Barbell Shrugged - [GLP-1] Blood Sugar, Metabolism, Gut Health and Beyond w/ Dr. Kyle Gillett, Anders Varner, and Doug Larson #710

Episode Date: August 30, 2023

Dr. Gillett enjoys providing holistic individualized care to his patients. His practice includes preventative medicine, aesthetics, sports medicine, hormone optimization, obstetrics and infertility, integrative medicine, and precision medicine including genomics. He believes that each human is a unique creation that requires attention to their body, mind, and soul to achieve optimal health. He enjoys caring for others using shared decision-making and an evidence-based, patient-centered approach. He is active in Obesity Medicine organizations and firmly believes “food is medicine” and “exercise is medicine”. Dr. Gillett describes the “6 pillars of health”: exercise, diet, sleep, stress, sunlight, and spirit. These are more powerful than any medication or supplement.   Dr. Kyle Gillett on Instagram Work with Dr. Gillett Anders Varner on Instagram Doug Larson on Instagram

Shark Family, this week on Barbell Shark, Dr. Kyle Gillette is coming into the show. It's very exciting to have him on. If you've been in this health performance optimization mindset for any amount of time, Dr. Kyle Gillette has clearly come across your radar. We're excited to have him on for many reasons. One, he's very, very good at what he does. But two, many people that come into Rapid Health Optim optimization are looking to pair our work at rapid health optimization with some sort of medical director type person in their life as well to get the

medical side as well as the optimization side all aligned. And one of the first people that we always refer those services out to is Dr. Kyle Gillette. So we have many people that are working with us and him at the same time, which keeps everything aligned and is a very, very cool process to just have that complete package and be able to work together with him. So it's great to have him on the show. And as always, friends, make sure you head over to rapidhealthreport.com. That is where Dr. Andy Galpin and Dan Garner are doing a free lab, lifestyle, and performance analysis that everybody inside Rapid Health Optimization will receive. You can access that over at rapidhealthreport.com. Friends, let's get into the show. Welcome to Barbell Shrugged. I'm Anders Varner, Doug Larson, Dr. Kyle Gillette. Welcome to the

show. Thank you, guys. Fantastic. I feel like we're in this, like, we're in the, we need to give, like, the Huberman bro hug. After Gallopin went on there, and then you went on there, now we've got clients on our side and your side all working together. Life is good, man. It's great to have you on here. Thank you. Today on Barbell Shrug, we're going to be talking about GLP-1, glucagon-like peptide one for many people that are interested in kind of understanding blood sugar.

But really, I'd like to start this off. One, can you give a little bit of a background on yourself and your practice? And then glucagon-like peptide one, just high level. Yeah, certainly. So for those who don't know, I am board certified in obesity medicine, which essentially means that I'm a medical doctor and MD that specializes in body composition and not just body weight. And I'm also board certified in family medicine. I always say that when it comes to a hormone, whether it's insulin or GLP-1,

which are both peptide hormones, by the way, just strings of amino acids, or whether it's testosterone or estradiol, then you're thinking about the systemic effects. The body is, of course, a collection of organ systems. And to be an expert in one thing, for example, hormones or insulin or GLP-1s, you have to be well-versed in its effect in all organ systems. So not just the pancreas, not just the skin, not just the liver, not just the blood, which should be hematology, but in all systems. So a lot of people know that I enjoy talking about this actual literal signaling molecules that go between systems. Those are called hormones

and peptides are just strings of amino acids. GLP-1, as you mentioned, glucagon-like peptide one is one of the classes of incretins. So incretins are not new. We've known about them for a long time. We discovered them in Gila monsters. Xenotide was the first one. There's a couple of classes, GLP-1, GIP, there's even dual incretins and there's a triple incretin that is being studied that will eventually kind of be like the new evolution of it. So we have exenatide, and now we have semaglutide, and then we have terzepatide, which is a dual, and then we'll have a triple eventually. But it is a type of peptide hormone that is released from the gut. It is a gustatory response. So when you eat something that you enjoy, for example, fat, it can release endogenous GLP-1 for a long time. It can be released from the gut, and it can also be released from the pancreas.

So your pancreas has alpha cells and beta cells. Beta cells release insulin, of course, and also amylin. Alpha cells release GLP-1 and also glucagon. But a thousand foot view on GLP-1, if people have heard of ozempic or semaglutide, that's kind of your classic example now of GLP-1s. And there's two main camps, the camp that starts clinics where they prescribe pretty much exclusively GLP-1 to everybody, no matter what, no matter the risk factors. And they say, everybody should be on these, even if they've been controlled with diet and exercise, start these no matter what. And then there's the other camp that says,

these will burn away all of your lean body mass. Don't start these no matter what. And of course I'm in between. So both groups might not like what I have to say, but there's a lot of nuance in there. Well you're the fan favorite and the heel, that's a great place to be. That means you're telling the truth. It's fantastic. I was actually shocked to hear that you just said that. If you're trying to control blood sugar, burning away your lean body mass seems like the opposite of what you would want to do. What's the nuance there? Why are they saying that? Is that 100% true? And why would that be beneficial if it was true?

