APOE4: Your Brain Is Insulin Resistant (Even If Your Labs Are Normal)

[0:00]Your lab says you're fine, but your brain says otherwise. I've just finished my second deep dive with our resident board certified anti-aging physician, Dr. Grant Fraser who is a fellow ApoE4 carrier and of course, a Phoenix member. And what he told me about insulin resistance in the brain honestly changed how I completely think about this.

[0:23]Because even though your HOMA-IR is perfect, even if your glucose is in a healthy, let's say 80s, your hippocampus might already be starving for fuel today. And as ApoE4 carriers, we actually should just assume that it's already happening. We get into the exact biomarker to test, and the actual one cheap test that your doctor somehow never orders.

[0:48]We'll also get into why some people can't get into ketosis no matter what they eat. And the one class of medication Dr. Fraser puts most of his patients on that only cost $40 for 100 days. I hope you stay for the full conversation. I really believe it's worth it. Let's get into it.

[1:05]You should presume that you have insulin resistance in your brain. my hemoglobin A1C, I think it was like 5.4. My fasting glucose, I think, was 80. But my insulin was 80. Fasting insulin. I had a bunch of chips and salsa, I had a drink that had some sugar in it and next thing my blood glucose was like 230.

[1:23]these insulin receptors end up oftentimes getting tied up by APOE4 and end up not being effective. Even if you're not having a massive improvement, it may mean that you don't have any significant cognitive impairment if you end up not supplying adequate glucose to areas like your hippocampus, over time it's going to shrink

[1:48]Hello, everyone. Welcome back. This is episode two of our monthly series with Dr. Grant Fraser And last time we went deep into lipid management for APOE4 carriers specifically. So if you missed that episode, just go on YouTube. You can get access to it. Today we're tackling something that I believe is a little bit underappreciated in the APOE4 community.

[2:12]We'll be talking about insulin sensitivity, specifically why it matters for us, ApoE4 carriers, more than the general population and what we can actually do about it. So we'll cover things like what to test, the biomarkers, the exercise you can do, the dietary protocols we can do that specifically target insulin sensitivity, and of course the medication and supplements.

[2:33]I know everyone likes medication and supplements here. And we'll also connect it all back to the lipid conversation we had. We also collected all your questions from Phoenix community members. So we'll weave these in throughout the conversation. I feel like this is a more natural way of doing that rather than separating the two.

[2:52]And as always, to vote for the next topic that we'll cover with Dr. Fraser or to ask your personal question, just ask them into the Phoenix community. All right, that was the introduction. Let's dive into it, Dr. Fraser I'm so glad to have you here. I always love these conversations we have.

[3:08]So very excited to have this chat. Very, very good. Now it's a pleasure to be here. This is a complicated topic and I think the goal is to at least get people to understand that there's a lot of complexity to it and actually give people. things that they can practically do without getting too overwhelmed with the science behind it because it is complicated and it's evolving.

[3:34]And I had to do a fair bit of reading to get ready for this because this is a topic that did not even exist when... was a medical student and certainly we did not learn about, you know, glute transporters and all this stuff stuff that is possibly was known back in the early 90s when I went to medical school but you know, this is uh a complex and evolving area of uh new information and what I say today will probably change and evolve a little bit over the next few years with more research.

[4:04]I actually like the fact that it's evolving very fast and I'm glad to have you with us to be able to translate all the hard science into what you mentioned, actionable insights, which is I think what people look for. So to begin, I'd like to spend a bit of time to explain to the audience why insulin sensitivity is so important for us, ApoE4 carriers.

[4:25]Yes. Well, I think that the big issue is separating out the discussion around insulin sensitivity in the periphery, which is very important for the rest of your health. So I think that certainly as far as coronary artery disease, your risk of stroke, fatty liver disease, you know, all these things, it's very important that your periphery have insulin sensitivity and that your average glucose is at a good level and that you're not having to generate excessive insulin for this.

[4:59]But then there's the issue of brain insulin sensitivity and that's much more complicated to measure and deal with, but it is something where we know that in the brains of individuals with ApoE4s that the brain is much more likely to be insulin resistant. And interestingly, in areas which we see shrink in individuals with ApoE4s, which is when you get an MRI and you take a look and say, here's your hippocampal size, and then there's a hippocampal occupancy.

[5:29]index, which initially will give you an idea as to whether there's been some shrinkage in the area of the hippocampus already. That is the area that requires a transporter, which is insulin sensitive because the other receptors in the brain, Glute 1 and Glute continue to just let glucose in, and the blood-brain barrier, and the rest of the neurons, but in specific areas of your brain that seem to be maximally impacted in Alzheimer's pathology, for receptors there and those areas get shrinkage and this is something where the insulin sensitivity in the brain is important and ApoE4 alters that.

[6:04]And beyond that, so these insulin receptors end up oftentimes getting tied up by APOE4 and end up not being effective. just for reference, insulin when it binds to one of these receptors is a signal to let glucose into the cell. And if these areas end up getting affected to where they're not letting that glucose in the cell, you get a lower level of brain function in that area.

[6:32]the neurons are going to get stressed and the hippocampus is particularly susceptible to this. we see, you know, we see in people with ApoE4s 20-25 % decreased amount of metabolism in these areas, which I suspect is part of the pathology that ends up causing these areas to shrink And hippocampus and caudate nucleus are a couple of areas which when they shrink very much correlates with symptomatic Alzheimer's disease.

[7:00]So I think it is relevant. that we want these areas to be getting adequate glucose so that they can metabolize and do their functions. And this is impacted in APOE4s. And probably the big part of it that is tougher to deal with is with mitochondrial dysfunction, which is downline from is that even when you supply these neurons with adequate glucose, the mitochondria has impaired electron transport, we end up seeing increased reactive oxygen species.

[7:33]we see an energy deficit even when you're getting glucose into the cells. So it is a complex topic and something where your brain has the alternative fuel that it can use. There's receptors, it's a MCT transporter which doesn't stand for the same thing as medium chain, but with the oil it is something where this is where...

[7:57]ketones can kind of bypass that because it's an alternate fuel, but you still probably have some of the same, you're gonna have the same issues in the mitochondria. so as far as the question around insulin resistance in the brain is something where we do have a challenge and it's tough to measure.

