307. GLP-1 Agonists, Fat Loss Biohacks & Hormone Optimisation With Dr. Kyle Gillet
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Thank you for listening to the Boost Your Biology podcast. My name is Lucas Owen. I uncover the most cutting edge health information on the planet, ranging from hormones, nutrition, supplementation, fat loss, biohacking, longevity, wellness, and a whole lot more. Welcome to the Boost Your Biology podcast.

What is up, ladies and gentlemen, and welcome back to the boost your biology podcast. Today, I'm super excited. We have a special guest who's already featured on my podcast before. We have Dr. Kyle Gillette. Kyle, welcome to the podcast. Thank you, Lucas. My pleasure. Always good chatting with you. Awesome. Kyle, you've been up to quite a lot in the last six to 12 months, your clinic has been growing exponentially, you're seeing numerous clients.

And you're definitely a great resource for people looking to understand hormone optimization and also some of the new pharmaceutical drug research as well. So I really do respect a lot of what you publish online. And for anyone listening in, make sure towards the end of the podcast, I'll let Kyle announce where they can connect with his content. But otherwise, let's go straight into it.

Kyle, I want to learn more about GLP-1 research that you sort of alluding to before we started recording. What have you found with the... What have you seen from clinical studies with the higher dosage GLP-1 agonists? Yeah. So these studies are now being released and basically...

Bumping the dose up really high, for example, from 2.4 milligrams of semaglutide once a week to 7.2 milligrams, you only get about 3% extra weight loss, 17% to 20%.

But you get significantly more side effects. And this is, you know, we know this from a study that lasts about a year. So if someone took this for 10 years, then it would probably be more than that. We know that at a dose of one milligram once a week in the form of Ozempic, Ozempic has been out for more than a decade. And we know that it's pretty well tolerated by most people.

Of course, there's gallbladder side effects, potential retinopathy. So that's an eye complication side effect that usually just diabetics have, but pre-diabetics on GLP-1s can get it. And for those who aren't familiar, GLP-1s are just glucagon-like peptide 1. Those are things like the ozempic or generic ozempic and munjaro or generic munjaro.

I've spoken with several people in the industry, both MSLs, PhDs of companies that have these, and they think that between the diabetes meds, compounded meds,

Research chemical meds, people can go online and buy these things. We obviously don't recommend it. And also just off-label prescribing or on-label prescribing for obesity that of overweight Americans, about one-third to one-half of Americans have tried at least one dose. Now, that might be a free dose that they got to try at their med spa, get your money back if you're not happy with it. But yeah, somewhere between one-third and one-half people have tried it.

But, you know, five years ago, my good friend Derek with More Plates, More Dates, of course, helped start his clinic, another good clinic, Merrick Health. And more than four years ago, we were prescribing these off label as well. So I was, of course, a very early adopter. And it's still my second favorite medication to bioidentical hormones for the right person, of course, always for the right person, whether it's a supplement or a med.

But yes, I am working on that documentary right now. We're filming it. I've paid actors and whatnot. So hopefully it turns out well, but it's going to be called Ozymsk because like everything, GLP-1s have downsides too. So this is interesting. I mean, I was shocked to hear that. So you're saying almost one in two US citizens have tried some sort of GLP-1 agonist in like

just at least once. Yeah, of overweight adults. But you can look at, there's a study that comes out and basically this system of EHRs follows about 17% of adults in the United States. So of overweight adults, it's about two thirds of adults. So it's a little bit more than 150 million, which is a lot of adults. And you're looking at how many of these have tried

a GLP-1 or gotten at least one prescription. It's very common to get one or two prescriptions and maybe they don't fill them. Maybe they do fill them. Maybe they take it once and have nausea. Maybe it's too high of a price so they don't continue it. But of the people that do continue them, the ones that have a lot of side effects tend to be very loud, which is okay. You want to have a balance. There's nothing that's too good to be true and the dose does make the poison.

Now, in terms of the muscle loss, this is obviously shattered around online. A lot of social media channels are now talking about the fact that it can result in muscle loss. Of course, it can if you're in a severe calorie deficit and you're not hitting your protein intake. But realistically, from your clinical application, what have you seen? At the right dose, most of my patients gain lean body mass while they're on a GLP-1.

The caveat is when you're on a high dose of a GLP-1, it is easy to over suppress your appetite. For some patients, for example, patients with diabetes, the benefit of a very high dose of GLP-1 might outweigh the downside. For example, maybe they need the high dose to get their A1C down enough to where they don't have microvasculature disease. In most non-diabetic patients, they

the lowest efficacious dose to where you can have relatively consistent fat loss, not even necessarily weight loss in some people, but relatively consistent fat loss. Say that's only £5 a month. That's still enough. And maybe it's as high as £10 a month, but more often than not £5 a month.

then you can have relatively low lean body mass loss. If you compare it to very low calorie diets, you have the exact same amount of weight loss if you're in the same caloric deficit. It's just much easier to make that deficit too extreme. Now, in terms of mechanism, even though they considered working on that GLP-1 sort of pathway, I do believe, and from what I've researched, is that if we had to do like a Venn diagram where you compared metformin

versus like semi-glutide, there would definitely be a lot of crossover in the middle where they actually do also hit some of the same like pathways. Is that correct?