Any intervention that will put you into a significant caloric deficit, you will lose a lot of lean body mass. And some of it could just be detected as lean body mass. I know that this podcast has talked about it plenty. For example, you could use glycogen and water and you lose a lot of weight that's detected as lean body mass, regardless of what you're using to measure composition. But it is true that as you lose a significant amount of weight, maintaining a high level of lean body mass, because you're at the end of the day, your metabolism is basically your lean metabolically active lean body mass plus non-exercise activity, thermogenesis plus NEAT. So you want to maintain your metabolism because if you look at when you stop, for example, let's take a group of people, even let's say non-diabetics, you give them on, um, the classic dose system of glutide, you titrate every one of them up to 2.4 mgs per week. They lose a whole bunch of weight and then you take them off cold turkey and they

gain a whole bunch of weight. And that's for a few reasons. One is rebound hunger. And GLP-1s are not just appetite suppressants. There's at least four different mechanisms of action in different tissues. But after that, a lot of those individuals do lose a lot of lean body mass. But if you took a group of people and put them into a similar huge caloric deficit, losing huge amounts of weight, 10, 20, sometimes even 30 pounds per month, then you'll also see their lean body mass decrease, especially if they're not exercising. So I think of this as a crutch. If you're in the midst of metabolic syndrome, let's say you're the average American, maybe you have prediabetes, maybe you just have insulin resistance, you're stuck in quicksand and it makes sense to use tools to help get out. But semaglutide is

like a crane that picks you out of the quicksand. If you're not going to use lifestyle interventions like diet, exercise, sleep, et cetera, even hormone optimization to get out of that area, then you're just going to be put right back down and sink back in. Yeah. You mentioned the four areas. What are the, what are the four areas that you're referencing there? Those are just general lifestyle interventions. I call them pillars of health. And you could probably come up with pillars indefinitely. I guess I'm up to seven now, but the main ones are diet, exercise, and sleep. Sunlight is being outdoors, getting hot and cold exposure. Stress is making stress and effort feel good, not avoiding all stressors, but enjoying to

love them, not just in the gym, but outside of the gym as well. Even if that's enjoying the stress of taking care of your kids or whatnot, that's a mature coping mechanism to deal with stress. And you also have social health. So there's a lot of these lifestyle pillars. And I like to say, because it's true, the lifestyle interventions are more powerful in any medication or supplement that you can take, including GLP-1s. But I'm not against supplements and medications, because at the end of the day, those are just tools to help

the lifestyle intervention work better. Yeah. Yeah. I've heard Huberman say many times that testosterone specifically helps make effort feel good. And you just mentioned something similar there. Like what's the, what's the background on that? And they've actually heard him cite any specific research on it, but I've heard him make that claim a handful of times. Do you know the backstory there? I'm not sure how he came to that conclusion, but it's certainly true. Testosterone and any androgen in general is dopaminergic. And part of this we know because when you remove androgens or when you decrease your free circulating androgens, you have a high incidence of what I'd call low motivation or low

dopaminergic tone related to depression. And you have a significant increase in the incidence of actually psychiatric admission and initiation of pharmaceutical antidepressants, even when compared with placebo. We know this from huge trials, those that are interested in which specific synthetic hormones or birth control pills or birth control implants, injections, whatnot, are the most anti-androgen and the most correlated with these low dopaminergic tone psychiatric illnesses. You can go to the Gillette Health podcast, my new podcast, so shameless plug, and see a comparison of all those. And at some point I'll release, there's an anabolic steroid family tree. There's also a progestogenic steroid family there's an anabolic steroid family tree. There's also a progestogenic steroid family tree and an estrogenic steroid family tree. So at some point I'll release

graphics of those as well. But what we do know is that when we remove the androgen from the equation, then you certainly have a higher incidence of that. And then another thing to note is those that have pituitary adenomas, very high prolactin and presumably lower dopaminergic tone also feel similarly fatigued, low motivation. Yeah. And kind of like the escalating blood sugar, I guess there's like a spectrum there. We have diabetes, then we just have kind of like an elevated blood sugar. When is like an appropriate timealthReport.com, you will see an area for you to opt in, in which you can see Dan Garner read through my lab work. Now, you know that we've been working at Rapid Health Optimization on programs for optimizing health. Now, what does that actually mean? It means in three parts, we're going to be doing a ton of deep dive into your labs. That means the inside out approach. So we're not going to be guessing your macros. We're not going to be guessing the total calories that you need. We're actually going to be doing all the work to uncover everything that you have going on

inside you. Nutrition, supplementation, sleep. Then we're going to go through and analyze your lifestyle. Dr. Andy Galpin is going to build out a lifestyle protocol based on the severity of your concerns. And then we're going to also build out all the programs that go into that based on the most severe things first. This truly is a world-class program. And we invite you to see step one of this process by going over to rapidhealthreport.com. You can see Dan reading my labs, the nutrition and supplementation that he has recommended that has radically shifted the way that I sleep, the energy that I have during the day, my total testosterone level, and my ability to trust and have confidence in my health going forward.