[8:16]There are ways to measure as far as taking a look at glucose uptake, with some of the fancy scans. But in general, I'd say that you just kind of anticipate that you're going to have these challenges with your brain getting adequate glucose, especially in the areas that have a Glut 4 receptor.

[8:34]Okay, tons of things to unpack. It was a lot of information here just to help clarify a little bit because I think we went like very technical straight away. Yes Very, to clarify, so you have a different type of insulin sensitivity whether you are in the brain or in the general body, which is the periphery.

[8:55]And mainly because the ApoE4 protein which we produce or we code from the APOE4 gene, so the APOE4 gene codes for the APOE4 protein, and that protein somehow competes with insulin for receptors binding for the neurons, more than APOE3 and more than APOE2 protein. And that is, I'd say, the main reason why it's so important for us to care about insulin resistance here.

[9:20]If we go very fast on a communication, actually, because I have a long list and I feel like that is perfect here. Like Christy from the community, she asked quite a good question. She wanted to know, can you be metabolically insulin sensitive in labs? So she mentions HOMA IR under three, which I believe is still already quite high, but let's say like below two or below one, but still insulin resistant.

[9:48]So can you be metabolically insulin sensitive in labs, but still insulin resistant in the brain? Absolutely. I think that most people that have, especially people that are homozygous for APOE4, should presume that you have insulin resistance in your brain. It's good to be metabolically healthy for other reasons.

[10:09]And I suspect that there is a correlation between being peripherally insulin sensitive and having less effects in the brain. We know that people that have type two diabetes, the more poorly controlled it is, the higher the risk of getting dementia. So I think that there is a reason to do the best that you can out in the rest of your body.

[10:34]But I think the presumption should be that you have insulin resistance in your brain. And then the challenge is what to do about it. healthy you are by traditional measures like HOMA IR or for the HOMA's and slash S which looks at insulin sensitivity specifically. I think that's a really good good thing and probably is going to be a benefit to your brain also but it is something where I would presume that there's some insulin resistance and and then the challenge becomes what to do about it and there's interesting stuff on the pharmacotherapy.

[11:07]side of things, there's interesting stuff on the diet side of things, but I think the presumption should be that you've got at least some degree of insulin resistance in your brain and probably is going to be worse in individuals who have elevated HOMA. And I think the goal really, so normal is less than two, And I think the goal really, so normal is less than two, but I think that we should be goaling for better than that and trying to get down into low ones or less than one, which is certainly doable for a lot of individuals, but it can be a challenge as people get older.

[11:41]is certainly doable for a lot of individuals, but it can be a challenge as people get older. I see more and more of this kind of insulin resistance creeping in even in people who have ideal body weight, and it is complicated as to what to do to optimize this because it's very simple when I have somebody who's 100 pounds overweight who's insulin resistant.

[11:55]I've got a lot of levers that I can pull with that, but when I have somebody who's ideal body weight, they have no weight to lose, then it becomes pharmacotherapy, diet can even be a challenge where you do all the right things and you still end up having the same numbers and this creeps up with age oftentimes.

[12:12]So you mentioned that we should presume that we have like insulin insensitivity in the brain, right? So how would we know that whatever therapies or whatever interventions we're doing are working? What type of, is it only a PET scan that can give us some information or is there other type of proxies that we can look at? yeah there’s basically there are PET scans that will take a look and see as to what your uptake is where you have tagged glucose and you can see as far as how it getting metabolized.

[12:41]I'm not sure that that is massively actionable and it's certainly not cost effective. I think if you do the appropriate things that you can do that there's evidence for or logic for, that's probably a good baseline because if you get one of these scans and it ends up being abnormal, which we would anticipate that it would be I'm not sure that scan really changes your actions because we would anticipate, especially if you're a homozygous, that you're going to have an abnormal scan.

[13:13]in these areas and it wouldn't be an area that I would tend, know, for my patients who are completely cost insensitive, sure, go ahead and do it for curiosity. But I think for general patients who have APOE4s, I would simply say, presume you've got this defect and do the right things.

[13:30]mean, optimize your peripheral numbers, but anticipate that even with that that you want to be doing some things to optimize how your brain's going to access glucose and use glucose and just presume that defect is there. Okay, so let's start with the periphery first, because we can basically assume that if your biomarkers for the periphery are bad, it will be bad in the brain no matter what.

[13:54]So let's fix that one first as a layer. If we look at all these biomarkers, which one do you recommend to get tested? How often? Which are the good values? Yeah, so I think that for somebody to start, I simply will take a look at a fasting glucose with fasting insulin and do a HOMA IR If that is completely normal, I think that we can usually stop at that time plus add a hemoglobin A1C because we will see people that are insulin sensitive.

[14:26]And yet, and including, you know, they have fasting blood glucose of 110, but they're not really producing much insulin. They will have a HOMA IR that is normal. And yet their hemoglobin A1C will be, know, six. And this is a real challenge in a lot of patients. And so I think you do have to put those things together.

[14:49]But a lot of times in that situation, you just, your body is not signaling that, that glucose of 110 or 120 requires any type of insulin release. So in those patients, I'm going to map out a five or six point blood draw, which is important when you go and get this, that you...

[15:14]have it done at a hospital where somebody can stick an IV in you so you're not getting five or six blood draws because that inevitably gets messed up because you're wanting to get them 30 minutes apart. But you do a glucose tolerance test, but you don't only get a glucose.

[15:28]You'll end up, so you get an initial glucose. and insulin level. Some people also allowed to see peptide, which adds a little bit of expense and I don't think is massively actionable. But just getting an insulin and glucose and getting that five or six point and getting an initial then kind of I usually started about an hour of getting the subsequent four tests is what I usually do.

[15:53]Then you're going to just take a look and map that and see what somebody's response So yeah, so a lot of those people that end up having elevated levels hemoglobin A1C. they will end up just having what I refer to as kind lazy pancreas syndrome, is not, they will end up just having what I refer to as kind lazy pancreas syndrome, is not, they will end up just having what I refer to as kind lazy pancreas syndrome, is not, which some people say, you know, it's autoimmune disease of the pancreas degenerating with age.

[16:15]And it's very common as people get older where we'll see this fasting glucose that's up. not a lot of insulin, you go, you know, do you have some pancreatic failure? And what we see in a lot of those individuals is that as you give them a glucose load, they end up actually producing stacks of insulin later, but your body just doesn't recognize that your pancreas is not recognizing that a sugar of 110 or 120 requires any type of insulin release.