Yeah, they're both certainly insulin sensitizers. And they both have actually significant effects on the gut microbiome. It can be good and it can be bad. My rule of thumb is the worse your gut microbiome to start, the more metformin and GLP-1s can help. But the better your gut microbiome, probably going to make it worse and more likely to lead to GI side effects.

But as far as the incretin effect or the effect on growth hormone, that's what's kind of unique and where they're the most opposite. Whereas metformin is going to tend to blunt IGF-1 signaling, especially at the cellular level. Whereas at the pituitary and brain level, GLP-1s are actually growth hormone releasing peptides and increase growth hormone and IGF-1.

Now, in terms of what you've seen in clinic, I know IGF-1, it's not oftentimes measured on a blood test, but what you're saying is that have you detected changes in IGF-1 on patients that have been using hydrosmetformin? Very common to see IGF-1 changes.

increase if growth hormone increases high dose metformin igf-1 does not tend to increase especially if insulin decreases however if someone loses a a decent amount of body fat and they sleep better then their natural growth hormone production will likely go up but metformin is not going to directly um increase or significantly increase growth hormone um

So it is also possible for growth hormone to go up, but not IGF-1. For example, this happens in type 1 diabetics. They generally have very low IGF-1s, but very high growth hormone levels naturally. So off-label GLP-1 use in type 1 diabetics, you want to be careful about not getting too much growth hormone.

In terms of the application, so there's obviously a certain demographic that you think can benefit significantly from these GLP-1 agonists. What population would you say, and I'm just assuming that that's like those that are really carrying a lot of extra body fat, what does that demographic to you look like? Yeah, generally people with pre-diabetes,

And also people with severe insulin resistance. Females over about 40% body fat and males over about 30% body fat, maybe slightly higher if they're very active. So the higher your body fat percentage, certainly if somebody is over 50% body fat, then they can very likely benefit from a GLP-1 supplement.

Because if they use a low enough dose and are consistent enough, they'll have significantly less risk of rebounding and less risk of developing diabetes. And it's going to have beneficial effects on the cardiovascular system and the renal system, the kidneys as well.

That's actually what I wanted to get into as well was some of the lesser known benefits of outside the scope of insulin sensitivity and obviously dropping weight. Are there any particular areas that you think are not well known by the general public in terms of its beneficial actions?

Yeah, the increased growth hormone is a significant one. You know, there's correlations with low growth hormone and low IGF-1 and cognitive impairment of age. That's certainly one of them. The benefits outside of just glucose levels, of course, your endothelial cells will be healthier, basically the lining cells. And then if you're at risk, you know, if you're a very high body weight, maybe your body fat percentage is not extremely high.

let's say you have a male that is a retiring i guess you guys have rugby doesn't matter what sport it is pick your sport of choice american football rugby whatever you can call it hand egg if you want

But you have a lineman or whatever the equivalent would be of a male that maybe they weigh 150 kilograms. What is that? 330 pounds, 350 pounds?

and they're only 32% body fat, that's still going to put them at increased risk of relative venous stasis and maybe not ischemic heart disease, but congestive heart disease and/or electrical heart disease. And also hepatic and renal relative decreased function.

So they're probably a great candidate to use that as they transition out of their body size that they have to be for their professional sport. Another candidate would be someone who is a completely normal body fat percentage, but perhaps whether it's genetic or whether they have some sort of inflammatory arthritis where they have not been able to accrue a lot of lean body mass.

And they are kind of the opposite. They have relatively low total body weight, but they have relatively high glycated end products like hemoglobin A1C and like fructosamine.

And maybe they have pretty poor glucose tolerance if they did a glucose tolerance test or were a continuous glucose monitor. In that case, especially if they're starting to become in a more advanced age, then that might have a benefit on their cognitive outcome. But what you would need to watch in that patient is they might also be at risk of essentially diabetic retinopathy despite not having diabetes.

So there's a lot of these things that you have to balance out. But there are benefits for patients that wouldn't meet the criteria that you would think would be classic. What about in terms of a certain demographic, which is more so the aesthetics, like bodybuilding, you know, athletes, that sort of stuff. What I am all for is...

These athletes and or bodybuilders leveraging safer compounds to reach their target goal, right? So instead of resorting to potentially dangerous compounds like clenbuterol or some other like really powerful fat loss drugs or agents and or methods to lose fat,

Personally, I'm all for them thinking outside the box, looking into potentially compounds like semaglutide. Yeah, I suppose as long as they do it under the care of a healthcare provider. One good example would be, it is certainly true that...

DNP is almost never worth it, if that makes sense. For people that don't know what DNP is, it is a pretty toxic fat burner to where you'll also probably feel pretty terrible while you're on it, much more terrible than if you're on clenbuterol. But yeah, the dose does make the poison. And I suppose sometimes as people go into a big bulk phase, they do develop some degree of insulin resistance.

even natural bodybuilders. So it's not out of the question for someone in that situation. But yeah, you're always trying to assess what option could be worth it if you're trying to get to an aesthetic outcome. And a good rule of thumb is supplements are usually worth it, but there's often other ways that you can get to the aesthetic outcome without pushing things too much. Yeah.

Yeah, definitely. Now, you mentioned earlier to me about this, I guess, the amylin calcitonin sort of CGRP axis. This is all pretty new to me. I've only briefly heard about amylin in one context, but did you want to sort of explain that to my audience? Yeah, so this is going to kind of be the next big thing. So just like...

