UNLOCK the Secret to Your Health: CHOLESTEROL Levels - Are You Really Healthy? | Dr. Robert Lustig

45% of Americans have fatty liver 25% of children notice I didn't say obese adults or obese children all adults all children this is something that didn't even exist before 1980 and here we are now 45 years later and 45% of the population has a disease that we never heard of before so we know something's going on this is a clear indicator of metabolic dysfunction a clear indicator of in Ability to utilize fat because of defective mitochondria because of insulin resistance so these things all go together so your fasting insulin and your uric acid and your

Al T should all line up together because they're all part and parcel of the same pathophysiologic [Music] pathway the Genesis of today I'll sort of set this up a little bit before we get into it the Genesis of this Conversation is you know levels at its core is is an app designed to help people get healthier like that's the mission cut out everything else we just want folks to get healthier my mission too but that begs a really key question how do you know when you're getting healthier how do you know the things you're doing

are working and it's really hard to know you didn't get sick in a day you're not going to get better in a day and the markers that we look at to Determine metabolic Health didn't go south in a day so they're not going to get changed in a day either so this is why this is a mess in terms of you know people Hawking one idea versus another people Hawking One supplement versus another people Hawking one lab test versus and another um this is a very murky area and if there was one test that could

tell you whether or not you were getting healthier or not everybody be doing it and they're not because it's Not that simple different people have different problems different people need different solutions and different people respond differently to the different paradigms so this is um shall we say a u a mange of different ideas and you know I'm happy to discuss each of them with you for the you know purpose of the audience understanding the value of these different things but if you think you can just go to your doctor and get a Test you know

think again I think that's really helpful context and I think I think we'll split this into sort of two parts one we'll talk about broad set of markers and then we're going to we're going to narrow in a little bit I think on glucose and Insulin because that is where a lot of of levels bread and butter is and where a lot of our members are are measuring or paying attention to or maybe visualizing their health or at least their metabolic health I think That setup is is helpful for getting into it that realizing we're

not going to determine in this conversation here are the five key markers well I would love that headline as an old magazine editor uh we're not going to come out of this this conversation with that what I think might be helpful is to maybe narrow in on some markers that to my mind need to have two criteria one is that they tell us something about our underlying physiology which is to say There there's some Clarity in the signal um that that relates to something happening in our body a process that we want to to maybe

be working functionally and the second is that they're movable they're things we can actually do something about well and that they're tight tradable sure that is that they actually you know they're on a scale and that they tell you something about severity it's not just an onoff type of deal you know that there's a a dynamic Range of whatever the marker is to tell you oh you know you're at this level you're at that level you're at the worst level you know that's very important as well and it has to then change with the either

the worsening or with the Improvement right that you know those are hard to come by yeah so I think most people's interaction with markers with biomarkers is if they go to an annual physical which so many folks don't but if you go to an annual physical you get Your labs and essentially in there you're getting glucose and cholesterol right that's that's primarily what's being measured yeah and that's about the worst thing you can get yeah so let's start there tell me what's wrong with with that as a sort of core set of things maybe what's

right with it but also what's wrong with it in terms of a core set that we're at least checking in on annually let's start with glucose fasting glucose fasting glucose is the Single worst thing to measure but it's the thing that everyone measures and the reason everyone measures is because it'll tell you if you have diabetes or not and in that way well that's an onoff okay if you're fasting blood glucose is above 125 you have diabetes if you're fasting blood glucose is below 125 you don't have diabetes and that's basically what the physician you

know is drawing it for and that's what they're referring to and that's what the guidelines Say and there is so much more information to be gained and that is just the tip of the iceberg and most importantly if you're waiting for you to develop diabetes you are so far behind the a ball okay you have missed the train okay Train's pulled out of the station okay you are already sick so the goal is to catch that way before so you go to your physician and the physician does your fasting blood Glucose and it comes out

back 102 and he says well that's fine you're far away from 125 no that's not fine at all at all in fact let's say you had you went and got your fasting blood glucose and it was 91 and you say oh you're doing great no you're not that's already a problem okay it's on the way to glucose intolerance it's on the way to diabetes it's not there yet but that's an early indication so how you read it and uh understanding what it means is Extraordinarily valuable in and of itself and it's the last thing to

change now if you take a look at glucose tolerance test fasting glucose glucose tolerance test over the last 50 years the Excursion of the glucose is pretty much the same for the last 50 years but the amount of insulin needed to keep you at a normal Excursion has gone up two to fourfold and that's a sign of chronic metabolic disease that is not measured in the fasting blood Glucose that isn't even measured in the glucose tolerance test you're already sick and you don't even know it so a fasting glucose is by far and way the

worst metabolic parameter test than you can imagine if you're waiting for that to change okay you're waiting for a good do if you've heard me talk on other podcasts before you know that I believe that tracking your glucose and optimizing your metabolic health is really the ultimate life hack we know That cravings and mood instability and energy levels and weight are all tied to our blood sugar levels and of course all the downstream chronic diseases that are related to blood sugar are things that we can really greatly improve our chances of avoiding if we keep

our blood sugar in a healthy and stable level throughout our lifetime so I've been using ggm now on and off for the past 4 years since we started levels and I have learned so much about my diet and my Health I've learned the simple swaps that keep my blood sugar stable like flax crackers instead of wheat-based crackers I've learned which fruits work best for my blood sugar like I do really well with pears and apples and oranges and berries but grapes seem to spike my blood sugar off the chart I'm also an notorious night owl

and I've really learned with using levels how if I get to bed at a reasonable hour and get good quality sleep my blood sugar levels are So much better and that has been so motivating for me on my health Journey it's also been helpful for me um in terms of keeping my weight at a stable level uh much more effortlessly than it has been in the past so you can sign up for levels at levels. link Health get access to a continuous glucose monitor and the level software that helps you really uh dial into a

lot of these strategies for your life and your body couple things that I want to follow up On but but one tell me why the ogtt the the oral glucose tolerance test doesn't do a good job of capturing that insulin response isn't that what it's sort of meant to do is to say here's how your body responds to a glucose load and and that's true how your body responds to a glucose load by having to put out more insulin to handle it insulin in and of itself is part of the problem everyone thinks insulin is

