolic health is so important for longevity and the opposite
2:37:09 is true, right, where you’re metabolically unhealthy and that is essentially accelerating aging.
2:37:16 Mhm. Um you mentioned something that kind of surprised me early on and that is we you were kind of talking about mechanisms by
2:37:23 which insulin is so damaging independent of glucose. And I was sitting here
2:37:29 thinking one of the main reasons why being metabolically unhealthy, being insulin
2:37:34 resistant is so unhealthy is because you’re having high levels of glucose which is
2:37:40 glycating everything from your endothelial cells lining your blood vessels to your mitoardium
2:37:48 heart, your skin, proteins, DNA, lipids, everything’s getting stiffer and damaged. Um what’s what what are the
2:37:53 mechanisms that are that are involved here with you know accelerating aging
2:37:59 and just the glucose alone? Yeah. Well well what yeah in general is it the glucose alone or what else?
2:38:06 Yeah. Yeah. Well so insulin will promote aging by by an a persistent chronic mTor
2:38:12 activation. So I mean and insulin inhibits autophagy. If autophagy is a mechanism for aging that we want to
2:38:19 leverage. I’m unaware of any signal that will inhibit autophagy stronger than insulin will. It abhores catabolism. It
2:38:25 only wants anabolic, which can be favorable when leveraged wisely. But when it comes to aging, if you are
2:38:32 inhibiting that catabolic process of autophagy, that’s not going to be facilitative. So I rarely I have the
2:38:38 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
2:38:44 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
2:38:50 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
2:38:57 a partner in crime. I just sort of say, um, it’s sort of who would be who would
2:39:03 be the partner. So, it’s sort of Joker, the main villain is the insulin. And then the glucose would be like Harley
2:39:10 Quinn, sort of Joker’s right-hand gal in this case to invoke a comic book reference, which I am delighted to do
2:39:16 because of a misspent childhood. So insulin, I believe, matters most, but
2:39:21 glucose on its own is pathogenic. But before I even defend glucose, I just
2:39:27 want to say because so much of modern medicine is obsessed with glucose at a
2:39:33 cost, as I articulated earlier, that obsession not only causes us to miss the
2:39:39 metabolic problem as early as we could by focusing on insulin, but it also leads us to unhealthy interventions
2:39:46 where you have a hyperglycemic, hyperinsulinemic type 2 diabetic and you’re only caring about lowering the
2:39:53 glucose and you do so by pushing the insulin higher. If the glucose were the main pathogenic signal, this should
2:39:59 result in improved outcomes and nothing gets better. When you give a type 2 diabetic an insulin therapy, they get
2:40:05 fatter and sicker and die faster. All while glucose looks good. This is well documented. Their risk of dying from
2:40:11 heart disease triples. Their risk of getting dying from cancer doubles when you give them insulin. So I defend
2:40:16 you with a type 1 diabetic. Ah, well that’s different. Yeah, because in a type one diabetic there’s no
2:40:23 insulin and so you have to give them insulin therapy just to bring them to normal insulin. In the type two diabetic
2:40:29 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
2:40:35 diseases of total opposites. The only thing they have in common is that the glucose looks the same in that it goes
2:40:41 high. Now glucose is not benign. As much as I have an insulin centric view
2:40:46 unapologetically, glucose is a problem uh through multiple mechanisms. You
2:40:52 mentioned glycation that is a huge one not only because of the change in the structure of that protein or that
2:40:57 molecule itself like skin a lot of like you can induce premature wrinkling by
2:41:04 under undergoing by forcing glycation of the skin. you can result in a compromised glycoalix of the endothelium
2:41:10 by all that glucose compromising with glycation. So glycation itself is a way
2:41:17 to um irreversibly alter a molecule and eliminate its utility. And indeed at the
2:41:23 same time when you form an advanced glycation end product, it becomes a a
2:41:29 substrate for or a molecule that can b a lian for rage the receptor for advanced
2:41:35 glycation end products. And when rage gets activated you have a lot of inflammation. So the glycation goes
2:41:40 beyond the altered structure of the molecule itself leading into some chronic subclinical inflammation. But
2:41:42 How high glucose levels damage cells—from glycolysis to sorbitol
2:41:48 there’s another mechanism too where when you elevate glucose substantially you may you will have cells that are taking
2:41:54 in that glucose but it’s overwhelming its ability to undergo glycolysis. And
2:42:01 if most cells if you if you you know there’s so much glycolysis happening that it starts to inhibit entry into the
2:42:08 glycolytic pathway then you divert the glucose into the sorbital pathway. Now you have glucose turning into sorbital
2:42:15 which the cell can’t do anything with and so sorbital begins to accumulate in the cell and that starts to increase the
2:42:21 osmotic gradient into the cell and now you have basically a water balloon that’s getting overfold and you can have
2:42:27 over full and you have this what’s called hydroic degeneration where you basically force water into the cell
2:42:33 because of this glucose metabolite and then the cell can burst and this is a large part of the problem with like
2:42:40 macular degeneration and retinopathies In the nephropathies of the kidney, the main mechanism whereby the glucose is
2:42:46 damaging or one of the main mechanisms is the conversion of the glucose into sorbital. And when sorbital accumulates
2:42:51 in the cell, it can’t go anywhere and it starts pulling in water and the cell will burst.