[16:35]recognize that your pancreas is not recognizing that a sugar of 110 or 120 requires any type of insulin release. so those people are my most complex patients in order to optimize good news is that they're not having a lot of insulin secretion, which could be bad thing for the brain because you're not going to be utilizing energy very well.

[17:00]And it is real challenge as to what you do with these individuals who when they've had the glucose load and their blood sugar gets to 170, suddenly they start releasing a whole bunch of insulin. So it's not an inability. whatever your sensor is in your pancreas is not recognizing that this is abnormal and that is a common thing that I see especially more so in men, interestingly, and a lot of these men in their 60s and 70s who are doing this and a lot of times you're really going to be looking at pharmacotherapy which can be a challenge with these individuals to get their hemoglobin A1c down but that's probably more of an issue for the periphery but it is an issue for the brain if you're not making insulin.

[17:41]when you probably should be. So just to go back very fast on the lazy pancreas and those sensors not recognizing a very high level of glucose, you mentioned that it happens with age. Is it very common for everyone basically just with age it happens? Or is it start earlier for some other people?

[18:00]Is there a genetic aspect? I see with metabolic. people that you would take a look at and say they're metabolically healthy, they've got adequate skeletal muscle, they're not overweight. It is something where I'm seeing that in a lot of individuals in their 60s and 70s where we kind of have this It is something where I'm seeing that in a lot of individuals in their 60s and 70s where we kind of have this creep upward of their average blood glucose without an adequate or expected insulin response.

[18:26]that is something where, and I don't see that same thing happening in my patients in their 30s, 40s, 50s so much. in my patients in their 30s, 40s, 50s so much. And those people where there's an issue, it's much more straightforward to fix because people that have insulin resistance, so your body's making plenty of insulin, but your cells are not taking up the glucose as they should be.

[18:48]Those people, we have much more effective therapies and most of individuals have weight ton lose is probably the big thing. And that ends up being an easy issue to address. Whereas the issue of you not producing insulin when you should be is a more complex one. And the way that you figure this out is that you do have to do a glucose tolerance test and you do need to get these serial blood draws to actually map out what your body is doing.

[19:14]And that is something where, you know, my patients have a normal HOMA IR normal hemoglobin A1C, which I would target, you know, 5.3 or lower in people with APOE4s Those people were kind of done with the workup and saying, look, right now you're fine, we'll monitor this over time.

[19:31]But the group of people that have this fasting glucose that's up and aren't producing a lot of insulin for it, so they're technically insulin sensitive, those are a complex group in order to deal with when they invariably are metabolically healthy. So as far as their heart health and so forth is fine, there's going to be the minor effects on the blood vessel.

[19:54]of having a little bit of high glucose, but. With that, I don't see that they're massively increasing the risk of vascular disease, kidney failure, and so forth, having a fasting glucose of 110 or 120. I think the bigger issue is that you're not generating insulin, which is going to be a problem for the brain.

[20:13]A lot of the brain insulin is made in the brain. Some of it certainly traverses across blood-brain barrier, but a lot of that seems to be made in the brain. science behind this is still not entirely clear. It looks like some of it's made in the choroid plexus, which makes the cerebral spinal fluid.

[20:34]But but it is something where, you know, the brain has its own closed system to some degree. And and it's difficult to measure that for obvious reasons. Yeah. What about triglycerides to HDL ratio? I know quite a lot of doctors, measure that as a proxy as well. Do you use those? or another Which test is that?

[20:55]triglycerides to HDL ratio. Yeah, yes. So I don't use that routinely as far as looking at your time as far as using that to look at insulin sensitivity or utilization. Yeah, I have not routinely used that. You know, I'm happy to take a look into that, but that isn't something that I've utilized as far as, you know, assessing whether somebody is going to be getting.

[21:19]access to glucose in their brain. I'm not sure that there would be lot of evidence for doing that. I mean, certainly high triglycerides are a problem, not for your vascular health, but just an indication that you're metabolically not healthy is a big issue as they kind of get above 150.

[21:40]So we certainly, that's probably the only reason why I get a standard lipid panel is, there's two reasons. One, because people People are used to seeing them, so it's of a historical interest. But as far as for lipids, APOB is really the target. But I definitely get a lipid panel to take a look at triglycerides because that's certainly an indication that we've got some metabolic issues.

[22:03]And that's probably more in the periphery. I don't know of anywhere where we would utilize that for looking at the brain as far as, you are we utilizing glucose? And I think the assumption just goes back to you're going to have a defect here in the brain and you should presume it and do the things that you can in order to get your brain adequate glucose, especially in the areas that are going to be insulin sensitive such as the hippocampus.

[22:34]Yeah, makes sense. What about the frequency of those tests? So mean, HbA1c would take like around three months for your blood cells to regenerate anyway. So that's around that for HOMA-IR. So HOMA-IR to just for those listings, if you don't have it directly on your test is because it's just like a multi multiplication between like fasting insulin and fasting glucose.

[22:54]And I think there's a number somewhere on top. But yeah, it's calculated basically between those two. So how often would you measure those fasting insulin and fasting glucose. I usually get labs quarterly on my patients because there's a lot of things that we kind of trend that are, you that, you know, your average life of your red blood cells is 100, 120 days.

[23:20]So changes that we make are going to take that long to reflect on the hemoglobin A1C. You know, also a lot of things as far as like omega-3 index, vitamin D, those are all going to take three months to stabilized. So for a lot of our interventions, your lipid treatments usually only take four to six weeks.

[23:37]So sometimes I'll check those earlier if we've changed something. But probably quarterly is a reasonable plan for a lot of this. But if you're doing active interventions, you know, for example, if I had somebody that had a abnormal glucose tolerance test and we ended up doing some things to modify that that were not lifestyle, that were pharmacotherapy or other supplement you know you could check as soon as a week or two to see the effect you know if you put somebody on SGLT2 or GLP1 or on Metformin or you know one we're on Actos if they're insulin resistant you know those types of things we're going to see changes pretty quickly.

[24:15]All right, cool. I have a few community questions here. I think we covered a little bit, but I'll still go over them. Like Donna from the community, she has a great series of questions, actually several. The first one is, we measure glucose as a proxy for insulin. How reliable a proxy is it?