good because it lowers blood glucose well insulin has its own Negative side effects it is uh a growth factor so it causes vascular smooth muscle growth like coronary artery smooth muscle growth it causes glandular growth like for instance breast growth and prostate growth so it is a risk factor for both breast cancer and prostate cancer so things that we associate with aging are made worse by insulin going up so if you need more insulin to do the same job and keep your blood glucose Constant you're not in danger because your glucose is rising you're in

danger because your insulin's rising and that's not measured in the glucose tolerance test we infer it but you don't know it right so two people could essentially have the same ogt score but one is pumping out twice the amount of insulin one is much fur further along in an insulin resistant State than the other one and that's not going to be revealed in that test exactly right so the Glucose tolerance test is good and certainly what we do at levels can glean a lot of information from that glucose Excursion that will tell you but it's

not necessarily the amplitude it's not necessarily the fasting level and it's not even necessarily the peak it's actually more how it gets disposed of decline downward that's why the curve is valuable that's why we do this that's why levels exist is because the uh uh change from the uh Peak down to Baseline Has lots of information in it but in fact what you really want to know is how much insulin did it take to do that and how quickly did the insulin clear to bring you back to Baseline and you're not getting any of that

from a standard uh fasting glucose or GT is there anything this is jumping ahead a little bit to where I want to go with some of the the Dynamics of a glucose curve um but I think it's relevant here what can I infer about my insulin sensitivity From simply looking at the shape of a glucose Spike or a glucose curve right so the higher the glucose goes the less insulin Reserve you have and the slower the glucose return to normal the less well insulin's working so the more insulin resistance so there are two phenomena that

you can capture but neither of them are direct measures so the the height of the glucose response basically tells you hey what's going on with my beta cell I I should be Able to keep up with this there must be defective Reserve or delayed response either way that's a problem of the beta cell then how quickly things go back to normal if they go back to normal quickly that means that insul chugging out and it's working and it's clearing and everything's fine that means you have good beta cell function with good insulin sensitivity but if

you've got a plateau and it takes a while for it to come down Then that's a marker for insulin resistance and you couldn't see that from a fasting specimen and you may not even see it from a 2hour specimen which is all that your physician is concerned about I'm use the phrase there keep up because one of the things I found that I I didn't really understand in trying to explain even these basic Dynamics is a question of timing so a glucose Spike if I watch my glucose go up very sharply and come back Down

that's at its most core reflection of something that I have done right I've eaten a High car load there's a bunch of glucose now in my blood the cgm's going to measure that as a as a peak and then it's going to come back down so how much of that Spike is the result of what I've eaten is directly related to the just the amount of carbs I have poured into my body and how much is related to my insulin response which is another way of saying how fast can I expect my insulin To actually

work and bring it down is there a world in which I am so insulin sensitive that even if I eat a ho ho I'm not going to see a big spike or you will you will always see a spike okay you will always see a spike um the reason is when you uh consume the glucose it will go first to the liver you know it will be absorbed from the intestine it will go via the portal vein to the liver the liver will take uh 20% of that glucose and throw it Straight into the liver

for conversion to glycogen that means 80% will make it past the liver and generate a glucose response you will get a glycemic Excursion now the beta cell will then see that because it's got to go circulate in the blood the beta cell will see the rise in the glucose and will start pumping out insulin saying hey I've got to clear this you know this is this is not the Baseline let's get The glucose back down so you will see a glucose Spike no matter what the only way to not have a glucose spike is to

not consume glucose so if you're consuming straight fat you know you won't see much of a glucose Spike if at all uh if you are fasting you won't see a glucose Spike but otherwise if you're consuming food you're going to see a glucose Spike the question is how high and how long those are the two questions how high tells you what was in that but It also tells you whether or not your beta cells keeping up and how long basically tells you if you're insulin resistant so the how high gives you uh information about the

beta cell how long tells you more about the body and in terms of that just to keep on this path of sort of understanding the the glucose curve uh how much can I expect that to change as I get more insulin sensitive and if I start eating lower carb getting my insulin in in a proper place should I Expect that if I'm eating the same diet I'm going to see lower Peaks and I'm going to see faster returns right we did that study in children and we saw that if we Chang the diet we could

see changes in the glucose area under the curve the peak glucose response and the insulin sensitivity in 10 days in children and my colleagues at uh San Francisco General did it in adults and they saw those same changes in two weeks so doesn't take long but you know Will you see it after one meal unlikely will you see it after one day probably not you know but 10 days you know most people can tough it out for 10 days to be able to see something that will uh help uh uh shall we say solidify their

belief in you know making metabolic Health changes for the better and then if if it can change that quickly to get healthier how durable is that change then can I can I revert it back to being less insulin sensitive by giving up on My low carb diet absolutely within two weeks so you you but bottom line uh it's relatively responsive to changes in diet and also by the way changes in exercise so if you exercise you will start seeing improvements in insulin sensitivity too if you stop exercising within two weeks you'll be back to Baseline

so I would say there's a Bas a two week uh uh transition from metabolically unhealthy to metabolically healthy at least as far as glucose Dynamics go and We'll come back to insulin for a minute because I think we're going to want to talk a lot about that as a marker but again just on the glucose curve side how do you think about glucose spikes like a lot of what we've talked about you know over the years and I do all the content at at levels is uh you know the the simplified version is glucose bike

bad glucose bike unhealthy don't do that that's true because it can have short-term effects you might feel really Bad you'll probably have a post you know a reactive crash uh also long-term it can do damage can cause you to be insulin resistant can also have some effects on its own like gation or or inflammation that just extra glucose can be having but in that Nuance of what counts as a spike how many can I have uh how tall can they be these are the questions we get I was just looking at some member questions this

week these are the questions we get All the time from people and My worry is that in putting out this message I have freaked a lot of people out about about everything they're eating and what I hear from so many of them is an anxiety that if I'm not going keto I'm screwed and well so I'm curious how you think about the the sort of um the detriment of a glucose Spike all right so I'm going to start with a controversial uhh saying we're all GNA die okay you're gonna die sometime Everyone dies and no