GLP-1s were emerging and becoming very popular around the time or even before Wegovy and Zepbound were brought to market. How I felt four or five years ago about GLP-1s, I feel now about two things, amylin agonists and myostatin inhibitors. The caveat with myostatin inhibitors is that right now they're all infusions, at least the ones that are being clinically studied.

But amylin is made from the beta cell of the pancreas, just like insulin. So when you have death of the beta cell of the pancreas, you don't just lose your insulin production, you lose your amylin production, and it basically helps the insulin work. So a true artificial pancreas would have both amylin and insulin.

So for a long time, we've thought about putting different amylin agonists like primalinatide into insulin pumps. But now there's newer generation amylin agonists that are longer acting that you don't have to put in a pump and you don't have to inject three or four times a day. Kind of reminds me of Bayeta and Bidurian, kind of the two old school GLP-1s.

But Cagrelenotide or Cagre-Semma is one of the first ones. And one of the trials is actually proceeding along with a combination of Cagrelenotide and Semaglutide. And they also have an earlier phase, phase one or phase two, on an oral version of Cagrelenotide-Semaglutide combo.

Very promising for type 1 diabetics for obvious reasons. They don't have beta cells, so they have no amylin. And amylin also, so anything that kind of binds an agonist of amylin also binds calcitonin, which helps with your bones. That's why people will take calcitonin salmon, which is a nasal spray. And then it also binds CGRP receptors, which helps basically relax veins. So all these different new things.

migraine medications that work quite well with almost no side effects. They are mainly CGRP. Some people actually prescribe them off-label for weight loss just because they also bind amylin, but they only cause you to lose a couple pounds and they do have some downsides. So unless somebody also has migraines and or calcium slash bone density issues, I generally don't prescribe CGRPs.

like aimvig or like um nertek or um uber lv or culipta there's a lot of different cgrps there's a whole host of them but i'm excited to see what the stronger amelin uh

agonists look like. Calcitonin salmon has been around for quite some time and is very infrequently used. So I am also interested in its potential anabolic aiding because, you know, we figured out how to get people to lose weight relatively well, at least if they have a decent enough provider and they're able to find an affordable regimen.

But now the emphasis is getting people enough protein, getting them to actually learn how to train and do exercise they love, and potentially add in things like myostat inhibitors or amyl anagnus, calcitonin anagnus to help with anabolism of lean body mass. Yeah, I'm glad you brought up the myostat inhibitors is definitely an interesting route to explore for muscle growth. I think that's like

Back in the day, there used to be like old school bodybuilding supplements that would use ingredients like epicatechin from Dutch. Yeah. Yeah. All those sort of compounds. But you're saying that like there's new research coming out around like infusions. What was the number one like well-researched one right now called? The Magromab.

It's such a complex name. Magma map. It's an infusion center to get it. The data on it looks unbelievably good.

um many orders of magnitude better than phallostat and gene therapy for those who are wondering but wow but yeah the macromab is going to be pretty great I'm pretty sure Eli Lilly I could be wrong this might have been a different one but I think Eli Eli Lilly bought this for two billion from the company that had it after uh one of its clinical trial results so companies are also betting big on this it's no secret

for those that are kind of following long clinical trials. And you know, how it works isn't until it's done with all of its phase threes and some degree even its post-approval clinical trials. The jury is certainly not out.

But I think that this is going to be a great tool on hand. I mean, the state of research right now, at least in the United States, is amazing. If people check out the last episode, or maybe it's going to be the next episode we post of the Gillette Health Podcast, we talk about all these trials. And we also talk about a trial of semaglutide with osterine, which is a Novosar. Oh, yeah.

Yeah, there's actually a clinical trial that prompts to the authors to, you know, enroll patients and counsel them. And this trial was done on older patients. So people who don't know what Ostrane or Anobosarm is, I believe it's MK2866. So it's a SARM, selective androgen receptor modulator. And previously, I've only seen trials in prostate cancer and breast cancer.

and a couple tiny trials on sarcopenic patients, which is patients with low muscle. But in this trial, they gave them both some semaglutide, which is ozempic, and some osterine. I mean, it seems simple to us, right? But this is a decent-sized clinical trial. I think they had more than 50 in each. I think they had 50 in one group and 100 in another group. And the results were excellent.

When I came across that research, I immediately said to my team that we have to create content around it because I was like, Osterine is actually making a bit of a comeback. But obviously, the dosage determines the poison. You look at Psalms on the market, a lot of them are like 10 to 20 milligrams. But from what I read on Osterine is that like three milligrams is

There literally was no suppression of testosterone at that dose or hardly any. Yeah, at least in the short term. I think certainly similar to things like oxandrolone, I think ostarine is similarly suppressive at the right dose. I think that you'll see a graded decrease in gonadotropins, which is LH and FSH. But it's certainly...

a better option than some androgens, partly just because it's not going to virilize as much. And then also partly because there's less concern in males for prostate issues and in females for, you know, easier virilization, if that makes sense. Virilization, for those who don't know, is just masculinization of a female. So the osterine, because I remember looking into like, all right, thinking outside the box strategies to lower SHBG.