[24:31]It depends on the individual. I don't think that it is reliable in any way in looking at what your insulin is because you can be insulin resistant and have a normal glucose and normal hemoglobin A1c. There's our typical situation in which, years ago before I got into this, one of the things that got me into longevity medicine and led me down this is that I was overweight, working a lot in the ER, I used to telehealth doctor and he ended up ordering a Insulin, which I never thought to do.

[25:10]I mean, this was years ago before I got into this and was working just in the ER. In my hemoglobin A1C, I think it was like 5.4. My fasting glucose, I think, was 80. But my insulin was 80. Fasting insulin. And that was kind of a wake up for me and going like, okay, you're going to, continue doing this.

[25:29]You're going to next have diabetes or pre-diabetes. And it was, is a big wake up call. So in that situation, if I was just monitoring my glucose, I go, I'm great monitoring my hemoglobin A1C. I'm great. And yet I've got, got massively increased insulin, which is certainly going to be doing damage to damaged blood vessels.

[25:49]it is something where the two things can be, in individuals who had a normal glucose tolerance test the two things will correlate because you'll know from that and go, okay, I'm normal. And those things probably can correlate, but it is something where you can have a low insulin, a high insulin, And those things probably can correlate, but it is something where you can have a low insulin, a high insulin, normal insulin with exactly the same glucose number.

[26:11]So this is an individual thing where you have to test and get the data to know where you're at. So I wouldn't rely on that at all because you can have any of those situations withexactly the same glucose. Interesting. My follow-up question is a little bit like similar to your case.

[26:28]If fasting glucose is low, but fasting insulin is high, what does it mean? Does it mean that the pancreas is working overtime and approaching burnout? And is that the ApoE4 specific thing or is it just an individual overall specific thing? I think individuals with APOE4s are more likely to be insulin resistant.

[26:47]But it is something where I would say that it's not that the pancreas is working over time, it's that your your cells are resistant to insulin and your pancreas is doing its job, doing a great job of, like in my situation where you know my fasting glucose I think was, I don't know, the 80s.

[27:08]And yet I had this huge insulin level. So my pancreas was doing a great job recognizing, hey, you know, we would like to have a good fasting glucose, but it's having to produce all this insulin because of my body being resistant and my cells not wanting to take up glucose.

[27:23]So I don't think it's, I mean, yeah, you are going to get pancreas burnout at some point with this, but it's not due to your pancreas, it's due to your periphery, due to your liver, due to your fat that is required. this amount of insulin for you to maintain a normal um blood glucose.

[27:40]So in that situation, I would say the issue is you're going to have a HOMA-IR that's very elevated. Like with mine, I'm sure that the HOMA-IR would have been eight or nine with those numbers. So insulin resistant. And if you're overweight, then that becomes a simple thing. Lose the weight, your cells will become more insulin sensitive, then your pancreas can will and can back down and not have to produce much insulin.

[28:07]I mean, my fasting insulin levels now are two or three. But that's purely due to weight loss is a big thing that's done that. But the challenge is the group of people that are insulin resistant and are already at ideal body weight. those end up being the challenging ones.

[28:23]But yes, you do need to measure both. And insulin's a cheap test to get, you know, eight or nine dollars. And it's something where primary care doctors almost never measure this. Just ask them to add it or self order your labs through Ulta or one of the other services where you can cheaply order your stuff and just get the labs that you want to get.

[28:44]Cool. We also have like Donna and Anne, two other members who are both insulin sensitive. So they estimate that because their glucose comes right back down after meals, probably with a CGM they can measure that and they have good overall numbers. But their A1C creeps to 5.5 to 5.6 despite eating lean.

[29:03]Is that an issue? Like, you try, how would you like bring it lower? I think you mentioned like 5.4, right? As a good overall target. Yeah. So I think that before jumping in with pharmacotherapy, so that is representative of someone who their pancreas is not necessarily putting out.

[29:23]insulin when it needs to so it's waiting until your blood sugar is higher than what it used to be and this is part of what I see with aging is that your pancreas will sit back and wait until the numbers are a bit higher by you know 10, 20, 30 on your glucose before it kicks in and starts secreting insulin.

[29:44]This is the common situation that I see in so many of my patients because most of my patients are pretty healthy the fact that they come and see me most of the time. they're engaged and they're physically fit and doing stuff that makes them fairly optimized and yet we still see this exact issue.

[30:02]And I have a lot of patients that come to me and their hemoglobin A1c is in the sixes and yet they're insulin sensitive and at ideal body weight. So this ends up being the challenge. with that, I think that doing things such as after a meal, going for a walk even when you do have a good meal.

[30:27]The eating order is important. This is one of the values of wearing a CGM is saying, you know, have your fats first. This is one of the values of wearing a CGM is saying, you know, have your fats first. You know, a lot of times fats and proteins are going to come together and then have your complex carbohydrates last will generate a different glucose You know, a lot of times fats and proteins are going to come together and then have your complex carbohydrates last will generate a different glucose curve and spike.

[30:46]But then if you go out and take a walk afterwards, that will utilize a fair amount of that glucose and minimize that spike. But then if you go out and take a walk afterwards, that will utilize a fair amount of that glucose and minimize that spike. So those are things that you can certainly do.

[30:56]Limiting the number of times that you end up creating glucose spikes is part of this also. So the person that snacks frequently ends up who has this issue is going to worsen this issue. So the person that snacks frequently ends up who has this issue is going to worsen this issue.

[31:10]lot of times, you know, getting things down to two good meals a day is something and you know, each time doing a little bit of, a little bit of exercise afterwards is a sensible thing Having, you know, more prolonged periods where you're not consuming any calories, both Having, you know, more prolonged periods where you're not consuming any calories, both between meals and say, you know, get, get most of your calories, you know, in, in, you know 10 or 12 hours during the day or eight hours.

[31:36]And that, is something where, where that oftentimes can be quite helpful. And then also eliminating simple carbohydrates is, and potentially also some of the artificial sweeteners, which interestingly, your brain can signal your body to secrete insulin And it's a small but modest effect. And this is probably where artificial sweeteners end up creating a little bit of a spike of insulin sometimes, and that's gonna be generated primarily from your brain, not elsewhere.