matter how metabolically healthy you are you're still going to die now the question is when obviously we all want to put it off for as long as possible and as George W bush famously said we all want to die as uh young as late as possible Right for for sure and that's why levels does what it does and I'm again I'm totally for it I'm totally in support of it you're going to have glucose spikes you can't not have glucose spikes you can't freak Out about it either if you do now you've got something called

orthorexia you know and you start worrying about actually what you're eating all the time now we do not want to be contributing to orthorexia and you know some people will take this information and use it shall we say not for good and you know we we need to protect against that as much as possible so you know I'm here to tell you you're going to have spikes the question how many spikes well preferably Three spikes a day called breakfast lunch and dinner or May maybe two spikes a day you know lunch and dinner do you

need breakfast I mean that's the concept of intermittent fasting and maybe that's one of the reasons why intermittent fasting works is because you only have two spikes we don't know that yet I'm you know I'm just throwing it out there as a possible we do know that intermittent fasting helps if you're insulin resistant now the reason I think Intermittent fasting works is because it gives your liver a chance to metabolize the fat that built up over the previous 16 hours hours well that will help your Spike because you'll be able to process the glucose because

you're less insulin resistant so these things are all sorry these things are all related to each other it's not like these things work separately they're not in silos so what the glucose spike is doing what the insulin spike is doing what the fat is Doing in both the liver and the muscle all of these things relate to each other now if you're going to have a spike you want to have a spike that doesn't go to say 1880 or above because that's when the kidney starts spilling glucose so that causes um uh damage to the

kidney unpack spilling glucose out of the kidneys for a minute for so your kidney resorbs glucose so the glucose filters through it as blood filters through it and your Kidney has a method for pulling the glucose back into the bloodstream instead of it going out in the urine and that system works until what's known as the TM which is basically the maximum amount that you can resorb and that occurs at a blood glucose of 180 milligrams per DL so at 180 you start spilling glucose into your urine and when you spill glucose you take water

with it and that dehydrates you and that's one of the cardinal signs of Diabetes is polyurea and polydipsia too much peeing too much drinking and dehydration so you obviously don't want that and in addition the higher the blood glucose goes you know it's been uh glucose has been equated with like grains of sand you can imagine if you had grains of sand running through your uh you know arteries you know it might do some damage like the the finish on your you know car when you're out on Pacific Coast Highway you know just from The

sand you know and the saltwater hitting your car well if you're running around with high blood glucose a lot of the time you're going to have some endothelial dysfunction and that may be actually one of the contributions to high blood pressure so um high blood pressure can occur due to Sugar dietary sugar because of the increase in uric acid which reduces uh nitric oxide which raises blood pressure or it could be because of the endothelial cell dis Function you can see that in the release of a a hormone called enden one that you can measure

again it's a research test for the most part we don't you know do that routinely but either one of those is a sign of uh arterial damage and ultimately uh you know that would shorten your lifespan uh it's been shown that if you can get your blood pressure down by 2 millimeters of mercury you have a 10% reduction in risk for stroke so even a little change in blood Pressure has big changes in terms of uh vascular health so all of these things are related to each other obviously you don't want your blood glucose to

go super high but more importantly you don't want it to hang around you want it to clear and that is a sign that your insulin's working that's a sign of insulin sensitivity that's a sign that your muscles are working your liver working working your whole body is working I would say that insulin Sensitivity is the pathogenic factor most associated with all of the chronic diseases that we have today if there's one thing to fix it's your insulin resistance and so then the question is okay how do you measure that and we'll get to that in

just a minute yeah I just want to go one step further on this story we're talking about and I think this is a use framing of sort of what's happening to the glucose in the body and how it relates To the sort of height of the spike so we talk about let's say your very let's say two people are spiking to 160 one is uh insulin sensitive and the other is less so and so it's taking longer to clear it but when we talk about clearing where does it go even if I'm healthy is there

a difference in where that glucose goes between the insulin sensitive person and the non-insulin sensitive person once they're back to Baseline has a different Thing occurred in each one of them absolutely so where does it get cleared to where does glucose get cleared to well every cell in the body uses glucose for energy but not every cell in the body is responsive to insulin okay now every cell has glucose Transporters but those glucose Transporters are not necessarily insulin dependent Transporters which glucose Transporters are the insulin dependent ones glute Four so there's glute one glute two

all the way up to glute 11 okay 11 different glucose Transporters depending on which tissue you're talking about fructose by the way is handled by glute five and also glute seven so the different glucose Transporters do different things in different tissues like for instance the brain uses glute one no other tissue uses glute one but glute four is the only one that's insulin sensitive so Where's glute four because if your insulin level's high that means that the glute four specific tissues are going to be influenced the greatest and the answer there is your muscle and

your fat and so you're going to drive energy into muscle and fat if you drive energy into muscle that your muscle is not using you're going to get fat deposition in your muscle called intramyocellular lipid that's a cardinal feature of insulin resistance if you drive the Glucose into fat cells well the fat cell is going to turn that into actual adapost tissue it's going to turn it into triglyceride in the atopos tissue it's got all the enzymes to take glucose turn it into fat and so you're going to lay down more fat and now you've

got obesity and of course if it's visceral fat you will have insulin resistance yet uh worse you know it'll basically be a vicious cycle so the higher the insulin the more your fat and muscle are going To gain fat because of the glute 4 transporter it's not going to make much difference in terms of the glute one the glute two the glute three the glute five the glute and all the way up to 11 it's really going to be that glute four but that's what causes the illness so getting the insulin down is job one

and the only way to do that is to become insulin sensitive and the only way to do that is lifestyle so if it's just make sure I understand this so if I Take in the same amount of glucose um but I am insulin sensitive what is happening such that I'm not getting those fat deposits either in my muscular tissue or in the adapost tissue that that are all the risk if I am insulin sensitive the glucose has to go somewhere right if I've taken in that amount of glucose load if you're insulin sensitive it will

go into all of your other tissues equally and will be burned you know by The mitochondria to carbon dioxide and ATP and will fuel all of those uh metabolic processes and you will therefore be metabolically healthy as soon as your insulin goes up what that's a sign of is the fact that you're not burning that glucose to carbon dioxide and ATP well okay if you're not burning it you've getting a backup and you need insulin then to clear it what is that saying about your cells what that's saying is that the Mitochondria the little subcellular