2:42:56 Um, wow. I was just started thinking about prunes because prunes are like high in sorbital.
2:43:03 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
2:43:11 ideas. I actually have my students, as a funny little assignment, look up the customer reviews of sugar-free gummy
2:43:16 bears. And it’s so funny because these these derivatives of glucose like
2:43:22 sorbital or manitol, they can’t move across cell membranes. And so wherever
2:43:28 they are in the body, they’re doomed to stay there, including if it just comes into the intestines. So part of the
2:43:34 humor for these 18, 19 year olds is finding these people giving customer reviews of how the gastrointestinal
2:43:40 distress of these sweetened gummy bears that are like sorbital that all stays in
2:43:47 the guts and it pulls a lot of water in the guts anyway creating some socially awkward situations for these poor people
2:43:52 to put it politely. I also like how you’re talking about this insulin centric sort of model of how that’s
2:43:54 How insulin shuts down your body’s stress defenses
2:44:02 really the most damaging and it really is when you think about insulin you know shutting down I mean
2:44:08 I guess I should say it another way when you think about like insulin’s role in activating AKT which then is shutting
2:44:14 down all these stress response pathways everything from autophagy to you know
2:44:19 making stem cells to just just everything being being shut down by the
2:44:25 action of this one hormone. Yeah. A humble little peptide. Yeah. I mean, and most people, it’s one thing
2:44:31 for like a steroid hormone to have a kind of global effect, but peptide hormones don’t often do that. You know,
2:44:37 glucagon, for example, insulin’s opposite. Muscle doesn’t have glucagon receptors. Like, it’s very much tissue
2:44:43 specific. But insulin just operates at a different level. And I’m glad to see that you’re a maybe you always have
2:44:50 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
2:44:56 my first, you know, experiments as a young biologist. I was a chemist before I was a biologist. So, so I previous
2:45:02 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
2:45:09 chemistry major at UCSD, there’s only a little bit of biology requirements. So, I didn’t really have
2:45:15 vast experience in biology until I graduated from, you know, UCSD with my
2:45:22 degree in chemistry, biochemistry. Then decided I was kind of like, I don’t know that this is really what I want. I’m
2:45:29 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
2:45:35 experiments was what happens, you know, when you when you shut down the insulin
2:45:42 signaling pathway and these little nematode worms that share a lot of homolog homologous genes with humans,
2:45:48 including the insulin receptor um and IGF-1 receptor. And
2:45:54 it was so clear to me that when you decrease the insulin signaling in these
2:46:00 little worms, they you doubled their life expect. Exactly. Doubled it. 15 days to 30 days. Boom.
2:46:06 Like that. And their health span. I mean, you look at these worms and you get to know them
2:46:11 after about, you know, 15 days like they’re like, “Hey, yeah, you can you name them.” And you see like, you know,
2:46:17 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.
2:46:25 They get old, they like move less, they like it. It’s very clear when you shut down insulin going that doesn’t happen.
2:46:30 They are youthful. They’re moving around like they’re young worms when they’re supposed to be dead already. Yes.