[32:14]But that also can then cause your blood glucose to go a little bit low, and then you get hungry, and it stimulate more consumption. This is one of the reasons why the artificial sweeteners... can oftentimes be associated with people gaining weight, not due to consuming those, but in response to that with it causing hunger.

[32:34]So it is something where, you know, avoiding all these things in your diet can be helpful. And then there comes in the question as far as whether you end up doing something, you know, such as a Mediterranean keto type diet, because you want to be careful with the keto diets, and I know you've spoken a fair bit on this, is that you want to do it in a way that doesn't decrease, doesn't increase your risk of vascular disease.

[33:01]Cause you can absolutely have a very, very high fat diet that is extremely healthy, but it has to be carefully crafted. And it is doable with, you know, having, you know, nuts and olive oil and avocado oil and, you know, and having just modest carbohydrates. you do, you know, if you end up doing it, you know, like carnivore diet, you're going to have, you're going to have other health consequences that are negative as a result of it and your lipids are going to also be more of a problem.

[33:32]So it's an issue of crafting that diet so that you end up not worsening other areas of your health by doing that. And, you know, this is certainly something where if you can generate ketones, that is an alternate fuel for your brain, which including those areas like your hippocampus.

[33:49]Okay, I think there's a lot to unpack like suddenly. Let's separate. No, no, it's great. It's great because we're touching on all the different topics. Let's separate the dietary part and the exercise part. Let's start with dietary, I guess, since we're here. You mentioned, I think, one of the easiest quick wins, right, which is like the order at which you eat your food, which I believe doesn't make any difference, right?

[34:10]You still enjoy your food in the end. You mentioned like fats and protein first and then carb last. I'll just add probably like the fibers first. I agree, actually, fiber is incredibly important and that ends up being the challenge. Most of the things that have fat in them and protein don't have much in the way of fiber.

[34:28]so it is something where getting, if you have something which has significant dietary fiber which tends to go hand in hand with complex carbohydrates, getting that earlier in the phase of consumption is also quite helpful. But the eating order for the glucose spikes is, know, start out, you know, if you have some nuts and some olive oil and you know, if you are going to have, you know, whether you're going to be doing, you know, tofu, tempeh, some meat, some eggs, you know, whatever your protein source is, getting that early and then getting in stuff that has fiber because fiber is also, you know, critically important for gut health and, you know, getting 30 grams of fiber per day is important.

[35:14]getting foods that have a lot of flavonoids and phytonutrients and so forth is quite important. that's where I think kind of a keto Mediterranean diet is a very sensible thing. we've tracked our diet and at times we have greater than 50 % of our calories from fat, but it's all healthy fat.

[35:34]certainly if anything has a beneficial effect on... your lipids so you can do this and be metabolically very healthy, but you have to craft it carefully. It's not something that you just kind of slap together in order to do it in a way that you don't force in other areas of your health.

[35:52]But then the challenge also, I saw one of the questions, as far as you have somebody who does what is a fairly ketogenic diet and they're still not generating ketones, which is more of an issue in women, interestingly. And that can be a challenge and some people are going to do all the things that you would typically think would work and you still don't generate ketones.

[36:19]And we of course have ways to monitor that. There's the same way as you have a glucometer, you can monitor ketones and get a measure of it. And there's a lot of times where you're going to find that to be a failure, but it's worth measuring. and seeing as to whether that is working for you or not.

[36:36]But ultimately, there's limits to what you're going to be able to do and do healthily. If you just completely kick out anything with any type of carbohydrate, you're probably going to have a tough time with your other health. Looking at the community question since we're going there, there was Kelly and Aljosa, they both basically have been low-carb for a year.

[36:57]They can't get into ketosis or they can't get above one millimolar, which is already not too bad, think, one millimolar. The thing I'd say mechanistically, I think we have to remember that whatever fingerprick we're using to measure the ketone level in the blood technically if our brain is using that ketone already, maybe it's just the rate of utilization might be too high and then the ketone still reaches the brain, but then obviously it's not in the blood anymore and then it detects a lower level, right?

[37:25]So I would also think that as long as you feel sharper and you feel like you have the benefits maybe it's working to not use that proxy too much, the blood fingerprint. It might be just a proxy because you might be utilizing it too fast. absolutely I think that subjective thing become quite important.

[37:44]There's other things that we sometimes do to improve mitochondrial efficiency. it's interesting with that, with things like NACF lester to increase your glutathione, methylene blue to skip over some of the electron transport areas in the mitochondria to allow more efficient production of ATP. I'll have half of people, I'll give them a trial of it and half people go, this is great, this really improved things.

[38:15]Half people go, I don't feel any different and it's literally one dose. mean, one dose you're going to know as to whether this is helpful for you or not. It's not some lengthy trial. For people that it works, it works and you can say, look, this is an issue where improving how your mitochondrial function is as far as the efficiency.

[38:33]made a difference and in other people you go didn't and the same thing is going to be with ketones. If you're doing this and you go look I feel mentally sharper it's a subjective thing but I think that's hugely valuable of saying for you that is something which is working, stick with it.

[38:47]Yeah, definitely. And I think a good way to do that is really to track it either in the journal or we have a Phoenix app where basically you can enter every day if you feel sharp or not, like on a rating from zero to 10, and also enter if you are in ketosis, if you had like carbs or not, if you're not in ketosis and so on.

[39:03]So you can see the pattern because the memory, if you try to recall the past two weeks, if when you are like above like one millimeter, you've been sharp or not, your memory might not be good enough to be able to derive those insights. You want to at least write it down in an Excel sheet if you don't have access to the Phoenix app.

[39:19]I that's very important. Regarding, since we're under the ketosis, ketones topic, what do you think about ketone esters, about MCT oil, about all these different shots that you can take to boost the ketone levels. I think those are kind of second line to doing things dietary and lifestyle.

[39:37]I would first go with that. And also it's a subjective thing, which is as far as, know, go ahead and take a good dose of ketones. One of the early ones, which was, because these things used to cost ridiculous amounts of money. now they're still expensive, but not nearly as bad.

[39:56]But one of the groups that makes kind of concentrated ketone. I've talked with a guy who owns that company and he said, look, there's some people that had significant cognitive impairment that had APOE4s and you'd give them a dose of ketones and they would be notably sharper to where their relatives are going like hey, this person is now actually functioning where they were not even doing a standard act.