And it's like, cause I've got a massive cohort of guys that are like desperate to find, like for some reason in their mind, they think that SHBG is the, is the be all and end all. I'm sure you've heard this as well, where they think if we, if I, if I can suppress my SHBG and my free testosterone goes up by a hundred points, then I'm going to feel like a thousand times better or whatever. And they have obviously eliminated, well, they've,

They're modulating their carbohydrate intake. They're optimizing liver function. They're doing that. They're optimizing thyroid. And it's like, all right, what else is out there? Apart from like boron and tonka dali that can lower SHBG. And I was like, three milligrams of osterine could probably do it. I've done it myself and I've actually seen my SHBG go down. And within the first couple of weeks of using osterine, there was a noticeable like uptick in like

free test related symptoms, however you want to describe that. So I thought that was a bit of an interesting experiment. Yeah, no, it's certainly true. In fact, if a female is injured and sensitive, they can take Osterine and it can free up so much DHT that they can virilize from Osterine. Unless the Osterine that they were taking is not actually Osterine. That's a different issue. That's also possible that with these anecdotal

it's kind of hard to parse out what's what. But yeah, I mean, one of the main reasons why this is also exciting to us is as more and more clinical trials are done, then more things will need to be supplied. I remember when they did the clinical trial on Tabix in the New England Journal of Medicine, which is a nicotine receptor agonist, comparing it to nicotine replacement. You know, they put in the paper, we got this from SoPharma in Bulgaria. So, you know, once the, you know,

New England Journal of Medicine is posting that it's totally fine using this Bulgarian pharmaceutical company to supply this to their clinical trial patients. Then many healthcare providers, including myself, absolutely jumped on that bandwagon because we were looking for other options other than classic nicotine replacement. And it's done quite well. So it's always nice when you find, I guess, a new accepted drug.

methodology like that. Yeah. Yeah. It basically opens up our toolkit and it's like, all right, now we can sort of draw upon this or now I've got research upon that. And it's like, we just, it actually excites me how fast things just,

Like idea, concept, and then bang, there's like something cool that we can draw upon. Yep. That's what academia is supposed to be because I don't want to be the first wildebeest in the Nile. You know, there's crocodiles in there. You just need to know where to cross and I want it smart to do so. So when there's a cutting edge therapy, you want to make sure it's not a bleeding edge therapy. And academia is supposed to do things like these clinical trials that we're talking about.

to dip their foot in the water and they can kind of do so safely with more oversight and just more resources so that we can follow them going back to the migrumab and i'm going to spell that for my audience because they're going to be wanting to know it's b-i-m-a b-i-m-a g-r-u-m-a-b b-m-a-g-r-u-m-a-b

Sorry. Yeah. Bimagrimab. So going back to that one, what's the evolution of the drug? Like, was it initially designed for sarcopenia? Like what was the, why did they even, why were they even looking at developing it in the first place? Yeah. So that's what they were looking at is to look at pathologic sarcopenia and several drug companies, you know,

have worked on this or whatnot. And I think it's been sold a couple of times as well. But yeah, I believe it works on actinivin to light chain, something similar to that. I don't remember exactly, but basically when it works on this actinivin to light chain downstream to that, it will inhibit myostat. So it's not a direct myostatin inhibitor and that it is also not a direct phallostatin inhibitor.

modulator. So it's not an inhibitor or up regulator directly of phallostatin.

So it's a novel way to decrease myostatin signaling. If people have seen Derek's video on myostatin inhibitors, like the Belgian blue cattle that have a genetic mutation, there's mice as well. I think in the Gillette Health podcast, we posted pictures of the mice that have myostatin knockout genes. And in the embryo, if you're exposed, then at least if you're an animal, you look like you have no fat and insane amounts of muscle.

So, of course, bodybuilders took great interest to that. But so far, the trials on this Bimacrimab do look quite good. We generally use it in aging populations that might be wheelchair-bound or recovering from a hip surgery or have had terrible burns and have had muscle loss related to that. That's one of the things we used to use Anovar or Oxandrolone for as well.

But yeah, and generally would not recommend it to people who are pregnant because who knows what, we actually don't know what the baby would look like. The baby will be too muscular to evacuate there. Yeah. Tech bros and biohackers, please do not try this. Let's research it more and then see what happens.

So going back to that, like, cause realistically there aren't many, it seems like having a direct drug that targets directly myostatin as an inhibitor seems to be a damn difficult thing to develop. Like why is it somehow it just seems like

Well, this is not even a direct drug for that. They're just finding that it does it as like a secondary effect. But is it, do you think it's, do you think like there'll be companies looking into more specific action related drugs for this? Yeah, there's several other myostatin inhibitors that are being studied. I just don't remember the names of the other ones. Yeah.

There's also several supplements that are very weak myostatin inhibitors like fortitropin, which is made from specific protein and fertilized egg yolk. I think they have a dog version of it that I used to have one of my wolfhounds on.

But I forget what it was called. But it's a pretty weak myostat inhibitor and it works better in animals than in humans. But that's probably something, you know, fertilized egg yolk protein. You can give your kids fertilized egg yolks. And so I think it's reasonable to give your kids some fertilized egg yolk. And then certain chocolate derivatives, I believe epicatechins are also weak in

phallostatin and myostatin modulators. But for adults, it's probably not going to be a really significant driving force. Yeah. It's like if we're looking at muscle growth strategies for somebody who is trying to optimize as much lean muscle mass as possible, you've got compounds like testosterone, you've got creatine, you've got protein powder, EAAs, things like that. But you're also...

