How to Avoid Insulin Resistance and Why it's Important | Dr. Robert Lustig & Dr. Dom D'Agostino

one quarter of all the people on the planet two billion adults have fatty liver disease now prior to 1980 if you had fatty liver disease you were an alcoholic but these are not alcoholics we don't have two billion alcoholics so why do they have liver fat and why is the liver fat generating the insulin resistance and the reason is because the liver is the primary target of insulin action and so when your liver cells start accumulating fat they don't work very well and so your pancreas has to make extra insulin to make the liver do its job the liver is really Ground Zero for why we have this phenomenon of insulin resistance [Music] hey Rob it's great to be with you here today and I'm excited to cover this topic on insulin resistance what we know what we don't know what we have to learn and what are actionable things that we can do indeed I'm so glad to see you as well you know we've uh piled around at meetings you know we have to now do this on the internet instead but you know between the two of us I think we'll be able to knock this out of the park yeah there's a lot to discuss in this topic I mean it's Central for metabolic Health it's the etiology of so many of the major chronic diseases including diabetes of course but uh all the way to even cancer and cardiovascular disease so let's talk about maybe like what is insulin resistance how do we Define it well I'll be honest with you I before we Define insulin resistance I think we ought to Define insulin insulin is a hormone it's a chemical that is made in the pancreas circulates in the blood and goes to different parts of the body to do different things and it does different things in different uh tissues the main thing that insulin does is it stores energy insulin is the energy storage hormone insulin shunts energy in the form of glucose and sometimes other foodstuffs as well like amino acids and fats into tissues especially adipocytes fat cells to accumulate energy um insulin makes fat more insulin more fat and so this phenomenon of insulin resistance has always been a question mark because people say well how come if it's more insulin more fat if you're insulin resistant how come you get even fatter and this of course is the big Paradox in insulin resistance and we're going to try to answer that for you today yeah good good overview route and you know a question that that we get quite often even from the medical students is you know what is the difference between insulin resistance and type 2 diabetes and how do you define it and does one precede the other and and also I mean you talk about you know what insulin is obviously it's one of the most important metabolic hormones I mean I don't think anyone would dispute that you know another question that comes about in medical you know curriculum is why are we not measuring insulin separate question but why is insulin not part of a comprehensive metabolic panel so sort of two questions there would like your insights from a clinician's perspective the first issue is why is insulin resistance the big issue and the answer to that goes all the way back to 1959. when Rosalind yellow and Saul Burson first developed the radio immunoassay their very first attempt was to measure insulin and what they found was that when they took the blood of type 2 diabetics they expected to see no insulin after all they have diabetes but what they saw was that the insulin levels were actually higher and this was you know sort of like did we get this right you know are we measuring the right thing well it turned out not only were they measuring the right thing but they discovered a completely in new and important uh uh manifestation of chronic disease the phenomenon of resistance to a hormone so how come insulin levels are high when insulin function is low the answer is because the receptors for insulin the proteins that bind insulin on the cells have been down regulated they are not working as well because there are fewer of them and because the signaling that goes on beyond that receptor is dysfunctional and that is really what insulin resistance is about why does that happen and it happens in different tissues and it happens for different reasons and in fact those different tissues are important in terms of why insulin resistance manifests different diseases so for instance type 2 diabetes is a manifestation of insulin resistance at the level of the liver polycystic ovarian syndrome is a manifestation of insulin resistance at the ovary cardiovascular disease is a manifestation of insulin resistance at the heart Alzheimer's disease we are learning is a manifestation of insulin resistance in the brain so this phenomenon of insulin resistance is extraordinarily important for all of these chronic diseases but it's Regio specific different tissues manifest insulin resistance at different times and it is because of that that we end up with these different manifestations excellent overview Rob I'm glad you mentioned the brain a question that I got the other day actually was can you have type 2 diabetes without insulin resistance and I could not answer this unambiguously with a particular reference uh I printed a couple papers out and I didn't get a chance to read it but a question that you know in our discussion of teaching this is can you have from from your perspective can you have type 2 diabetes without insulin resistance no but you can have a disease that masquerades as type 2 diabetes without insulin resistance so how do you define type 2 diabetes Well anything that's not type 1 diabetes so type 1 diabetes we know how to define because there are antibodies in the blood so you can have antibodies against the beta cell you can have antibodies against ica2 anti-gad antibodies now there's a zinc uh transcription factors the nt8 antibodies point is all of those demonstrate immunologic destruction of the beta cell and so if you have immunologic destruction of the beta cell you have type 1 diabetes if you don't then everybody assumes you have type 2 diabetes now that is actually incorrect because there are many many different forms of diabetes that are not type one there's cystic fibrosis related diabetes there's mitochondrial diabetes there's a whole host of different diseases and there are genetic forms of diabetes known as Modis m-o-d-y mature onset diabetes of Youth and there are 14 of them because there are 14 different genetic defects that will ultimately lead to beta cell dysfunction and lead to hyperglycemia those often get binned in with type 2 diabetes those patients with Modi account for about five percent of the type twos and those patients don't have insulin resistance so you have to know which patient you're looking at but if you have