[40:26]of daily living and all this stuff that made this massive difference. And it's probably got to do with how severe your cognitive impairment is as to what the benefit is. And I've had some people that end up benefiting from this, but it's short-lived. It's not something where it doesn't last all day.

[40:45]You kind of use up those ketones. And it's something where you need to take many doses per day if that's a beneficial thing or how. a diet in lifestyle that's generating ketones, but I think it is a reasonable thing to test for somebody who says you know, hey, I'm a little bit cloudy, you know, taking some exogenous ketones and go, does this make a difference?

[41:03]And if it makes a difference, then I think it's something reasonable to go, you know, let's see what I can do to push my lifestyle so that I'm doing this naturally. And if it makes no difference, it's probably something which is not going to be massively effective for that.

[41:18]for that condition, but in the background you have to think about it and go Even if you're not having a massive improvement, it may mean that you don't have any significant cognitive impairment but you still, if you end up not supplying adequate glucose to areas like your hippocampus, over time it's going to shrink and you're going to then have cognitive impairment and that's the whole thing that people want to avoid.

[41:43]I think that just the assumption that you've got a defect that's worth generating some alternative fuel for. is probably the take home message is to do some things that generate an alternate fuel for your brain is probably a reasonable baseline assumption. And we have multiple studies showing that for individuals who have mild cognitive impairment and Alzheimer's pathology, that having ketones available as an alternative fuel is a sensible thing and does seem to improve.

[42:14]your function, I think for the Phoenix group, most people here do not have mild cognitive impairment and the goal is to not get it. So I think you'd use the same strategy where you go the things that improve mild cognitive impairment. You've already got significant disease in your brain.

[42:29]All of us want to make sure we don't get significant disease in our brain. So doing the things that would treat that would be sensible before you have symptomatic disease. Yeah, that's a very good point. And I like your idea of just taking those exogenous ketones, the ketone esters, just to see if it does something to you, right?

[42:46]Because you'll know right away after like 20 minutes, you'll know if it spikes your cognition or not. By the way, if you take those, I take those without caffeine, because otherwise you might not know if it's the caffeine making effect or the ketones itself. Are there any downside other than the cost?

[43:00]Like I can't remember the cost, but it's probably like $10 each shot. and it lasts maybe one, two hours maximum. Other than the cost, is there a downside in taking these regularly? Like I say, every day. I don't see any downside to it. You're going to utilize the ketones. this is something that a lot of people do naturally.

[43:20]If you're just simply fasting, you're going to have some ketosis for most people. So this is a natural part of physiology. You're not going to be generating huge levels in your bloodstream. the thing with ketones is that some people associate it with having a metabolic issue, but that's mostly in the context of type one diabetes.

[43:40]So people get worried when their ketones are going up. It's a, but that's in a different scenario in which essentially you're not utilizing energy normally, but this is a different situation because you are utilizing energy normally. So there gets to be the confusion and people that have no insulin and their ketones are up, that's a red flag.

[44:03]But for somebody who's not a type one diabetic, this is absolutely fine to have ketones, including exogenous ketones. any health risks with doing this, not that you'd chug an entire 20 doses of it at once, which still probably wouldn't do anything. But doing a therapeutic dose is probably no risk except for to your wallet.

[44:26]Yeah, yeah, because those end up like being very expensive. Yes If we zoom back into the, mean, zoom back out to the dietary thing, not only on the ketones you mentioned like CGM, like wearing one like since the beginning, I think that's also like very, important, right? Because I believe that the food impact, it's really like highly individual dependent.

[44:45]I know there are like few studies where they looked at sweet potatoes. For some people, it spikes the glucose, for some people not. So just wear it, wear the CGM. And for example, for me, think I just bought it once and then I knew what type of food would spike it, my glucose or not.

[44:59]And then that's it. We don't need to wear that for life. Any comments on CGM from your side? Yeah, I wish that every single doctor, nurse, practitioner, physician, assistant, pharmacist was required to wear one for two weeks. The amount of knowledge you can get looking at your physiology in real time.

[45:19]it can, can be a real eye opener. And, and I think that it's a, I think it's a really good thing to do periodically. we've just got, got, um, a couple of, the Dexcoms, that, arrived last week that we're going to put on today. so we periodically do it maybe once a year.

[45:35]and you usually get sick of them at about day eight, um, and pull them off. We've gotten enough information, but the, the big thing is, is, is this is a great way. of looking at basically an n equals one study on yourself and understanding that one individual can have rise and get a minimal spike.

[45:55]Another person can have rice and the glucose goes up to 180. And same thing with, you know, potatoes, sweet potatoes, bananas you know number of different fruits where you can kind of see what your body does with it and get that feedback. And that is a great, great area of knowledge to have is to just trial a bunch of things and see what it does.

[46:17]And then you can go, OK, these foods are things that probably I should avoid because they're going to give me a big spike. And then these are other foods that seem to give me a much flatter curve. And you're going to be different than another person with that.

[46:30]And that usually ends up being very consistent over time. And that's just your individual physiology, how you're processing, absorbing, those types of things. And then furthermore, if you have things that are really healthy that are generating spikes you know test and see what happens if you end up having an ounce of nuts and a little olive oil beforehand.

[46:49]and have a little bit of fiber and then have that item that you think is quite healthy that was spiking and see what happens. So you can kind of craft, how do you do this for yourself so that you minimize those spikes? it's interesting when I was wearing, at the first time, we ended up going out to Mexican restaurant and I had a bunch of chips and salsa, I had a drink that had some sugar in it and I had a bunch of chips and salsa, I had a drink that had some sugar in it and next thing my blood glucose was like 230.

[47:17]which is something where you go like, well, that meets criteria for type two diabetes any glucose greater than 200, and I'm not a type two diabetic, but it is something where, you know, doing the wrong things, know, I mean, seeing how far you can push it, you you'll see these big spikes, but also seeing how to flatten that out.

[47:38]And it's the area under the curve is something where you do want to take a look and see, you know, not only the height of what the glucose is going to, but how how long it up in a high level. And you'll get all that information with CGM.

[47:52]And I was just gonna say with CGMs, just for everybody's knowledge newly Dexcom has got a group that looks to me as part of Dexcom, it's called Stelo And there without a doctor's prescription, you can self order and for two Dexcom G7s, just a one-off is basically a hundred dollars.