organel in inside each cell the little energy burning factories inside each cell what it's saying those aren't working very well for whatever reason those mitochondria are fallen behind because if they weren't fallen behind your insulin wouldn't be high and you'd be clearing the glucose well so insulin resistance and mitochondrial dysfunction are part and parcel of the same Phenomenon so what that's telling us is if you're insulin resistant you've got something wrong with your mitochondria and you need to step up your mitochondria well what's wrong with your mitochondria and that's where the whole question of our

environment starts coming in okay so let's go back to this question of of timing for a moment because I think this is really helpful in understanding this this glucose journey and then what what I'm seeing About this glucose Journey on a glucose graph is is telling me so if I am healthy I take in a load of glucose I see it rise but I'm seeing it clear quickly which is a sign that my cells are taking it up as efficiently as they possibly can it's not then going to be deposited in my muscle and fat

tissue as as fat right so if I see a a long if it takes a long time for it to clear that's essentially a sign that in other would let me see how to phrase this if it's Being cleared quickly it means it's going into the cells if it's not being cleared quickly that means it's not going into the cells where I want to to go and it's going to go into this other tissue is that right exactly right exactly right the longer it stays in your bloodstream the worse off you are and you can't

learn that from a fasting glucose you actually can't even learn that from a fasting insulin although fasting insulin is a much Better Arbiter of that because the fasting insulin basically tells you how well your mitochondria working if your mitochondria working your fasting insulin's low if your mitochondria not working your fasting insulin's high it's our best proxy for mitochondrial function and so I think that the fasting insulin is the single best marker for metabolic Health that we could order and I routinely suggest it and order it on my Patients and I am trying to get the

medical profession to you know glom on to this idea but I will tell you there are super number of obstacles one is the insurance industry because they don't want to pay for it even though it's not expensive runs between 12 and $120 medium $48 so it's not that expensive so and they can learn the patients and the do their doctors can learn so much from it if they knew how to interpret It and of course the food industry food industry is not happy about that at all because it's one of the ways they get away

with putting junk in our food because if you're fasting insul we're going up and the only way to fix it is your food they don't want you to know and then third the American Diabetes Association now you would think that the American Diabetes Association would be very happy for people to not be insulin resistant you would think that that Would prevent them from getting diabetes Well the American Diabetes Association is really not into prevention they're into treatment they're into pharmacology they're into Pharmaceuticals because their entire budget is basically underwritten by big Pharma fact matter is

the American Diabetes Association says do not draw a fasting insulin and that's one of the reasons why the way that the insurance industry doesn't cover it because the Ada says that all right so why do they say that two reasons and they're both specious they're both wrong first reason they say the different assays for fasting insulin are not standardized across platforms so if you get it done at your local lab if you get it done at the hospital if you get it done you know through a send out you know you're going to get all

different results from different assays not standardized And there's some truth to that I don't even argue that that is true one of the reasons that this occurs because it ought to be something that you should be able to measure easily one of the reasons this occurs is because some of the cheap assays use uh antibodies use basically what's either an radioimmuno assay or an Alysa enzyme linked immunosorbent assay and so it's looking at epitopes it's looking at specific areas of molecule to determine whether Or not the molecule is there or not and that determines you

know the level and that's worked for us for a long time but you can have cross reactants you can have other peptides or proteins that you're measuring in the same sample that crossreact with the antibody and will give you a fictitiously elevated level the most common of this is pro-insulin now what's pro-insulin you've heard of insulin what's pro-insulin Proinsulin is the peptide that has to be cleaved to make insulin so it is a pro hormone it is not a hormone you should not be releasing pro- insulin you should be releasing the mature insulin after the

C peptide is cleaved out of it now there's an enzyme in your beta cells that Cleaves that c peptide out of it it's called pro hormone convertase one well when your beta cells are stressed when they're working overtime because you're insulin resistant and you then Have a big glucose load you need to bring that glucose down and that's insulin's job and that beta cell is going to work as hard as it can to put out as much as it can and it doesn't have time to cleave the piece of C peptide out and so it's

going to release the proinsulin too now Pro insulin has only 5% of the activity of insulin but basically what it's a sign of is beta cell exhaustion but it gets measured in the Insulin assay because proinsulin and Insulin look a lot alike so you're measuring something that's not insulin in the insulin assay and so can throw off the assay well the American Diabetes Association is saying well then don't draw it because it's not necessarily measuring what you want to measure and that sort of you know at a uh uh shall we say at a common

sense level sort of makes sense but who cares who cares if it's high it's a problem irrespective of Whether you're measuring insulin or proinsulin or anything else for that matter if it's high it's a problem and as long as you're using the same assay on the same patient you know over time you can still use those to understand Dynamic changes so I think that's a specious reason that the Ada says don't do draw it what's the degree by which that Pro insulin can throw off that reading are we talking small or quite a bit so

there we know that there is a Phenomenon called hyperproinsulinemia was uh first uh uh espoused by Dr John S yudkin not the John yudkin of sugar Fame but his cousin okay John es yudkin famous British endocrinologist wonderful guy um and he was the one who demonstrated this phenomenon called hyperproinsulinemia and it is without question if you're putting out Pro insulin it means you are sick that's a bad thing to be doing um so no this it's a very real thing uh so that's the first Reason then the second reason that the uh American Diabetes Association

says don't draw it they say fasting insulin levels do not correlate with obesity that's exactly right they do not they correlate with metabolic health because they correlate with mitochondrial dysfunction and you can be obese and have normal mitochondria and you can thin you can be thin and have crappy mitochondria and the fasting insulin Will tell you that of course it's not correlated with obesity that's exactly why you should draw it because it's telling you something otherwise you could just get on the scale and you find out the same thing no no no so the reason

they say not to draw it is exactly the reason to draw it but they don't get it so I'm working on them but boy oh boy I'll tell you it's like pulling teeth what's the just to dig into let's dig into insulin as a marker A little bit because we do offer it in the the blood test you know that that we offer we include fasting insulin right we do Labs 2.0 and fasting insulin is at the front and center of that what's the best faith argument for maybe not ignoring it entirely but what's the