You're excited by the fact that these myostatin inhibitors could be just another tier to focus on. Yeah, certainly. The next problem for people who have already checked the lifestyle boxes, they're training, they have their protein intake, they have their diet with mostly whole foods and good amounts of protein and fiber. And perhaps they've improved the metabolic health. They've lost lots of body fat.

but especially the aging population, you know, periandropause or perimenopause or later, then getting the strength and also bone mass back, which is why I'm also interested in amylin and calcitonin. Those two things can be particularly hard to the point where people say it's impossible to gain bone mass. We know it's not impossible to gain bone mass, but you just have to gain actually pretty significant amounts of lean muscle mass in order to gain bone mass.

And that can prevent a significant amount of morbidity or mortality. You know, people can Google around and look at mortality rates within five years of a hip fracture, and they're exceedingly high. And yes, causation correlation, but major fractures and also general weakness lead to not just death, but terrible quality of life in the last several decades of life for most people, actually, the majority of people. Interesting.

So in terms of that particular pathway, do you think there's a lot of like specifically going back to the protein element? I would love to hear like within your clinic, is there like an upper threshold on protein that you typically will never go beyond in terms of grams per kilogram or grams per gram? Yeah, good question. For some patients, yes.

Generally, those patients have chronic kidney disease. A lot of times, I'm not concerned. For people with healthy kidneys, their blood urea nitrogen, which is a protein breakdown product, it could be 35, and I'm not concerned as long as they're hydrated. They're probably eating a lot of protein and breaking down a lot of excess, potentially unnecessary protein.

Um, but, um, you know, from a standpoint of, uh, well, what if technology increases is the protein going to drive more cell turnover and turnover telometers faster and less hormesis, which is kind of like a cell stability. So it basically is these super high protein diets. Are they aging us faster? Maybe, but honestly, our technology is still a ways off from getting to 150 or 200, um,

and if people are trying to tell you otherwise i think they're probably just trying to sell you their product their supplement or whatnot but eventually there might be a case

There might be a case for slightly decreasing protein, but this is something that scientists like David Sinclair have promoted in the past. I don't think he even promotes it anymore, just from like a theoretical standpoint. And I understand that theoretical standpoint, but for the most people, there's no unsafe upper limit of protein. Your body and your gut will tend to tell you this is too much before you reach any of those. And even some of my patients with stage four chronic kidney disease, they're

which I think would be pretty bad. And classically, we would put them on decreased protein diets. A lot of times their nephrologists, the guinea doctor that we work with, says, yeah, we don't really have to be as careful with protein as you thought, even for them. Is it more so that they're more focused on the electrolytes, the sodium, potassium intake more so than protein, it sounds like?

Yeah. And they're also, they tend to be focused on cardiac function and liver function as well. Interesting. From a blood testing standpoint, I was just thinking now, like in terms of your level of knowledge has evolved so much probably in the last two to three years when looking at blood test results and even ordering lab tests and things like that. Has there been one particular biomarker that you're like,

You think that most practitioners should be looking at, but they're oftentimes overlooking it or not even considering it in the first place.

Yeah, any hormone, but I guess I've always thought that. So testosterone, sensitive estradiol, DHT even, those are two easy of options. Certainly LH, FSH as well. Fasting insulin is one of them that everyone really should be looking at. To give a different answer than my usual podcast, if people have listened to other ones, I will say creatine kinase, CK. Okay.

It's an interesting gauge of one, how hydrated someone is to some degree, but mostly two, are they really training as hard as they should be training? Because if your CK is not very high, let's say it's only 30 or 50, then you really haven't been training that hard. So it's a good reality check in some cases. Do you mean like in terms of when you say training hard, do you mean like

reps to sort of failure where they're actually accumulating a significant amount of lactic acid? Or do you mean like... Because could creatine kinase go up just from like five by five strength training? Yeah, it can even go up from a hard run. Yeah, a hard Metcon can increase CK. Most CrossFitters have very high creatine kinase. The things that increase creatine kinase the most is anything that will...

puts you at risk of rhabdo. So rhabdomyolysis is breakdown of muscle to the point where it harms the kidneys. And if your CK is 30,000, 50,000, 70,000, then you have some rhabdo or a ton of rhabdo. The more muscle you have, the more it can go up. So

uh just like let's say the analogy for breaking down your muscle is cutting your grass in order to grow your muscle you have to break it down if you want your lawn to start growing again you have to cut it and then it starts growing again um dolotropism whatever it's called so um the uh

The case when you have a larger lawn, more muscle mass, you have to break down more muscle in order to make some. So if you have 200 pounds of lean body mass, then your CK will probably be significantly higher than if you did the exact same workout and have the same amount of light rhabdo as someone that has 100 pounds muscle mass. If they did take... So for example, if we wanted to like cause a false positive on a blood test, they would have to do...

a really hard workout right just before the blood test. And then obviously creatine kinase would spike, but if they waited 12 to 24 hours, then of course their levels would somewhat normalize. To some degree, yeah. You can also have some delayed creatine

creatine kinase detected in the serum that just has not come out of the muscle yet. I've looked at my CK right after I work out and the day after, and it's usually not significantly different, even if I get my blood drawn within 30 minutes of a very hard workout. That being said, occasionally you do find some slight false positives, but I don't consider it a false positive unless it's more than 5,000.

What else did you uncover when you did that blood test immediately after the workout? Did you check testosterone and obviously the hormones? Yeah. My SHBG always runs high. I was on HCG monotherapy at the time. I think my testosterone and I was also on... Was I on Dutasteride at the time? I can't remember. But anyway, my SHBG is usually...