[48:17]You can get three months worth of them for about $215. I think it was $220, but much, much lower. And you don't need a doctor to prescribe. And the Dexcom is probably the best one. It's well calibrated. at the company, you can manually calibrate it where you do a finger blood glucose and then you can adjust the G7 through software.

[48:42]So, their absolute numbers look very good to me. The Libre 3 Plus, which is the other one that's commonly utilized, I find the absolute numbers to oftentimes be significantly unreliable. For example, when I had a blood draw where my glucose was 66, For example, when I had a blood draw where my glucose was 66, And at the same time that I had the Libre 3 on, and Libre 3 was telling me it was 95.

[49:05]And at the same time that I had the Libre 3 on, and Libre 3 was telling me it was 95. Ohh wow So, and a lot of my patients have times also where they're getting flagged with Libre that their blood glucose is low, but on finger stick it's not.

[49:17]So it's something where the trends are really useful with the Libre 3 as far as what your spikes are and all that. But the absolute numbers, I find that there's often a significant problem with that in my population. So I'm glad that Dexcom has come down to a reasonable price and accessibility because that I used to be the limiting factor where I go like, you're going to pay a lot more for Dexcom than you pay for Libre, but that's not true anymore.

[49:43]Yeah, very interesting. Thanks for sharing about those. If we again go to another topic, but still in nutrition, we have quite a lot of members. So we have Ellen and Jennifer and Dara who have the same issue. Basically, they are struggling to get into fasting protocols because they go into hypoglycemia.

[50:03]Any advice there on because like they want to do fasting for metabolic reasons or a lot of reasons, right? What would be the advice you give them? I think the first thing is, they truly hypoglycemic? And for most people, that's fairly hard to become hypoglycemic, but it is something where for some people they do.

[50:25]The first thing would be to document it, you know, and actually get a finger stick or a blood draw that actually shows that you're hypoglycemic. For most individuals, even when you're kind of in the 50s, if you're not a diabetic and not used to having blood sugars that are high, most people are asymptomatic with that.

[50:43]But for people that are symptomatic with that, you're going to need to take some things that slowly generate some glucose. So you're going to tend to be somebody who is going to need to take some complex carbohydrates or even you'll still get spikes with, you'll still get maintenance of blood sugar a lot of times even with things like nuts or proteins oftentimes will still end up generating some stability.

[51:12]But it can be a challenge in individuals who are in this situation where they truly do go low and they're symptomatic. you're going to need to have some calories, but they don't have to necessarily be carbohydrates. And this is the value of having a CGM, is that you can actually track that and see, if I have a little bit of nuts, something that has some fat and a little protein, for example, it's not gonna spike your blood sugar, but it may maintain it very well.

[51:43]And other individuals do well with things like like some yogurt with some berries oftentimes will not end up creating big spike, but it is going to be of limited duration and you're trying to fast and that can be a challenge and a limiting factor and there's no magical solution to that unfortunately.

[52:05]If you're getting symptomatic, you're probably going to need to consume some calories but try and get something which is released over a long period of time. Also, if you have uh significant dietary fiber with it that will kind of give a slower response to that. And those individuals were going to be reluctant to have them on medications that end up lowering their blood glucose because they're going to get into more issues with it.

[52:33]And that's another topic as far as things to improve your glucose use in your brain. And there are some things that seem to be beneficial in that area where you don't necessarily need to head down the pathway of going, you know, I'm going to be doing these prolonged fasts and so forth to try and generate ketones.

[52:54]If that is an unsuccessful strategy for you because you're falling over or passing out, there are some alternatives to that. Yeah, makes sense. Okay, let's move on to exercising now. I think it's an important topic, especially regarding insulin sensitivity. What do you think about the different types of exercises, whether it's like cardio, like muscle building, like hypertrophy, HIIT, strength training?

[53:17]Which one do you recommend here? Just getting calories out of your system is going to be beneficial as far as getting some degree of ketosis. And your biggest way to do that is going to tend to be through zone three, four activity aerobic. There's different benefits that are, that's kind of the short term stuff as far as like, what do I do now that's going to end up?

[53:47]utilizing glucose that I have and potentially generating a bit of ketosis. And then there's a long-term issue, which with the strength training is important because the more muscle mass you have... the more those muscles are going to be uptaking glucose on a regular basis. So having that muscle mass is quite important to just as an ongoing background, utilizing energy and your muscles take up glucose in a way that is not dependent on insulin.

[54:17]So it is something where, the more muscle mass you have just sitting there doing nothing with it, that's going to continue to be a tank that you're pulling from. and making it little bit easier to get into ketosis. So yeah, if you have low muscle mass, you're not going to have anything that's going to be pulling your glucose in as much.

[54:37]So there is some benefit. I would say that the short term and long term benefits, there's the ongoing utilization when you're doing nothing, and then there's the utilization when you're actively doing some stuff But even with strength training, when you're working hard, you'd be burning a lot of calories.

[54:51]It depends how you're doing that strength training and how much of your muscles you're using at one time. either way, I think that there's a good argument to do both of those, but for slightly different reasons. Yeah. like one advice I have that I realized after weighing a CGM is to actually do a bit of exercising before eating.

[55:13]And that somehow will like pull in all the glucose, probably not into glycogen, but probably just in glucose in the muscle. So if you can do like air squats or pushups relatively hard to do pushups when you're in a restaurant, but as course you have probably do that and not look too weird if you do that in the toilet.

[55:29]but like 20 air squats will be like, really have a huge impact on the glucose spike, at least for me. So yeah, if you guys are listening to this, try that. It'll be a quick win there. It'll be a quick win there. Yeah. These little, what we call exercise snacks, basically is, is something where, you know, you just work into your routine.

[55:41]These little, what we call exercise snacks, basically is, is something where, you know, you just work into your routine. go, you have a break for a few minutes and you go, okay, let's go ahead and do, do some squats, do some pushups. Doing that several times, several times per day actually is, is metabolically beneficial.

[56:00]Doing that several times, several times per day actually is, is metabolically beneficial. And the other interesting thing people will notice with CGM is a lot of times when you start exercising. For most people, you'll end up getting a big spike of glucose. And that's normal. You go, I'm using all this glucose.