2:46:36 And that was like No, you in fact I love that you mentioned this. So you of most people
2:46:42 may be but you I know you’re familiar with Cynthia Kenyon’s work. Yes. Where when I first heard about that kind
2:46:49 of pathway I it was further justification of this insulincentric view. Now not to the extent not that
2:46:57 either of us I am certainly not suggesting there aren’t other variables. Oxidative stress is a variable. Um,
2:47:03 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
2:47:08 kinds of results where you can just control one single variable and a simple
2:47:14 one at that because insulin is a signal that we can control within 24 hours. Like a person listening to this who’s
2:47:20 thinking, okay, I have all these signs and symptoms of insulin resistance. What do I do? Control your carbs. That is the
2:47:26 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
2:47:32 about what carbs you are eating and be a little and then focus on these good sources of protein and fat which aren’t
2:47:38 going to have an insulin spike. That’s why these other variables people want to invoke the mitochondria. I am extremely
2:47:43 familiar with mitochondrial bioenergetics. And yet, why don’t I invoke the mitochondria as a primary
2:47:48 source of disease? Because you can’t measure it in the average person. Like someone listening could say, “Well, it’s
2:47:53 my mitochondria.” All right. Well, good luck getting any marker of your M. I could do it in my lab if you’re willing
2:48:01 to give me a sample of your muscle tissue or something, but it’s not a clinically kind of supported focus. So,
2:48:07 I don’t mean to ever suggest other variables don’t matter. We know insulin matters. You saw it in the work with um
2:48:12 the worms and aging. I’ve seen it in the context of neuron bioenergetics and fat
2:48:18 cell dynamics and everything else we’ve been talking about. And it’s just a variable. It’s a lever. when you
2:48:20 mentioned lever earlier that you can grab and immediately start to turn down.
2:48:23 Which biomarkers best predict biological aging?
2:48:29 Okay. So, let’s talk about these key biomarkers for aging like from a metabolic perspective.
2:48:35 What do you think would be, you know, most indicative of biological aging and what biomarkers are good to look at?
2:48:42 Yeah. Yeah. My first one would be fasting insulin. If I could if I could change um health care policy and
2:48:48 practice in the United States, my one thing would be to have insulin be a standard measurement on every blood
2:48:54 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,
2:49:00 they’re going to get all their lipids and uric acid, those can be great. And there’s ones there’s some worth
2:49:08 revisiting in a moment. But to me, the fact that we don’t include insulin on that panel is an absolute travesty. It
2:49:14 is in my mind the best overlooked marker. So fasting insulin, if a person can get their fasting insulin measured,
2:49:22 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-
2:49:28 teens or high teens, that’s maybe an okay sign because insulin can be dynamic. But then if it’s in the high
2:49:33 teens to the 20s, it’s a problem. That’s a warning that you’re metabolically off.
2:49:38 Um, and then let’s come back to some of the common ones. The triglyceride to HDL
2:49:43 ratio is a great surrogate marker for not only metabolic and like insulin
2:49:49 resistance but also cardometabolic where we focus so much on LDL for
2:49:54 example but the triglyceride to HDL ratio is a way better predictor for
2:50:01 cardiovascular risk than LDL is. So triglyceride to HDL ratio if it is if so
2:50:07 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
2:50:14 test. If that number is less than 1.5, that’s a great sign that you’re doing well metabolically.
2:50:21 And then I maybe uric acid is is another one, although I could go on, but uric I did
2:50:26 mention uric acid. It’s another one of those that really well done longevity
2:50:33 study, the Amortis study from Sweden. It looked it found that uric acid was one of the very few predictors that when
2:50:39 they looked retrospectively at these people measuring the same markers for decades, their glucose control was a
2:50:45 predictive variable and their uric acid was a predictive variable as to who lived the longest healthiest lives. So
2:50:52 lower uric acid is going to be better. And just for general metabolic health, would you add in some of the HBA1C and
2:50:59 you know maybe APOB? So L, you mentioned LDL. I mean they don’t even directly measure LDL. Apo B would be obviously a
2:51:05 more direct measure but then looking also at particle size which I get I again think is important. It’s the small
2:51:10 LDL particles. Yeah. So I do too. Yeah. So LDL as you mentioned and I actually described this
2:51:16 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
2:51:22 studies say it predicts some studies say it doesn’t at all. Maybe it’s because we’re not accounting for the diameter
2:51:30 differences. Even then, most people won’t have had their diameter measured. The triglyceride to HDL ratio is an
2:51:35 awesome surrogate. There’s a beautiful figure of a study. I can’t remember the citation, but I can recall the figure
2:51:41 perfectly. It actually looks at the difference in population of the big LDL,
2:51:48 the buoyant versus the the small dense LDL. And wouldn’t you know it, right around that triglyceride to HDL ratio on
2:51:54 the x-axis of 1.5 is that crossover. So as the triglyceride to HDL ratio was
2:52:01 higher, it reflected a higher particle B or type pattern B rather LDL. The lower
2:52:08 the triglyceride to HDL ratio was, the more it reflected a pattern A, the large buoyant, apparently less aogenic. So
2:52:12 once again, we could come back to that pretty reliable surrogate. Okay, great. Um I think if you could
2:52:14 One simple breakfast change to lower insulin
2:52:21 leave people with just one practical takeaway about insulin, about their metabolic health, uh how they can
2:52:27 improve their life, their health span in the long run, what would it be? Yeah. Yeah. So to I would say the
2:52:34 simplest strategy would just be change breakfast tomorrow. Overnight fasting is incredibly
2:52:40 therapeutic. um insulin will come down during a fasted state and that sort of
2:52:46 re sensitizes the body to insulin. So in the morning you’ve finally been fasting
2:52:53 overnight, insulin has come down. The last thing you want to do is spike your insulin with a starchy sugary breakfast.