40 to 60 or if not higher than 60, which I like as long as I have enough free testosterone, you know, between 15 and 30, I'm perfectly happy with that free testosterone level. And yeah, I just want my total androgen pool to add up to around 1500. So multiply your total testosterone by one and multiply your DHT by 10 and you want it to be at least 1500 and in some cases higher depending on your androgen sensitivity.

One of the interesting things that that test also uncovered, not to change the topic, I can talk about hormones for days, but MCV was much higher. So after like a hard run or a jump, like if I jump rope or do box jumps, my MCV will go up two or three or sometimes even four points. That's the average red blood cell size. And then oftentimes my uric acid will slightly go up as well.

And my insulin does look pretty low because insulin is not doing a whole lot of work to push glucose into my muscle. The exercise is doing that. When you say low, you mean like less than two? Yeah, sometimes less than one. Geez, I thought that was really only... I've only seen one client ever have an insulin score of one.

ever in my entire life yeah yeah i i've seen it quite often but usually it's in either bodybuilders or uh powerlifters that are cutting or crossfitters it's not unusual to see in crossfitters but most often it's in people that are doing at least a daily cardio that are um

the seven day a week in the gym crowd. They have easy days and hard days and whatnot. You can't go hard every single day. But that just continued insulin sensitivity, insulin sensitivity. When you exercise, you just literally don't need insulin to push glucose into your cells. And if you do that every single day, then your body does become accustomed to that. That makes so much sense. I've always perceived insulin though, like as part of that

anti-catabolic cascade but i guess that's more so related to igf-1 as like a premier anti-catabolic hormone but going back to the oh sorry go on yeah um that being said if people want to gain a lot of lean body mass they do not want a low insulin insulin's not always bad i just figured you know at this point uh

I have other goals. The other thing, if you see a low insulin, that person, whether it's yourself or somebody else, has probably lost five or 10 pounds or at least has been in a bit of a caloric deficit the last couple months. So let's look at that. I mean, if we had to draw a graph, I don't even know if this exists, but if we had to look at ability to lose weight correlating with blood serum insulin levels, do you think there's a strong...

linear positive linear association between ability to burn body fat and levels of insulin so the lower the levels the easier it is to some degree it more so starts at a fasting insulin of around seven if your fasting insulin is much higher than seven it does get more and more difficult as it increases

However, below a fasting insulin, you know, seven, six, five, four, three, it doesn't really become easier to burn fat, but it does become easier to have rebound muscle gain. So it's especially for sarcoplasm, which is the cytoplasm of muscle cell. Let's say you get a DEXA scan and it says you have 200 pounds of lean body mass and 20 pounds of body fat.

your 10% body fat on a DEXA. It'd probably be like a 5% body fat on an N-body scan. And

If your insulin is very, very low, it's going to be very easy to put on 15 to 20 pounds of muscle. Most of these studies where someone's put on 15 or 20 pounds of muscle in two to three months, it's because they're extremely insulin sensitive and most of their gain has been wet muscle mass, the cytoplasm, and not actually lean, dry, contractile tissue. Super interesting. Oh, man, my head's now going down the whole insulin thing.

I don't want to go too deep in this rabbit hole though, because otherwise we'll lose track of... I feel like we're having a conversation that may not benefit our audience because it's too technical here. I think one of the benefits, at least in the future, is just understanding the relationship between insulin and amylin. Because amylin and calcitonin, I think, are going to be more and more popular or important, really, clinically in the future. So these long-acting amylin agonists...

Are these the ones that you're, so they would be administered like similar to like what maybe like once a week injection? Is that sort of what we're hoping to see? Yeah, I believe the trial of Cagri-Sema, C-A-G-R-I-S-E-M-A that was recently released, I believe they did a once a week subcutaneous injection.

And what advantages did they find over, was it a complementary to semaglutide or was it in replacement of? I believe it was combined together. Yeah. And the same, I believe it would be the same medicine, probably the same auto injector, I assume. And the benefit is the insulin that you do have,

works better. So anybody that's an insulin dependent diabetic, it's going to be particularly good for whether it's type one, type 1.5, type two, it's really going to be a game changer. It's going to significantly decrease their insulin requirements. Now the study, unfortunately, isn't long enough to show this and they only released their preliminary data. So it's like when a movie releases the trailer, they usually only release the good stuff. And then when you watch the movie, it's like all the other stuff. So they've only released the trailer so far.

But I think that on longer term studies, cagrelenotide will also lead to improved bone mass. And I wouldn't be shocked if it leads to less migraines as well. Such a like triple, weird triple action effect, isn't it? Yeah, it is.

It's like you've got a patient that specifically is coming for, I've got blood sugar instability, I get migraines, and my bones are weak. What do you got for me? Yep. And if people need to be talked into it, I remind them that it's a peptide. So it must work particularly well with no side effects. Well, the peptides, yeah, that's going to be a... I'm really excited about what's...

what's emerging in the peptide space, specifically around the mitochondrial enhancing related peptides. Just from a personal perspective, have you played around with any yourself just from like energy well-being standpoint? I've taken L-carnitine, which I suppose is kind of a, it's not a direct mitochondrial peptide like a lot of them, but it does shunt fatty acids in the mitochondria. It's kind of like a fuel pump. I have taken it. So I've experienced kind of like the

Slight discomfort when you inject it, kind of depending on how you inject it. But carnitine is just a two amino acid peptide that can be injected or taken orally, just not good bioavailability. I haven't taken a lot of the newer mitochondrial peptides yet.