context with which I should look at that insulin marker how should I understand that insulin number in the context of the other things that I'm measuring and let's let's say for these purposes the Other things that you would like us to measure not just the the things I'm getting at my standard physical right so fasting insulin is in a dynamic range so the lower it is the better off you are as long as you don't have type 1 diabetes then it'll be zero and that would be really bad you need some insulin okay otherwise you

end up in diabetic keto acidosis which will kill you pretty quick if you don't do something about it and the only Treatment for that is insulin so you always need a little insulin and that's one of the reasons why we age because you always need a little insulin there's no way to do without it all right so but the lower it is the more functional it is the better off you are and the longer you will live so it's one of the best longevity markers there is and the great thing about it is it will

change change in two weeks now it'll also change back again In two weeks you know if you stop you know applying you know whatever lifestyle modification that you uh uh used to get it down so it's a uh you know to me fasting insulin is where the action is and it's cheap and it's available and you can do it tomorrow there are even now fasting insulin assays you can do at home you don't even have to go to your doctor but you know they cost money and then the question is you know is it reliable

and you know Those are questions that you know are yet to be answered for each of the different uh uh assays that are out there the type of question we get all the time when we start talking about markers is when results don't line up with the story that we are telling right with this sort of basic picture of how things work and and I won't go through all of them because that could be an hours long podcast of what if this and then that yeah yeah not doing that but Just to stick to glucose

and insulin for a minute if my insulin is low and I'll be personally here my insulin is low it's under two good for you I'm a child of the 80s which means I grew up eating sugar cereal every morning for breakfast for 30 years which means daily and I know this now because I have a CGM on I would spike my glucose to 200 MH and it would come back down and yet in my late 40s my insulin is under two I'm delighted explain how that is to me oh It's very simple means that you're

insulin sensitive now and it means you have good beta cell reserve and it means you're fine now it doesn't mean you were fine when you were you know 12 the fact is we have this pandemic of childhood obesity and childhood type two diabetes and clearly they're not okay the fact that you escaped that you know period of you know Froot Loops and Captain Crunch and you know crackling You o brand you know and you know Live to Tell the tale and have a fasting insulin now of two you know hats off to you I wish

I were so lucky but that's that's great and it you know prends good things for the future if you can maintain that so how should I think then about my A1C My fasting glucose my um average glucose or sort of glucose stability if I'm wearing a CGM if those are not as I remember my last A1C was like borderline pre-diabetes right so I Look at my insulin I go I'm great walk away put the paper down all good nothing to worry about here I look at that A1C and I go if this weren't a member

they would be emailing us going that looks High what should I do about it right well understand that the A1C is not the fasting insulin okay they are not necessarily the same there are various uh uh uh I won't say disorders but conditions that can lead to a slightly elevated hemoglobin A1 see and it Doesn't necessarily portend anything bad example there's a disorder it's really a condition because you needs no treatment and has no Downstream side effects this uh condition is called Modi 2 m oy2 mature onset diabetes of Youth 2 now Modi is a

set of diseases that are all genetic defects in the beta cell they're 14 of them 14 different modies and some of them are really bad okay some of them will ultimately cause significant diabetes very intractable to treatment And will ultimately lead to early aging and death no argument Modi 2 is a defect in the sensing of the beta cell the level of glucose in the blood has to get a little higher before the beta cell will start kicking out insulin it just basically means that the gain has been reset the threshold for releasing insulin has

been reset so these people run higher blood glucoses Routinely but they still get an insulin Spike when their blood glucose goes up they still clear glucose just as quickly they just run a higher blood glucose so they hemoglobin A1c is higher has absolutely no implications for aging or for disease it's just a factitious you know it's not spurious because it it makes sense but it's a factitious biomarker that's out of range and means nothing so it only means something if the Physiology is consistent so if you have a high fasting insulin and a high glucose

and a high1 A1c that means something because they're all going in the same direction so you can point to the pathophysiology and say yeah that's what's going on we need to do something about that but if you see one lab test that's out of whack and it doesn't make sense with all the others that are in the same pathway probably best to ignore it or Possibly it's even lab error maybe it needs to be redrawn remember that F all 5% of all lab tests are errors that's exactly what I was just gonna ask is how

reliable Labs tend to be in general and does it vary among markers or the some we can trust more than others it depends on the marker yeah so some are much tighter than others like glucose is a pretty tight one okay although CGM glucose has a much wider variation than lab glucose so you Know we need to keep that in in mind but some of the other assays you know there are things that can interfere with it hey you know somebody spits in the tube you know there's there's all sorts of you know stuff that

goes on in Laboratories and I know because I used to work in a laboratory and you know you do the best you can but you know stuff happens so given how how rapidly insulin can change for instance in response to our lifestyle And what we're doing how often should we be testing it how frequently should I look at my insulin to understand let's just focus on metabolic health for now and we'll get back to the sort of broader Health marker but how should I keep a pulse on my metabolic Health what are the things I

can be looking at personally I think that everyone should get their fasting insulin done once a year along with their standard lab draw but they need then to be fasting because If you're not fasting you don't know where you are on the insulin curve and then it's useless but if you're fasting then you should get it done once a year and if you're changing diet or exercise or you know some lifestyle or environmental intervention that you think is going to improve metabolic health I would strongly suggest getting a second fasting insulin 4 weeks after the

change so that you can monitor it know that you're Doing the right thing that that the fasting insulin is coming down so that you will number one be U positively reinforced and you know continue to you know on your you know weight loss or metabolic Health Journey okay and be you know rewarded for your efforts and it'll um uh give your uh physician a new Baseline to work off of so I think that you know once a year and four weeks after change uh changing your lifestyle and how should I read it then in Conjunction

with let's say I'm wearing a CGM or I occasionally are am wearing a CGM how should I think about it in conjunction with with the kinds of curves that I'm seeing relative to what I'm eating and what I'm doing well if you're insulin resistant then the thing you want to look at is not necessarily the peak glucose but you want to how quickly it returns to Baseline if it returns to Baseline in 30 to 45 minutes you're doing great if it takes an Hour not as great if it takes 90 minutes clearly not as great

and so you should look at your fasting insulin in that context if your fasting insulin is say above 10 and you're clearing your glucose slowly that is you know an hour or greater you still have some work to do if you're clearing your glucose rapidly and your fasting insulin is low you're in great shape keep doing it so you should look at the trends you should look at the Pathophysiology you should understand that each of the markers doesn't exist in isolation they are not siloed they work together if I have relatively low fasting insulin and