2:53:01 And of course, tragically, breakfast is almost just a dessert nowadays all over the world where it is just like pure
2:53:08 dessert. It’s pure sugar and starch. I would say change breakfast tomorrow either fast through breakfast um like a
2:53:14 drink I like to drink a cup of yerba mate uh fast drink some coffee or tea uh
2:53:21 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
2:53:29 breaking a fasted state because I define fast as the endocrinology the the nutrients rather than the calories uh
2:53:36 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
2:53:42 let it be the low glycemic load vegetables um and berries and then more
2:53:49 protein and fat. So, whatever you can do to keep your insulin in check for as long as possible until say lunch. The
2:53:56 longer the insulin is low, the more you’re improving your insulin sensitivity and the more you are allowing that metabolic flexibility
2:54:03 where the human hybrid burning glucose or sugar burning or fat burning, it’s insulin that dictates that fuel. And
2:54:09 most people are stuck in sugar burning mode because they never bring their insulin down long enough to shift over
2:54:14 to fat burning. So you get to get into this fat burning state, enhancing metabolic flexibility, and you’re
2:54:21 improving your insulin sensitivity. So my one piece of advice, change breakfast and change it tomorrow.
2:54:26 So you want to extend that that that state where you’re you’re basically improving insulin sensitivity.
2:54:30 Yes, that’s right. What if you’re what if you eat dinner early? Is it as awesome way to do it, too?
2:54:31 Does eating dinner early improve insulin sensitivity?
2:54:36 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.
2:54:43 You know, you and I, we have families. And so sometimes there are for me, for me personally, as a busy dad and
2:54:48 husband, my even though I I’m home for breakfast, the fact that I’m not eating breakfast
2:54:54 in the midst of the chaos, no, it doesn’t disrupt the family dynamic at all. The kids are eating,
2:54:59 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
2:55:05 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
2:55:10 my biggest meal of the day. But as much as I am absolutely a fan of of being
2:55:16 careful with dinner because the evidence is so supportive of it, I also recognize that it’s the trickiest meal because of
2:55:22 social dynamics, family dynamics. But in so far as you can eat earlier, then just
2:55:28 stop eating. The very best you can do, whether it’s drinking some apple cider vinegar or having something bitter in
2:55:35 your mouth to um reduce the sweet cravings because bitter tastins can reduce sweet cravings, I would say do
2:55:41 it. Whatever tool, whatever leveraging you need in the evening to not crave or snack on junk, do it.
2:55:47 Great. Yeah. I mean, I I probably should have mentioned this earlier when we were talking about the late late night
2:55:54 snacking, but the the fact that melatonin shuts down Yep. insulin production in the the pancreatic ba beta
2:55:59 cells is hypoglycemia disrupts melatonin too. So even back to the glucose mechanism. Um
2:56:04 another reason to not go to bed hypoglycemic is it disrupts the melatonin rhythm uh at the same time.
2:56:11 Oh interesting. So it’s like a two-way thing here. It’s an ugly little battle. Well, this has been a very enlightening
2:56:16 conversation. Ben, thank you so much for coming on this show and talking to me about all things and getting
2:56:23 uncomfortable at times. I really appreciate it. My pleasure. people. So, you mentioned your book.
2:56:29 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
2:56:35 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.
2:56:40 We’ll do that next time. And then um benbickman.com is your website where people can find all
2:56:46 things. You have a YouTube channel. Yeah. Yes. Benickman.com is kind of my education. And then I also am a partner
2:56:52 with Insulin IQ. So, we provide some coaching at insuliniq.com and then just straight education at benbickman.com.
2:56:57 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
2:57:02 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
2:57:05 have a bit of a light touch. Same. Same. Well, thank you so much. My pleasure.