I don't have any mitochondrial storage diseases that I know of. And, you know, I think my mitochondria are quite healthy given all of the exercise and given that on the maternal side, which is how you inherit your mitochondria, there hasn't been any red flags for like genetic mitochondrial dysfunction of age or whatnot. So I have not tried any of the other ones.

Yeah, I'm interested in obviously dabbling in potentially like MOTC, SS31. I've responded very well to any sort of like acetylalcarnitine oral form has worked really well for me. You know, a lot of these mitochondrial enhancers I find are also satisfying what I'm trying to achieve, which is like oftentimes just how do I increase my baseline daily energy battery performance?

And I feel like every time I tap into anything that supports mitochondrial function means no need for stimulants, like no need for my general baseline energy is a lot better. But going back to, you said before around,

The myostatin inhibitor, the bimagrumab, that one there you say was more effective than folistatin gene therapy. Now I've had a few clients that have spent the huge amount of money on the folistatin gene therapy. Have you had patients as well who've sort of explored that?

Yeah, I've had patients get phallostatin gene therapy. I've had patients take SS31 and report extremely good things. I just haven't prescribed it yet. I have prescribed MOTC in some usually niche scenarios. But yeah, as far as like phallostatin gene therapy, I think it's too early to recommend clinically. I don't think it's unreasonable for someone to

kind of hard to say if it's going to affect you know i certainly wouldn't take it during a fertility window if that makes sense if you look into what phallostatin does instruction with fsh etc but my main question with phallostatin gene therapy is you know um it what is the main goal with this is it a quote unquote senolytic are you trying to slow the aging of the cells of your body

Are you trying to... For that, I don't think we... I don't think the jury's out on how good or not good it is. Perhaps it is better and better as age increases. That's possible. Most sarcopenic treatments, that is the case. And most sarcopenic treatments also look fantastic in animals, especially aging and or unhealthy animals.

But my main question to people who are interested in it is other than it's kind of like a new fad, what is the main reason to do it? Switching gears, Kyle, something that's very trendy at the moment is methylene blue. I'm not sure how much extensive coverage you have on this front, but what are your thoughts on methylene blue?

Yeah, I have tried methylene blue and I do use it. My main use for it is actually helping people get off of SSRIs and SNRIs, for which it does work quite well. In general, I think it's underrated for its nootropic or...

basically monoamine oxidase inhibition, even though it's not strong, you don't want a strong one. You know, we would more of us would use to satinib if sorry, not the satinib, selenolene, if that was the case, the satinib is a tyrosine kinase inhibitor. I'm not sure why I said that. Selenolene is the strong monoamine oxidase inhibitor that Sam Bankbrenfried was taking infamously, I suppose. But

Yeah, methylene blue I do think is quite helpful from the nootropic standpoint. Some people feel like they get a excellent performance enhancing benefit and they can feel its mitochondrial benefit as well, which might be the case. And I don't think the jury's out on that. My theory behind that is it does help you feel better. And in general, anything that helps you feel better will help your workout performance significantly. Maybe it's just the serotonergic effect.

There's a reason why there's a medicine called tramadol and I obviously don't prescribe it for this, but certainly there are professional athletes that take tramadol that is a serotonin derived pseudo opioid decreases pain a little bit, but also helps you feel pretty darn good with the serotonin and it's going to improve your performance significantly. So it does not surprise me when people say, yeah, I tried methylene blue and my workout was fantastic. Yeah.

Yeah, I think in terms of dosages, like what sort of dosage ranges are you hovering around? Yeah, I like the trochies and occasionally the IVs more than the capsules. But with the capsules, good high quality pharmacies do make it in a 15 mg dose, which I like. I am not scared of high doses. I have seen up to 50 milligrams per trochie, but I usually keep it more like teens or under. Yeah, yeah.

From my subjective experience, the higher the dosage, the more likely I am to notice reductions in muscle pumps in the gym because of the nitric oxide scavenging potential of methylene blue. Yep, that's what they use it for in the ICU is they can use it for septic shock.

Yeah, I'm glad you're reaffirming this because I had a number of people commenting on the post that I made on Instagram saying that methylene blue increases nitric oxide when I was saying, no, no, no, it actually decreases it. Definitely decreases it. Yeah, I have a few patients that are just very sensitive to nitric oxide and I give them, I think, 18 mg of methylene blue when they have that reaction. Okay.

Interesting. Nitric oxide is kind of difficult too, because a lot of things that decrease it, if you take it long enough, your body will become better at making it and actually make less phosphodiesterase enzymes. For example, sometimes we prescribe Viagra and Cialis for pre-epism, which you would think would be completely counterintuitive, but it's because after you take it for enough number of days, because they can also cause pre-epism the first couple of days that you take them.

Let's say you take... I wish you'd define pre-epism because I know what it is, but my audience may not know. So there's a high flow pre-epism and a low flow pre-epism. A high flow pre-epism is when you have kind of a pseudo erection that lasts a very long period of time. So generally after trauma, like in a tattoo on your penis, a low flow pre-epism is like the dangerous form of pre-epism where there's not enough flow. And that can also come after trauma.