I really, really hope that you're able to go over to rapidehealthreport.com, watch the video of my labs, and see what is possible. And if it is something that you are interested in, please schedule a call with me on that page. Once again, it's rapidealthreport.com. And let's get back to the show. When is like an appropriate time to start talking to you, somebody's doctor about GLP-1? Yeah. Even with a normal fasting glucose, if you have significant enough insulin resistance, whether

that's due from carbohydrates, like a HOMA-IR, or whether that's due from fats, like an LP-IR, it would be reasonable to talk about it. But in general, if you're able to improve your metabolic syndrome and optimize your body composition without a GLP-1, that is preferable. So some individuals have, whether it's their physiology or their genetics or their life situation, some that have similar numbers, it's more realistic to get to that spot without utilizing a tool rather than others. For example, let's say someone has a very strong family history of diabetes. Everybody in their family gets diabetes and they're not in a situation in life where they're likely to have success just using lifestyle interventions or other

weaker medications or supplements. Then you might consider a one to two year course of a GLP-1 because of its legacy effect. It's one of the things that has the best evidence even after you stop it. It continues to preserve your beta cell function, which is the cell in the pancreas that makes insulin. When that dies, you have insulin dependent diabetes. So preventing that, in general, preventing diabetes is almost always the most important health intervention. But if you're able to do that in different ways, that's preferable. So why is GLP-1 such a hot topic right now? Again, you're saying that you're kind of in the middle, but there's people that really

fall strongly on both sides of that camp. And there's a kind of a lot of a debate or a lot of fighting about how beneficial or not it is. Like, why is it such a big deal right now? It's popular in hollywood even for those that normal body weights without metabolic syndrome to take some of glutide for cosmetic benefit in fact of compounded some of glutide over 90 and i've uh talked to a rep that has a lot of volume of this over 90 is prescribed from med spas from your injector so if your injector um who

might be well versed in the dermatologic system, or even in aesthetics is prescribing you semaglutide, that's probably not a great long-term scenario for all intents and purposes. And it's not exactly this way, but for all intents and purposes, they get the patient addicted to semaglutide. They give them no tools to get out of the quicksand, no lifestyle interventions. Their diet's terrible. Their sleep is terrible. They're, they have no exercise. They're hemorrhaging weight and they do lose a lot of lean body mass. And then they essentially get addicted to semaglutide.

It reminds me of pain med clinics 30, 20 years ago and TRT clinics 10 years ago. Hold on. Talk to me about the addiction process there. Like what, What are they getting addicted to? Not addicted, but dependent on it? They include the price of your GLP-1 in your monthly clinic fee. The most important time for medical monitoring of GLP-1 is when you're at a high dose or as you're coming off, because that's when you see a lot of things like gallbladder attacks, people getting their gallbladder out, inflammation, poor peristalsis,

paralysis, if you will, of the entire gut system, not just the intestines, but the ducts that lead to them secreting enzymes. And most clinics, you know, if you're a patient, you don't want to pay a clinic to be a member if you're paying for the medication in your clinic price. When you stop the medication, you graduate and you just think that you can go about your day. But in reality, you have almost no chance of coming off of it and maintaining off of it without a huge rebound. So it's more a business decision than a care decision, is what you're saying? Yes. And on top of that, there is little to no discussion of what the side effects are. Again, most people...

Wait, so what are they? Some people do get their TRT from med spas or their TRT from cookie cutter, two minute call telemedicine clinics. But there was just a trial published called the SELECT trial. And one of the benefits in people at high risk of cardiovascular disease is that there's a decrease of 20% in the incidence of, I believe the primary endpoint was called MACE. So basically concerning cardiac events. But there's also a new black box warning. There's actually several new black box warnings. Biliary dysfunction. So I mentioned there's something called intrahepatic cholestasis. Even if you have a predisposition of gastroparesis or paralysis of the stomach and gut. In non-diabetics,

that patient population also has poor function of the gut. So you have constipation. People are familiar with how bilirubin can recirculate. For example, in newborns that are pooping, they get jaundice. That's bilirubin building up. Once the newborn starts pooping, that process stops. The same thing happens in adults as well. And it's not just bilirubin, which is broken down red blood cells that recirculates. It's also uric acid, bile acids, estradiol, which is the strongest estrogen. When you have a lot of estrogen, for example, you're obese, you're in your forties, you've got a couple of kids, you're female, you're premenopausal. That's why you're in your 40s. Estrogen, cholesterol, bile acids, those things tend to form gallstones. Very common to see gallstones, gallbladder attacks secondary to it, even after you stop the GLP-1. Then on top of

that, you're constipated, you're nauseous, and you eat less. So it does help you lose weight. But in animal models, there's also an increased risk of something called cholestasis, which you can get during pregnancy. But cholestasis can be very severe. And if it gets infected, like choledocholithiasis or ascending cholangitis, it can be life-threatening even. But the newest warning is for gastroparesis. So think of your entire gut being paralyzed and clogged up and outcomes secondary to that. The odd thing about these outcomes is a lot of times- I never want to do this. I thought this was like a viable option here 20 minutes ago. Yeah. The caveat is it's dose dependent. So what I do is when I do use them,