I'm seeing generally a trend of of pretty quick return to Baseline am I somebody who can then take in more carbs without worrying too much about what that that actual glucose I'm taking in is going to be what what kind of long-term damage that might be causing my body can I be more tolerant Of spiking 50 points as opposed to trying to stay under 30 or whatever the sort of guidance is yeah absolutely because you're clearing it and the clearing is much more important than the spiking that we're very sure of yeah the spiking tells

you about Reserve but the clearing it tells you about sensitivity and the sensitivity is the thing that is associated with disease so if I am in good metabolic Health how do you think about how flat My glucose curve should be you mentioned earlier that we can expect to see spikes or maybe Rises is the word we want to use instead three times a day when I eat but we also know and we see this in a lot of you know our members they're trying to eat to keep that glucose line as flat as possible how

flat do you want to see that line it's going to undulate all right if it doesn't undulate you know that means either you're not consuming glucose or you're fasting one Of the other it's going to it's going to change we don't know we don't have the data to tell you oh the amount of change predicts when you're going to die we don't have that right I don't think we'll ever have that what I can say is the longer it stays up the more problem it is that's really what I can say you should be able

to clear your glucose within an hour that's what I can say now different foods will give you Different Rises and different foods will probably have different effects on how fast that glucose gets cleared as well those are called craft curves okay kft for Dr craft who first utilized them so different foods will you know provide you with different information and that's one of the reasons why cgms are so great because then you can determine well what gives you the lowest glucose Excursion what gives you the best craft curve for your Personal body habitus and your

personal biochemistry you can get that out of the CGM now the craft curve of course measures insulin it doesn't measure glucose so you're not getting that but you're getting a proxy because if you're clearing your glucose fast that means your insulin's in good shape so you know we have to understand what we're measuring glucose but really what you want to know about is the insulin so if I'm having Those rapid returns to Baseline how much do you care about glycemic variability over the the course of the day if my line is still moving quite a

bit but it's coming back down or if I'm spiking every time I eat not that much as long as it's coming down if it goes up it goes up if it's coming down that means your body's okay actually there's one more thing I want to follow up on on the uh glucose and Insulin side this is maybe a bit of a Tangent but um I want to go back to diabetes we talk about diabetes is is diagnosed via glucose right via a fasting glucose test or an A1C but as I understand that what diabetes is

describing as a state of insulin resistant well not necessarily okay type one diabetes is not a state of insulin resistance it's a state of defective insulin uh insulin Reserve so if you can't make insulin doesn't matter how sensitive you are so it's a Combination of the two you know it's like two um uh uh uh levers you know that are in working in concert with each other and the more defective one lever is the harder the other one has to work in order to keep it uh stable so that's why you need both pieces of

information you need the spike to tell you about the reserve you need the uh rate of clearance to tell you about the sensitivity there's information in both of those and they're related to each Other so why do we diagnose diabetes with glucose and not insulin well because some people will have high insulin for a certain glucose and some people will have low insulin for a certain glucose where you going to draw the line it's not going to tell you and in addition because the glucose is you know doing damage you know it's obviously the thing

to measure and in addition because your kidney is now excreting the glucose you know it's an Easy to measure in the urine so that's a better marker for diabetes but it's not necessarily A U biomarker with dynamic range for metabolic Health insulin's much better for that and because insulin changes early and glucose changes late like I said said if you're waiting for the glucose to change horse is out of the barn one more question on Diabetes how arbitrary is 125 it's pretty arbitrary it depends on where you are in the curve if you're at the

Baseline then 125 is diabetes if you're in the middle of metabolizing your meal and that's your Peak you're doing great you know so a uh a blood glucose out of context tells you nothing that's why you needed to be fasting but it's the last thing to change because your body is doing everything it can to maintain a normal blood glucose it's the absolute last thing to change the hemoglobin A1c is the second to last thing to change it will start to rise before the fasting Glucose will so if you've got an hemoglobin A1c of 5.4

you've got a little bit of defective gluc glucose clearance if it goes to 5.5 you've got a little bit more defective glucose clearance and up and up and up until you hit six when now you've got pre-diabetes and when it hits 6.5 that's full-fledged diabetes so you can actually see the problem before the fasting glucose changes in the hemoglobin A1c but even that is late in The game the fasting insulin will change before that and how do I know that because you can go into any metabolic syndrome clinic in this country and see patients who

have normal glucose tolerance but are obese and Insulin resistant so they are not hyperglycemic they do not have an abnormal glucose tolerance test but they're insulin resistant they're fasting insulins High to keep Them at that glucose level and they are already spilling protein in their urine they already have metabolic kidney disease because the insulin caused the metabolic kidney disease not the glucose so there are things you can look at to tell you as an early Diagnostic and I'm actually giving a talk at Stanford in two weeks on early Diagnostics and fasting insulin is job one

and do you watch insulin on the way down if you're treating a diabetic Patient and you're trying to get that that gluc fasting glucose down are you also testing their insulin as you're as you're treating them and and expecting that to also be coming down how do they move on the on the reverse side if you're improving their metabolic health and their fasting insulin should be coming down now if you're giving metformin you will be improving insulin sensitivity so the fasting insulin should come down if you are giving Thadine diones to improve their diabetes their

fasting insulin might actually not change so it depends on how you're doing if you're doing it with diet it definitely should be coming down and if it's coming down then that's a good thing okay so let's leave the world of glucose and insulin for a moment so we have time for some other markers all right you mentioned earlier uric acid that's also included in our in our current levels Labs Panel is uric acid fit this criteria that we were talking about in terms of a marker that reveals something about underlying physiology is TI tradable and

can actually be moved yes um and it's also got a dynamic range and it um and the higher it is the more problem it is so yes and that that's another reason why we include uric acid in our biomarker panel for just that reason the question of course is what does uric acid mean people don't even know what it Means it is a breakdown product of energy generation it is a breakdown product of a ATP so when ATP you know the energy is in the phosphate bonds when ATP Cleaves a phosphate off to generate energy