The type that medications make, like trazodone or Viagra or Cialis or even melanotan or brimelanotide or setmelanotide, those are generally higher flow pre-episms, which are not as concerning, but they can still be very painful and lead to bad outcomes. So you'd think that Tadalafil, which is Cialis, which would cause pre-epism when you take it the first time, would not be used to treat it.

But the enzyme that it inhibits, basically your body is just going to make more and more and more of that and eventually overwhelm it. And you get somewhat desensitized to that medication. So your body is pretty good at going back to a homeostasis of nitric oxide. In terms of testing nitric oxide levels, there's obviously those nitric oxide strips that

Is that where you... Do you actually ever see patients come back that are actually really low? Because I've actually never used them myself. Yeah, I have seen that. I do occasionally use them. Of course, it's easy to, I guess, change things to where the strip will look different. So, you know, let's say...

You take the nitric oxide test strips. This actually happened. A rep was telling you about this, took the test strips into a clinic and the physician took the strip and had very low levels of nitric oxide. It was very surprised. Um, and my theory is that perhaps maybe he took some Viagra the night before and then, uh,

inhibited the PDE5 enzyme and then that enzyme is upregulated. So when you're not on the Viagra, the nitric oxide might look lower if you do an oral test strip or paper

But yeah, there's other ways that you can kind of get a proxy of your nitric oxide activity. And there's two main inputs into the nitric oxide system. I'm not scared that nitric oxide is a carcinogen. It's very briefly and temporarily in the bloodstream.

But you do want to be careful if you're taking huge amounts of beetroot, huge amounts of citrulline and also taking medications that can increase it like Viagra or Cialis. Mainly just because it's common to have a splitting headache and also skin flushing when that happens. Yeah. And or like very likely to run into like orthostatic hypotension and some sort of like

Yeah, I've got a number of clients that are leveraging a lot of the citrullines, the agmatines, arginines, that sort of stuff. And they've asked me questions about Cialis and I'm like, probably better not combine them. Yes, I specifically avoid pretty much all of those, maybe a little bit of L-citrulline when I do things like deadlift day or Bulgarian split squats. Because no matter what I do, I get a little lightheaded after I do a bunch of deadlifts.

So I don't want to increase my chance of having an orthostatic pass out episode. I'm exactly the same. And I have generally very low blood pressure as well at baseline. So then if I add any really powerful vasodilator, I am really ironically weaker in the gym, a lot weaker when my blood pressure is low. Like I just feel weak when my blood pressure is very low.

Which makes sense though. Like you, you don't want low blood pressure to lift weights. Yeah. Yeah. That's true. The higher the blood pressure, the better for lifting weights. Yeah. I actually, I've started having a look at some of my close friends who are like ridiculously strong and I've actually finally made a correlation. I've actually got them to do their blood pressures and the ones who are stronger actually have higher blood pressure. Interesting. Are they also higher body weight?

Um, one guy was not actually, he was about the same as me. Then the other one, yes, definitely was carrying about five kilograms extra muscle mass than me, I would say. But I think their sympathetic nervous system is way, like very dominant.

Whereas if I've done a proper like, um, HIV assessment, not using an aura ring or, or a whoop I've done, I've actually had a proper electrodes placed onto me to truly assess my HIV. And my parasympathetic always comes back as like more dominant and more like every time I do it, the guy's like, how do you, how have you increased your parasympathetic tone so much? And I'm like, I actually don't know. I actually don't know. Yeah. Yeah.

Well, it's certainly good. Yeah, I suppose there is certainly ways that you can increase your sympathetic tone without stimulants. But also at the end of the day, once you reach a certain level of acceptance with

your current, I guess, strength or cardiovascular capabilities, at some point, it just doesn't matter that much more. It's kind of a good problem to have. Not many people have that issue. Yeah. So what you're saying is like, up until a point, the sympathetic aspect of strength maxes out, and then it comes down to like muscle fiber, like other elements playing a role in strength.

Yeah. Also, even if you could train yourself to increase your blood pressure during exercise and be more sympathetically driven, it's not always necessary as long as you don't have lofty goals.

just depends on what your what depends on what your training goals are people have very different training goals some people only care about you know whatever uh high rocks or crossfit competition they're doing so people only care about aesthetics uh some people are mostly just doing it to stay healthy but and this is probably the camp that i'm more in mostly doing to stay healthy but at this point it's just a very good social thing it's one of the few things that i share in common with my wife

So that's, it's always nice to have something in common other than raising offspring. Yeah, so I think that that helps a lot for it to kind of become a social thing. As time progresses, it keeps you invested in the hobby when you don't care about numbers as much. Yeah, not for sure.

Awesome. Well, I won't keep you for too much longer, Kyle. That was an absolutely awesome episode, jam-packed with heaps of value. And I've written down so many drug names and pathways that I need to go investigate myself in further detail. But if my audience wants to find you, connect with you online, where can they do so?

Yeah, my main hub is Instagram, Kyle Gillette MD, Gillette Health on all other platforms. And it'll actually be sagebio.com for my recommended lab panels. Again, you obviously don't have to get them through us. It just tells you like the accurate assay. So if you want to know your actual estrogen and not just the estimate, then they can go there. But thank you for having me on. I'm always excited to hear what's new in the field.

Yeah, awesome. Now we'll definitely be in touch in the future. And if you enjoyed today's episode, guys, please do leave a five-star review. That does help to grow the episode and also share it around. And I look forward to seeing you guys in the next episode.

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