I use very low doses and I don't, I very seldom titrate a patient all the way up to the maximum dose unless they're diabetic or borderline diabetic. And then they get the most benefit without significant detriment. And you mentioned a little bit ago, coming off of that, or coming back to like a homeostasis and not being on it is very challenging. Is this similar to like a TRT where you're on it for two years, and then your body just kind of forgets how to make its own? Or is there something specific to GLP-1 that like your body's even, even a short period of time on it. And now your body's just not unable to make it itself. It's not that your body is unable to make endogenous GLP-1. It's more to do with your baseline metabolism is significantly lower

because you have less lean body mass. And if you're accustomed to intuitively eating, let's say 3000 calories a day, you lose a hundred pounds. You're not going to have the tools to use diet and exercise to intuitively eat 2000 calories a day. You're probably going to eat 3000 calories a day. And even more than that, when you have the rebound hunger, right? When you come off. Wait. So again, big picture is picture. Is this purely a conversation for people that are actually obese? Or if you're just like 20 pounds overweight, 10 pounds overweight, is this something you really need to pay attention to? In some scenarios, it is. Let's say you have a strong family history of type 1.5 diabetes, like MODY or LATA, which are, you're not really the classic type 2 diabetic.

You're not morbidly obese. Perhaps you have 10 extra pounds of body fat. You can check what's called an islet cell dysfunction group. So the islets of Langerhans are the endocrine cells. We mentioned the beta cells and alpha cells. If you check a pro-insulin which is the molecule that forms endogenous insulin the ratio of the two can tell you how well your beta cell is functioning so if your beta cell is not functioning well and you're starting to build up that pro-insulin and that could be a sign of impending beta cell death and you should probably check for insulin auto beta cell auto antibodies etc and make sure that you're not starting to develop diabetes but a lot of these individuals that have a1c's around 6.0 and aren't don't really meet the clinical picture of a classic type 2 diabetic should consider a glp1 for its beta cell

preservation effect and you mentioned those clinics earlier about how they don't have much of a focus on any of the lifestyle factors, sleep, diet, exercise, et cetera. Like if you are doing those things, again, is this something that's that relevant or is it again, completely independent if you're actually training hard and sleeping well, eating right, getting enough outdoor time, sunlight, et cetera. That can help as a general rule of thumb, the better your lifestyle interventions or habits, the less of a dose you need. So let's say you have your diet, your lifestyle, your exercise, your sleep dialed in, but you go up to 2.4 megs. In that case, you're just still going to be insufficiently hungry to eat enough calories to lose weight at a healthy rate.

Gotcha. Is this something my meathead brain immediately goes to? Are bodybuilders using this to get on stage or is it attacking lean body mass so much that it would be counterintuitive to their goals? A lot of bodybuilders use liraglutide because that it can be dosed daily. It's old school Victoza or Saxenda. And it's actually generic as of a month or two ago. You can take it daily. And then once you get off, you can immediately come off. So you can go off and come on, go off and come on. And some people will come off in the weekends because they do things that they couldn't do if they're on semaglutide, like drink more alcohol or have cheat meals or whatnot. Um, but it is often used. It's just, there's so many other options that could be used instead of it. It's often not a great option.

Gotcha. So once you kind of commit to GLP one, as it's you're, you're there, uh, even if you don't have the body fat specifically, does it eat at lean body mass specifically in that weight loss? Or is it able to fully focus on just burning fat, burning body fat? It doesn't target lean body mass or body fat any more than being an isocaloric diet where you're just avoiding calories. But at some point, unless you're using other appetites or presence, it's very difficult to get into as steep of a caloric deficit as maximum dose GLP-1s. And it doesn't have a stopping point.

I would assume, say you're 50 pounds overweight, you lose the 50 pounds. Now your body's kind of broken and dependent on it. Then you stay on it. Are you then just going like pure anorexic, basically? Like there's just no, there's no end. Yeah. The recommendation for most academic societies to keep people on, depending on the study you look at between 90% and 75% gain back all of the weight, if not more that they lost once they come off of it. So most

because they don't have the lifestyle interventions built in and yeah, correct. But that being said, what I've seen, especially when you use a lower dose, it's easier to get off and many more people can maintain, um, their, uh, desired body composition after, after they come off. If you come off too late, it becomes a bit harder. There's some sort of rebound effect if you lose more and more weight with it. Yeah. I would imagine many people too are when presented with the options to lose body fat, that have high blood sugar, that TRT is also an option that many people probably look into what would be, um, the reason a doctor or the patient would want one or the other, uh, TRT versus GLP-1, uh, a great reason for TRT is the opposite, or I guess

is the downside of a GLP-1. It will help you maintain more lean body mass. And it is a tool not just to restrict appetite, but a tool that presumably if you start TRT, then your doctor assess the benefit and the detriment and says, yes, the benefit outweighs the detriment. It is one of the most powerful tools to get your lifestyle interventions actually working, especially the exercise piece, because you will enjoy it more and you'll see more immediate results. And that self-fulfilling prophecy, when you work out, you love working out, people notice that you're working out.