it becomes a DP adenosine diphosphate so the energy gets released you um manufact you know it gets used to power molecular Motors within the cells so that the cells can Do their job okay then the adpak goes to a a Denine monophosphate which then goes to im an acetol monophosphate which then finally goes to uric acid and uric acid is then excreted in the urine so it is a measure of how fast your body is generating energy so a marker of cellular Health marker of cellular Health now the problem is that uric acid does two

things that you wish it didn't do one is It is the inhibitor of an enzyme in your arteries called endothelial nitric oxide synthes or Enos that's the enzyme that makes nitric oxide and nitric oxide is your endogenous blood pressure lowerer it's the thing that causes your blood vessels to relax therefore it's the thing that keeps your blood pressure down and so if you're inhibiting it it means your blood pressure is going to go up so it is a primary contributor to Hypertension well known been known since 1967 that uric acid is a driver of hypertension

the second thing it does and this was work of from Rick Johnson from University of Colorado he showed that uric acid inhibits an enzyme that's necessary for mitochondria to do their job called cpt1 carnitine poid oil transferase one now what is that that's an enzyme that regenerates this compound in your cells called carnitine and carnitine is a Shuttle mechanism for bringing fatty acids into the mitochondria so that they can be burned if you don't have enough carnitine you can't um uh uh cleave fatty acids into two carbon fragments and use them for burning in which

case you end up with fatty liver and so if you inhibit CPT one you can't transport the fat good reason for fat buildup which causes insulin resistance and clearly mitochondrial dysfunction because it's interfering with ATP Generation because it's interfering with mitochondrial function so keeping your uric acid down is super important now what makes uric acid go up well obviously kidney disease because you have to excrete it but like what else CU kidney disas you can't do much about okay you know at least not not I mean you can improve your metabolic Health that'll help but

it's not like you can fix that from you know from one day to the next um what makes uric acid Well two things make uric acid the first is purines because purines are adenosine and guanosine they are nucleic acid nucleotides that are in meat so Benjamin Franklin knew that his meat habit was the cause of his gout okay he wrote an Ode to his gout back in 1785 so it's been known for a long time that you know um uh uric acid is a driver of gout and that uh meat is a primary driver of

uric acid but the Other thing that causes uric acid is not so welln and it's sugar and why does sugar increase uric acid right and that's a complicated one but let me explain it remember sugar is two molecules glucose and fructose the glucose will get metabolized in every cell in the body fructose only in the liver the fructose enters the liver and the first thing that happens is that the fructose gets phosphorated a phosphate is added to the fructose so it can then Go on its biochemical journey to either energy uh utilization or more likely

fat storage when it's phosphorilated a phosphate has to be given to it well where does the phosphate come from it comes from ATP so ATP has to go to ADP in order to metabolize fructose which starts the uric acid you know that's what that's the pathway to uric acid so sugar consumption increases uric acid too so both meat and sugar consumption both increase uric acid If you want to get your uric acid down you have to cut your meat you have to cut your sugar consumption it's just that simple but because of the effects on

blood pressure and because of the effects on this carnitine transport that ultimately leads to mitochondrial dysfunction and fat deposition uric acid is a bad player in metabolic health and the goal is to keep it down all right so how down should it be if you look at the lab slip it'll tell You that the cut off for high uric acid is at seven that's wrong that's wrong okay the cut off should be at 5.5 now why do I say 5.5 and the lab slip says seven clearly they know something I'm guessing gout is the answer

well no no no it has to do with the um normal distribution has to do with the gaussian Curve okay so today if you take a 100,000 quote healthy unquote and we know that They're not healthy because 93% of Americans manifest some form of metabolic dysfunction but they may not know it and they say they're healthy okay but they go into this you know assay okay you're going to generate a bell-shaped curve and then you get the mean and then what we say is two standard deviations from the mean that's what we consider abnormal you

know that's just a statistical fudge is two Standard deviations from the mean so if you do that for 100,000 quote normal healthy adults who are not healthy that number is going to be seven but if you did that 50 years ago the number would have been 5.5 and the reason is because we were healthy then and we're not healthy now the entire bell-shaped curve has shifted to the right and of course there's no way to know that just doing that today you have To actually look at what happened before to show that and we have

so this is true for insulin this is true for uric acid you know it's it's true across the board for you know hosts of things it's true for alt which is a liver function test okay because everyone has fatty liver now 45% of Americans have fatty liver 25% of children notice I didn't say obese adults or obese children all adults all children this is something that didn't even exist before 1980 and here we are now 45 years later and 45% of the population has a disease that we never heard of before so we know something's

going on this is a clear indicator of metabolic dysfunction a clear indicator of inability to utilize fat because of defective mitochondria because of insulin resistance so these things all go together so you're fasting insulin and your uric acid and your alt should all line up together because they're all Part and parcel of the same pathophysiologic pathway so maybe let's wrap this up by coming back to where we started which is what is our our set of markers what kinds of things we want to look at we've talked about insulin a lot that being a really

key one we've talked about uric acid which I think is is still pretty much on the fringes of what people are are measuring um we talked about some some way of looking at glucose in relation to your insulin Whether it's with the CGM or whether it's with testing what else do you want to see what El what other markers fit these criteria we've talked about and give us some indication of our health so you had mentioned cholesterol at the very beginning let's turn to cholesterol for a minute everyone thinks cholesterol is important it's not okay

now there are different kinds of cholesterols and some of them are important but the total Cholesterol doesn't tell you that so the amount of cholesterol on the side of the of the package they took it off because they know the FDA knows that's not valuable that's number one number two your total cholesterol on your lab slip is not valuable it shouldn't even be listed because all it does is confuse people and it's spous so what does matter well there's this thing called LDL does that matter and the answer is no it doesn't matter Either and

here's why because there's not one LDL there's two and the LDL on the lab slip measures both at the same time and they're not the same now if we had a way of separating and we do the two different ldls you can actually learn something so that's called a VAP analysis or lipoprotein electropheresis where you basically can distinguish the LDL that causes heart disease called small dense LDL from the LDL that doesn't cause heart disease which is Called large buoyant LDL then you can learn something but you Insurance isn't paying for that that's a $500