[56:14]But as you start exercising, that's a signal where your liver kicks in and goes, okay, I'm gonna need to start generating a bunch of glucose. And you'll see this. So don't be alarmed when that happens. That's a normal finding for a lot of people, especially if you're going into some heavy aerobic activity that you will end up bumping your blood sugar up.

[56:33]It will settle down. but that is normal finding. Also, it's normal finding when you get up in the morning a lot of times before you have any calories, you'll get a glucose spike and that probably correlates very well with the morning cortisol rise, which peaks about 30 minutes after you wake up.

[56:50]So there's all these normal patterns that people really scratch their head about and that's the reason why those happen. Yeah, that's a, think we had like one of these questions as well in the morning, like the cortical spike and everything. So yeah, thanks for answering those. I know we're running a little bit out of time and the last topic is very important.

[57:08]So is the pharmacological supplements intervention. So let's move on there. We can go one by one or you can give me an overall answer. I want to discuss metformin for sure, GLP-1 for sure as well. What are your thoughts between these two or about these two? yes, I think that the the DLP ones are great for people that have weight to lose.

[57:29]There's certainly associated with a lower rate of dementia, possibly because you utilize glucose better in your brain. There's certainly associated with a lower rate of dementia, possibly because you utilize glucose better in your brain. It's a little bit of a mystery with the GLP ones because the last, the modern ones with Semaglutide, tirzepatide, and retatrutide are all molecules that do not get into the brain one and yet have very potent effects on the brain.

[57:55]So we'll kind of see this data saying, you GLP-1s, there's a, uh you know, there's a high level of receptors for GLP-1 in the hypothalamus as compared to other areas of the brain. But I'm not sure as far as the mechanism of how exactly that works, given that the drugs don't physically make it into your brain, but they certainly seem to have some beneficial effects for people that can tolerate a GLP-1 without becoming unhealthy as far as muscle loss or weight loss, where it puts them into an unhealthy state.

[58:26]Metformin probably has less evidence as far as improving glucose metabolism in the brain. It may make a small difference. It's not at the top of my list. And I think the thing that is at the top of my list, and I think the individual that asked the question mentioned it, is SGLT2 inhibitors.

[58:43]And I think the thing that is at the top of my list, and I think the individual that asked the question mentioned it, is SGLT2 inhibitors. I think that those, number one, they're associated with administrative dementia. I think that those, number one, they're associated with administrative dementia. have most of my patients on one of these.

[58:53]Dapagliflozin gets into the brain about 0.3 as much as it is in your bloodstream. Dapagliflozin gets into the brain about 0.3 as much as it is in your bloodstream. Empagliflozin which is uh Jardient, I think gets in at about half the rate. I don't think that the difference is huge, but those medications do seem to improve energy use in the brain, including the hippocampus.

[59:15]So I think there is a role for these medications. And certainly you do get a little bit of weight loss with them because their mechanism is that they're causing you to dump glucose on an ongoing basis out of your bloodstream and into your urine. Important precaution if you get a urinary tract infection, do cease that medication immediately until the infection is better.

[59:36]They do not increase the rate of urinary tract infections, but if you get one, feeding those bacteria with stacks of glucose is a really bad idea. need to stop that. But anytime you get a urinalysis, you're going to see greater than a thousand milligrams per deciliter of glucose in your urine.

[59:53]That's normal when you're on these medications. But they do seem to be probably a first line choice as far as if you're going to be doing pharmacotherapy. And just as tip to the community on this is it... These medications are not going to be approved by your insurance unless you have type 2 diabetes and you already have failed some cheaper medication like metformin.

[1:00:19]But for everybody else, my source for this and many doctors in the US can prescribe it. They just have to fax through a prescription to Canadian drugstore. Canadian drugstore pharmacy, think it is. Let me just pull that up really quickly. But the thing that's good with that is that you can essentially get...

[1:00:39]100 days of Canadian prescription drugstore. You can get 100 days of Dapagliflozin for like $40. where if you're going to your regular pharmacy, you're going to pay probably $300 a month um with a good RX coupon. where if you're going to your regular pharmacy, you're going to pay probably $300 a month um with a good RX coupon.

[1:00:55]So it's something where you can get these things cost effectively because price has been a big limiting factor for these medications. But we now have good sources where you can do this very cost-effectively. I think that for most people they're a good choice because they also diminish heart disease, they diminish your rate of kidney decline and function, decrease your rate of fatty liver disease, and they're probably one of the longevity medications out there if you just take a look globally.

[1:01:23]And the main thing is going to be that you may end up on the full dose losing about seven and a half pounds, a half dose, of three and a half pounds. which most people can afford that. And a lot of people don't lose that weight. But you will end up dumping a couple hundred calories of glucose, which also kind of smooths a lot of those spikes that you get with diet.

[1:01:45]so makes it easier to be in a bit of ketosis with you just dumping that glucose. So I think they're a good choice. And we have evidence that these improve glucose utilization in the brain. So I'd say that would be my first choice if you were to do a prescription medication.

[1:02:02]Yeah, very cool. I actually didn't look that much into it and I'll definitely look more into that. It seems like a kind of a no regret type of medication, especially if it's not that expensive. It's great. All right, to close the episode, if a Phoenix member wanted to take one step this week, like one thing they can do to not overwhelm anyone, to improve their insulin sensitivity, what should it be by order of priority?

[1:02:27]I think focus on eating order of what you're doing. Be mindful of how you eat your meals and do a little bit of exercise. Go for a walk after meal and consider avoiding any snacking and kind of plan deliberately as to when you're eating and when you're not eating and have a reasonable period break.

[1:02:50]Just simple things that will generate a little bit of uh ketosis is probably a sensible thing. And also those measures will end up improving your average blood glucose. I think those would probably be the simple things to do that should not have a negative impact. on anybody with doing those type of simple measures.

[1:03:12]Amazing. Well, thank you so much, Dr. Fraser Very packed session. I loved it. Very interesting. Very good. Hopefully we didn't overwhelm people with the technical side of things, but there are some practical takeaways. And this is a complex... subject and I think the other takeaway is simply to presume that you're having problems in your glucose utilization in your brain and doing some basic things that can help and getting things measured properly in your periphery.

[1:03:48]But even when your periphery looks good on insulin sensitivity, presume you've got a problem in your brain because you probably do. Yeah. Cool. Well, thank you so much for today.