TRT can really help flip that switch faster than otherwise. And some people start TRT and they have metabolic syndrome. They have low testosterone and maybe they have a baseline testosterone from 10 years ago when they were more healthy and it was normal. Now let's say there's someone at age 35, they have a baseline total testosterone of 750. And then at age 45, their testosterone drops to 250. They start TRT. Maybe they start a little bit of a GLP-1 as well. They get back to their optimal body composition. They've dialed in their lifestyle.

On average, total testosterone decreases by about 10 per year. So there's a 99 plus percent chance that that person can come off TRT and regain statistically average a total testosterone of 650. So that's kind of a little known fact about TRT. It is surprising even to me how many physicians have come to my clinic and already put themselves on a low dose GLP-1, sometimes even dosed twice a week for semiglutide and also TRT and said, you know, doc, or usually just say Kyle because professional courtesy, his first names, I because professional courtesy is first names.

I've already done the first part. I just need help getting off of these. And I take them off. And there's quite good success rates. Gotcha. Are there any differences, male and female, in how you guys dose this and recommendations? Yeah. Most females are dosed way too high for

testosterone. Females on HRT, in my experience, about 50% of them, um, have benefit from the addition of an androgen. The reason for this is because androgen production, both from the ovaries and the adrenals varies wildly from female to female, probably up to an order of magnitude. So, and then keep in mind that androgen sensitivity varies, just like androgen sensitivity varies a lot in men. See a lot of men with a total testosterone of 300 that have zero symptoms. And then you see men with a total testosterone of 400 that have a lot of symptoms. The same is true of females. So individualized dosing is very important. And then watching SHBG. So you're watching free androgens and how androgens and

estrogens are balanced. The average female has about three times as much circulating testosterone in the serum as estrogen at any one time. So that's a good rule of thumb that people can use to dose it. Of note, if you look at insulin clamp studies, which are kind of, I wouldn't say the gold standard for looking at what is an insulin sensitizer and what causes insulin resistance, it's how we know that NMN is an insulin sensitizer. In men with an insulin clamp study, testosterone is an insulin sensitizer, but in females in insulin clamp studies, testosterone causes insulin resistance. And I've done a podcast on this before, but I think it is a particularly interesting phenomenon. And part of it has to do with women have two X chromosomes

where the androgen receptor is, and there's mosaicism of that receptor, but there's also a lot of other physiologic reasons. If a woman has some level of insulin resistance, then hormone replacement therapies, particularly with testosterone, would be potentially problematic because it could potentially give her blood glucose issues. Is that what you just said? Testosterone can worsen insulin resistance in a female. However, if a female has very low testosterone and she uses testosterone to help the effort feel good of exercising again, and she uses the testosterone to build up lean body mass in the long run, it's likely a net positive when it comes to improving insulin resistance,

but at the cellular level acutely, it causes insulin resistance. So if her fasting blood glucose is high or her hemoglobin A1C is high, would that mean that you would not recommend testosterone for that person? Generally, no, but it's something that I counsel patients about. If it's extremely high and not in control, then that's not the time to add in an androgen because with a very high fasting insulin or just with a lot of insulin resistance with a high high fasting insulin, um, or just with a lot of insulin resistance with a high A1C, for example, someone with type two diabetes, often these people also have PCOS, although that's a spectrum, um, which we don't need to get off of that rabbit

trail. But the takeaway point from that is, um, in both females and males, insulin will potentiate the genomic effect of testosterone. So the way to think about this, if let's say in two different people, there's 10 molecules of testosterone binding to 10 androgen receptors. In the individual that has more insulin resistance, there will be more activity at the gene level, the androgen receptor gene, more transcription molecule for molecule in the female that has insulin resistance. That's why you see a lot of virilization like hirsutism, which is growth of hair in a female where in areas where males typically have hair, more androgenic acne, more androgenic alopecia, et cetera. And that would be only if they're at super physiological levels or if they're

at any normal level, they would still have that response with exogenous testosterone. Even at normal levels, if the female has a lot of sensitivity to androgens, for example, increased androgen receptor density in the cytoplasm or a high number of CAG or sorry, low number of CAG repeats. So the actual androgen receptor is sensitive. Female has two X chromosomes inherits one copy from the mother, one copy from the father. Um, if, uh, and in PCOS, we know that the copy of the androgen receptor that is most sensitive is almost always the active one in the hair follicle and in the ovary. And that's going to be hypersensitive. And even at a normal level of androgen with a normal level of insulin, then you can have signs of virilization.