test to figure that out so people don't know now if you can afford it great but you know that's not helping the masses so we have a still have a problem there um triglyceride turns out to be a more egregious uh lipid than uh LDL ever was the hazard risk ratio for LDL and heart disease is 1.3 meaning if you have a high LDL you have a 30% increased risk Of having a heart attack whereas the hazard risk ratio for triglyceride and heart disease is 1.8 so if you have a high triglyceride you have 80%

increased risk for having a heart attack 50% increased over the LDL but we don't even talk about it we don't you know pay it any heed and there are two reasons why first reason is because a lot of people get their blood drawn not fasting and you need to be fasting for triglyceride to mean Something because as soon as you eat your triglycerides go up okay just like your you know your glucose and your insulin have to be fasting in order to mean something and number two um the triglyceride doesn't just stay triglyceride the triglyceride

circulates in the bloodstream goes to your fat cell offloads the lipid into your fat tissue and then it becomes the small dense LDL so your triglyceride and your small Dense LDL are related to each other so what you care about is your LDL but you care about it in the face of your serum triglyceride so high LDL low triglyceride not a big deal high LDL High triglyceride very big deal now at levels we understood this and so we are not measuring LDL or triglyceride we're measuring something called APO APO lipoprotein B and the reason it's

because LDL and triglyceride both have aob B Because one's an evolution of the Other and so that's a way of figuring it out so that's another reason why Labs 2.0 for levels includes apob as one of the markers okay so that's basically what levels is doing right now with tests that are normally and routinely available and coverable by insurance is that all are there other tests are there things that we could get that would give us information as well well and the answer is yeah there are There are let me give you an example there's

a test called homosysteine now we are not getting it now turns out homocysteine is a metabolic metabolite of protein it go it's part of the TCA cycle but it's also in the protein cycle and it is responsive to B vitamins and omega-3 fatty acids when your B vitamin deficient and when you're omega-3 fatty acid deficient your homocysteine goes up and it turns out Homocysteine levels predict cardiovascular disease and heart attack as well and now we've also learned that homocysteine levels also predict Alzheimer's disease now we've known for years about a disease called homoy Uria this

is a disorder of the enzyme that clears homocysteine in the body if you have this disease you're tall and you're actually kind of gangly and you're mentally and you get very early heart disease it's a disease I used to take care of as a pediatric endocrinologist well people have now done a lot of work on whether or not that homocysteine was the cause of the mental retardation and the cause of the heart disease and we Now understand that that is a primary risk factor it's part of the pathogenesis and it may even be part of

the pathogenesis of Alzheimer's Routinely so could we get total homoy in our patients and learn something about their metabolic status and would that be fixable and the answer is yes it's also on a dynamic range and it's also modulable and it's also um uh you know it means something but it's not covered by insurance today should that change I think so so that's an example what other tests could you do that would be valuable one of the uh Cardinal features Of Aging is methylation so your DNA gets methylated and the longer you live the more

methylated your DNA gets well it turns out the degree of methylation predicts the degree of Aging you can measure methylation status by measuring something we now have a test for called epigenetic age can you measure epigenetic age yeah but insurance not paying for it it's relatively still expensive um our colleague David Sinclair offers u a Methylation test uh it's known as the denan pace method and you can determine that and we know from other studies like for inance is my colleague Bruce blumberg at UC Irvine has shown that the methylation status of an enzyme called

insulin degrading enzyme predicts insulin resistance because you can't clear the insulin because of its methylation status and that that is a primary Hallmark of obesity and Aging so the problem with the denan pace is you have to chop up all the DNA so you don't know which enzyme it's with or which Gene it's with so it lacks a certain shall we say specificity but it gives you a sense of how you're doing from an aging standpoint and my colleagues at um UC Berkeley and UCSF uh Barbara laiah and L Alyssa eel just showed a cross-sectional

study showing that the degree of ultra-processed food that you eat predicts your epigenetic Age compared to your biological age now does that mean you could fix your food and fix your epigenetic age we don't know that yet no one's done that but is that something to look at for the future and could that ultimately be a good marker for us to be able to draw very possibly you know that's an excite exciting place to go and then the last thing is inflammation so the degree of inflammation that's going on in the body how do you

determine that cu the more Inflammation the sicker you are without question and where's the inflammation coming from it's almost always coming from the gut gut inflammation so are there tests for gut inflammation and the answer is not good ones unfortunately but we can look at systemic inflammation we can look at high sensitivity Ser active protein so that's a test that's immediately available okay doesn't cost too much the problem is it doesn't have quite the dynamic range that the others Do it's not quite as good a biomarker but it's still tells you whether there's inflammation going

on or not and so if you know that your C HS CRP is low that's a good sign it means that you're doing something right and if it's high it means clearly things are not right and you need to start thinking about what it is you're eating in order to get that hscrp down doesn't tell you what's wrong just tells you something's wrong so that's another potential test that Can be added to the armamentarium and it's not too expensive and it's available now so this is an evolution this you know we're working on it we're

getting there you know we need the science in order to be able to justify you know the the the cost and the expense and certainly the insurance coverage because they're not going to pay for anything unless it works all right so we're still you know uh working on those things but for me Today the things to know are you're fasting insulin and your uric acid and your apob and you know then we can talk about you know the the rest the last question on this then which I think this leads into is you know we

do now have companies like function Health from our friend Dr Heyman and other companies like his that are offering these very broad arrays of of tests right I think they do over a hundred uh annual uh Markers what do you think about the utility of tests like that are there things that things that would sort of to be on your wish list either because they're precursors or because they're a good indication that somebody's going to get as part of that large set that you're just not going to get at your doctor setting cost aside right

because that is the the barrier to those um you know getting those kind of large arays but if one has the means what do you Think about people getting that amount of data I think it's probably premature and the reason is because we don't know what to do with it we don't know how to analyze it we don't know what goes with what pathway because you're trying to influence a pathway you're not trying to influence a specific biomarker okay the biomarker is a marker for the pathway and so when we when we have some more

data and we know that those things are actually manipulable And that the manipulation actually results in clinical benefit then I'll be ready to uh to uh support those I think it's a little too early for those I think that's a little premature it's nice to think about it's definitely a a hot research topic and I'm for that but you know terms of Clinic utility I think don't put the cart before the horse [Music]