Gotcha. Actually, I want to take a change of direction here. I remember, again, Huberman saying on a handful of occasions that a lot of people ascribe what they believe to be symptoms of high estrogen in males, and they're actually symptoms of high prolactin. Have you heard him talk about this or are you familiar with this? And I'm going to get a bunch of these details wrong, but I remember being very curious about what he was talking about and I've not looked into the details there. Can you go down that rabbit hole and kind of fill in the gaps for me? Yeah. So you can, let's take two different individuals. They both have the exact same level of estradiol. So estradiol is your strongest estrogen.

Testosterone converts to estradiol, high body fat, high conversion, high alcohol consumption, high conversion to estradiol. Firstly, make sure that the estradiol is measured correctly. So LCMS, which is liquid chromatography with tandem mass spec or equilibrium ultrafiltration, also known as equilibrium dialysis. Those are the two ways that you can accurately measure estradiol under a level of 100 picograms per mil. So most people check the Roche ECLA, which is an immunoassay. And the Roche ECLA is actually the most accurate immunoassay. But even the most accurate immunoassay has very poor accuracy under a level of about 100. So most males and most postmenopausal females are significantly under 100. So it could just be that they chose the wrong blood test to test. Secondly, if these two individuals have different dopaminergic tone or different mu opioid receptor agonism, then they're going to have a different prolactin response downstream.

So you start with estradiol. They both have the same level. Estradiol binds the estradiol alpha receptor. Estradiol alpha receptor increases the activity of PRL. PRL is the gene that causes synthesis and release of prolactin. That's why in states where you have high estradiol, for example, pregnancy, you generally have very high prolactin as well. So they might have a different response of prolactin. There's many things that put the brakes on this process between estradiol binding the PRL gene and prolactin being released from the pituitary. One of those things is opioids. So whether they're endogenous opioids or exogenous opioids, antagonist or agonist, things that increase opioid receptor activity, for example, kratom or things like oxycodone or even buprenorphine or methadone, that's going to increase the amount

of prolactin. And that's going to feel like hyper estrogenic symptoms because you'll have ED, you'll generally have symptoms of low dopamine and high serotonin, like delayed ejaculation and incomplete erection. And a lot of guys say, oh, I have that. I have that high estrogen, but it is due to prolactin. Other things that kind of put the brakes on the prolactin is anything that binds the D2 dopamine receptor. So if you take cabergoline or bromocriptine, those are direct agonists, but generally not used unless you have extremely high prolactin, pathologically high. Other signs of low dopamine are restless legs, so like cramps and movement at night. So you can use Requip, which is ropinerol or premipexil. Those things also increase the amount of D2 receptor binding, but there's a lot of natural things that increase it, like vitamin E mixed tocopherols or mixed tocotrienols.

There's eight types of vitamin E or pyridoxine, which is vitamin B6. There's pyridoxine 5-pyrophosphate and regular pyridoxine. But be careful with high doses because you can get neuropathy from that as well. And then there's other things that are going to affect the amount that you release and that binds to the tissue outside of that. So without going down way too much of a rabbit trail, that's the thousand foot view. Estradiol leads to high prolactin. There's a lot of ways to turn that up and turn that down. Yeah. I'd like to transition kind of into helping the audience specifically have the conversation with their doctor.

When if they're getting kind of their their standard blood work, what are some of the markers that they can start to look at to say maybe there is an issue? And this is probably going to be somebody, you know, 10 to 20 pounds overweight, low libido, low energy, motivation, recoveries, not where it used to be. And now they're thinking, why am I broken? Are there specific markers that they can look at on their own to have a more educated decision before they go in into their doctor to have the conversation? There definitely is a few lowanging fruit here, fasting insulin. You want your fasting insulin to be ideally about seven or below. It depends on the person, but look at your fasting insulin and your fasting glucose and compare the two. You also want to look at your lipid panel. If you have very high triglycerides, that can also be inducing insulin resistance. Look at an A1C as

well. They should also look at a cortisol. And ideally that would be a fasting morning cortisol within a couple hours of waking up, check serum first before moving to salivary or urinary testing. And anytime you do salivary or urinary testing, make sure to do serum testing that kind of that same day, because it's like testing the, what comes out of the exhaust in a car. You want to know what's, um, what's in the engine and the efficiency. So things like, uh, CBG and SHBG, those will tell you how, in general, how efficient the metabolism is, because if you have very low levels of hormones in the saliva, for example, cortisol, and you think, oh, it's because of hypocortisolism or maybe even Addison's disease, it could just be, you have a very high cortisol binding globulin, which also binds progestogens

all day enough. But again, try not to get into too much of a rabbit trail. Your other hormones you'd look at, we already mentioned estradiol and how to test it in certain patient populations. You want to look at total and free T. DHT is helpful to look at as well. DHEA sulfate would be your other adrenal androgen. Um, ACTH is sometimes checked in the morning, although that can vary. That can go up and down quite a bit. Your ratio of DHEA sulfate to cortisol can tell you a lot about adrenal function. You should also look at IGF one, which is your general marker of

growth hormone. Gotcha. And then for those ranges, I mean, blood sugar is like one that comes up with us all the time where I think 85 is the number, but people don't even freak out about it until 100 or like even higher than that. Their doctors still just kind of push it off. Is 85 the number? What can they do from 85 to a hundred? Like, I think that that really can causes a lot of confusion when people see those numbers, but their doctor just brushes them off and says, don't worry about it.

Yeah. I want to know what's the fasting insulin in that patient. Have they tried two weeks of a CGM? They might not, you know, it's not like you tell them you have to wear a continuous glucose monitor for the rest of your life. That's not the case, but two weeks can tell you a lot. And then what is their level of triglycerides? If their trigs are 25 and they're on a huge dose of EPA driving down their trigs, then it makes sense for your body's homeostasis to keep glucose between 85 and 90 and then it's not as concerning if their fasting insulin is 1.5 then that also makes more sense as long as they're making insulin fine in response to feeding yeah you mentioned the the cgm do you find a lot of value in those they can can be very helpful. It tells you more about

your diet, but it's not going to, um, for example, if your glucose spikes up to 160, I'm not in the camp that says you should never eat that food again. A really strict range of, yeah, I mean, uh, it can cause orthorexia and I understand that. I don't think they cause diabetes. There was a Harvard doctor that said CGMs are going to cause diabetes because people are going to eat more smaller frequent meals or something like that. So I don't think that I use them often in patients, but if they're not diabetic or pre-diabetic, usually just for two weeks at a time, they log their food. Hopefully they log their micronutrients and whatnot as well. And then they meet with myself and one of my dietitians or whatnot after that.

But I don't prescribe them to everybody and I'm also not against using them. Yeah. When you, when you talk about diabetes, clearly there's like a, a massive problem in our country with it. Um, it's, you don't have to go too far to, to see just the lack of health. Um, GLP one sounds like everyone should be on it because you're going to lose the weight and be healthier. Um, why isn't it just widely considered like something people should do to get out of diabetes? Yeah. In general, if you're already diagnosed with type two diabetes, most clinicians would at least want to start a GLP-1. Although I saw some statistics that 5% of or less of diabetics are on a GLP-1 and 5% or less of diabetics are on a SGLT-2,

which is another very helpful med that has other secondary endpoints that are beneficial other than controlling A1C. But I think most physicians and nurse practitioners do agree all diabetics should at least consider a GLP-1. But you said it's less than 5%, but you think they all should consider it? Is that what you just said? Correct. And there's a lot of theories behind that. One is patients not willing, not being willing to inject something,

although there's oral semiblutide, it's called ribelsis, that has to be taken fasting on an empty stomach, kind of like thyroid med. And then the other major reason is insurance coverage and what's called pharmacy benefits managers, PBMs, I believe. My colleague, Dr. Taylor Martin, who's a preventive medicine physician, has talked a lot about how these can potentially impede access to medications that a patient would

benefit from. So secondly, you mentioned GLP-1, and then you mentioned another one, which I can't remember the name of from a second ago, but can you expand on other potential options that are out there right now? I know GLP-1 is kind of the main topic of today's show, but if we expand on other medications that have been, that are widely considered to be effective, what's the range look like? Yeah. For diabetes, metabolic syndrome, SGLT2s are another one. They're essentially a diuretic, causes you to pee out some salt, plus they pee out sugar. So they put you in a caloric deficit and they do cause you to lose weight and lose body fat. The main risk is when you're peeing out sugar, genetic urinary infections, especially for females and uncircumcised

men. But other than that, SGLT2s have a lot of benefits, including they're cardioprotective, and they also can help prevent progression of chronic kidney disease. So even not in diabetics, ones like dapaglifzolin are indicated if you have protein in the urine or impaired renal function or impaired cardiac function. Past that, you have amylin analogs. You have semilin right now. There's another long-acting amylin analog that's going to be FDA approved soon. And these are great for type 1 diabetics because, again, the beta cell makes amylin, and it'll have a similar effect to a GLP-1. So it's basically potentiating the effect of the insulin that you do take. When your beta cells die and your pancreas dies, we replace insulin, but we don't replace

amlin yet, but in the future, it'll be a common practice to do so. There's also weight loss meds. So your classic one is phentermine, which is not really used much anymore because of rebound and you can't stay on it for too long. But there's other things that are essentially monoamines like bupropion or diethylpropion. There's contrave, which includes low-dose naltrexone, which can be very helpful for certain conditions or certain cravings. There's also chycemia.

There's a whole bunch of new options. There's fat blockers, there's carb blockers. But one of the ones that I'm most interested in that the listeners of the podcast might be interested in is a myostatin inhibitor. So it works on actin light chain, which secondarily blocks the action of myostatin outside of its action on folostatin. Some people might be familiar with epicatechin or YK11 or fortotropin, which are other myostatin inhibitors. And it just finished a, I think it was like called a stage 2B3A. Clinical trials are another rabbit trail. We don't need to go down, but it finished a clinical trial and its results looked really good. People gained about three kilograms of

lean body mass and lost, I believe, seven kilograms of body fat over not quite a year in the trial. And that it, to my knowledge is one of the only anti-obesity medications where people have done those two things, the Holy grail of body recomposition at the same time. Yeah. I remember hearing about myostatin inhibitors, you know, 10, 15, 20 years ago. And I kind of thought that was going to be like the next wave of bodybuilding super drugs and it didn't really pan out, but now they're being used for, for obesity and it's helping build lean body mass and, and then get leaner at the same time. Yeah. It at least seems to be based on that trial that the key was not targeting the phallostatin myostatin axis rather, um, the, uh,

actin light chain that it targeted. It's very promising. It probably works. It does likely work much better in individuals that have a very high amount of body fat. So it's probably not going to work great in bodybuilders and it will probably work very well in pediatric obesity. In fact, there's another pediatric obesity drug

that targets the gut microbiome. That's the primary endpoint they studied is gut microbiota changes. And that one is based on butyric acid. There's a whole bunch of type of butyric acid, magnesium butyrate, sodium butyrate, tributyrate, which is bound to glycerol. But at the end of the day, it's not just affecting the gut microbiome. Yes, it is a postbiotic, but it also has a lot of epigenetic effects, epigenetic switches, which make a lot of sense. You want to flip your epigenetic switches in the pediatric population, given the high incidence of cancer and heart attacks, even if

you're obese as a child and then not as an adult. So I got your opinion here as a physician, you just gave us a laundry list of different medications and ideas for the sole category. When people come to you and they say, hey, I heard about this medication on this podcast. I want to take it. What's your general response? Are you kind of annoyed by it? How should someone present the idea of taking any one of these things to their physician? We have a huge following in Kansas that's coming to you. So get ready. Yeah. And between myself and my partners, I think we cover 48 of the 50 states that we can see people in. But my response is not of annoyance. It's of interest when people come to the doctor or their health coach or their dietitian or whatever health care professional they seek out. It's because they want to improve their health. So that's the first step of change is that they want to do something. So that's great. My question is, what is the desired outcome and what all are you willing to do and what other options have you considered and or tried in order to do this? Then you take

the subjective and the objective. The subjective is how they feel and what they want. And the objective is the quantitative numbers, labs, vitals, et cetera, medical history. And then you synthesize the two and come up with a plan. I do something called shared decision-making and all physicians should be trained to do this in medical school. Supposedly they are, but that's when you take the goal of the individual patient and you explain the risk and the benefits, you actively listen to what their desire is. And then you come to a decision together of what intervention to utilize.

Fantastic, man. Yo, this was incredibly, incredibly informative. I really appreciate this. I've heard many things about GLP-1 and Joe, this was incredibly, incredibly informative. I really appreciate this. I've heard many things about GLP-1 and never had an hour to sit down and actually learn about it. So I really appreciate that, man. Yeah, my pleasure. I also hear a lot about it.

I drive my car on the radio. I hear, like, I'm not calling out the, I guess I am calling out these specific things, but I hear join the slim for life program. Your GLP one is included. Join the weight watchers pro weight program. Your GLP one is included. Join this regenerative med spa. We use PRP and semaglutide in every single patient, no matter what they have. Um, so hear a terrestrial radio commercial, I go, well, the people they're targeting right now, who knows what's going on? But it immediately puts the red flags up. Yeah, it gets me fired up. One of my favorite or least favorite, I guess, depending on how you look at it, was join this company.

Don't take any supplements and without any exercise, lose 30 pounds in 30 days just with nutraceuticals. Skip by all those pillars that you know that work for lifestyle intervention. Just skip them. No big deal. Go right to the end. Fantastic, man. For people that want to work with you or just learn more, where can they find you? Yeah, my main hub is on Instagram, Kyle Gillette MD, Gillette Health on all other platforms. We do have a relatively new podcast. The Gillette Health is a clinical podcast. And then After Hours is a entertainment podcast, which we try to do in relatively good taste. And any support on YouTube would also be appreciated. We're trying to grow that as well. Fantastic, man. Doug Larson.

Bet. Find me on Instagram, Douglas C. Larson. Pal, appreciate you coming on the show, man. That was a lot of nuance and a lot of details that most people can't do at that level. So I really enjoyed the show, and I've been stoked about you coming on for many weeks here. So glad to finally do it. Good to have you. Thank you, guys. My pleasure. I'm Anders Varner at Anders Varner, and we are Barbell Shrugged to Barbell underscore Shrugged.

Make sure you go over to rapidhealthreport.com. That is where Dr. Andy Galpin and Dan Garner are doing a free lab lifestyle and performance analysis that everybody inside Rapid Health Optimization will receive. You can access that at rapidhealthreport.com. Friends, we'll see you guys next week.