true type 2 diabetes you have insulin resistance yeah you mentioned a couple different diseases there like 14 different diseases associated with this and that kind of leads to the question you know what what's the ideological cause of insulin resistance and is that also heterogeneous and you know I know Gerald Shulman I've read most of his papers uh in his Banting like lecture I think in 2018 talked a lot about ectopic fat so uh and I know Dr Shulman has really kind of focused on the muscle fatty acid oxidation you know impairment of that in the muscle but it also occurs in the liver and I guess one of the questions is if we want to get an early precursor of insulin resistance should we be looking at ectopic fat uh well we should be measuring insulin but also ectopic fat in the muscle in the liver and I know a lot of a lot of your emphasis has been on the liver and I've certainly got a much bigger appreciation for the liver as the master regulator even working in mice and rats I'd love to hear your comments on on that this ectopic that as a precursor right so Jerry Shulman is of course the ultimate Guru through and I wish you were here you know to you know say his piece but you know Jerry has undergone a uh an Awakening of sorts and I know why um when he started doing all of his um analyzes of uh intra uh cellular fat uh intramyocellular lipid Etc he he was using a magnet you know for MRI that was only 1.5 Tesla and so it had to be small and the only magnet he could use was one that fit around the gastrocnemius muscle in the leg and so he knew a lot about muscle fat and so throughout the entire early 2000s he was publishing that this was a muscle fat issue muscle fat issue and he believed it and then in the late 2000s and 2010s we had the Advent of the three Tesla magnet and now of course we have a seven Tesla magnet and that allowed for a much bigger uh circumference and so we could actually start measuring liver fat the first paper that came out was actually on this was from Sam Klein's group in 2009 and what they showed was it was actually the degree of liver fat that mattered the most and so Jerry Shulman went back to the you know to the MRI machine and started looking at livers and found oh my God yeah the liver is even worse than the muscle and in fact the liver fat actually predicts the insulin resistance more than the muscle does so it is true that muscle insulin resistance contributes to type 2 diabetes and to overall General uh ill health I don't argue that but when you actually do the quantitation the real problem is in the liver and that's now been documented you know 50 ways from Sunday and so you know I think the liver is the big issue so my my the way I put this together and I am very happy for your uh for your input here Dom the way I put this together is that there are three different insulin resistances not one not two but three the first one comes from the general fat the subcutaneous fat now normally subcutaneous fat is protective against metabolic disease it's where your body wants to put excess energy it's the place where insulin stores the energy and you can gain a certain amount of subcutaneous fat without any cost to the rest of the body but then a certain point comes where you start forcing more energy into those adipocytes the fat vacuoles start to grow the perilipin border that that encircles that vacuole starts to break down and the fat in those vacuoles starts to actually seep into the cell and kill off the cell and this necrosis that happens individual fat necrosis then recruits macrophages to help clean up the grease those macrophages then secrete cytokines tnf Alpha il6 Etc which then go via the systemic circulation to the liver and activate nadph oxidase and ultimately lead to insulin resistance so the fat induced hypertrophy and then stretching of the membrane and then Associated uh rupturing or dysregulation associated with that is the driving I guess what we'll talk about later uh the inflammation associated with that but it's it's really uh and I as we age those membranes probably become less viscoelastic and probably you know that process is augmented by by age too exactly so subcutaneous fat can lead to insulin resistance but only at a very high level and so that's one of the reasons why we have metabolically healthy obese people because their stuffing energy into subcutaneous fat but they haven't gotten to the point where those membranes have ruptured so that's the first way to get insulin resistance the second way to get insulin resistance is from stress having nothing to do with energy and having nothing to do with food and the reason we know this is because patients with endogenous clinical depression who are not eating I mean they have their anhedonic they are you know suicidal you know you have to admit them to the hospitals to keep them from hurting themselves you stick them in a scanner and they're not eating they're losing weight they're losing subcutaneous fat but they're gaining visceral fat you can actually see the visceral fat on the CT scan and in fact they have insulin resistance too they have it because of cortisol they have it because of an altered sympathetic nervous system output they have a different form of insulin resistance which is not necessarily food driven not necessarily energy driven but rather hormonally driven like we see in patients with Cushing syndrome and then finally the third group the patients with liver fat now I just saw that non-alcoholic fatty liver disease is 45 of the American population and 25 of the world's population having nothing to do with obesity and this is true throughout the entire world one quarter of all the people on the planet two billion adults have fatty liver disease now prior to 1980 if you had fatty liver disease you were an alcoholic but these are not alcoholics we don't have 2 billion alcoholics so why do they have liver fat and why is the liver fat generating the insulin resistance and the reason is because the liver is the primary target of insulin action and so when your liver cells start accumulating fat they don't work very well and so your pancreas has to make extra insulin to make the liver do its job and so I think that the liver is really Ground Zero for why we have this phenomenon of insulin resistance and that's why you can be thin and Insulin resistant as well as being fat and Insulin resistant I have a couple follow-up questions on that so if the muscle has impaired fatty acid oxidation then could that be sort of the site of you know impaired glucose oxidation and fatty acid oxidation and then that contributes to the buildup of fat in the liver or do you think one precedes the other I know that uh Gerald Shulman is very I I didn't know that uh I didn't have an appreciation for the history of uh the Imaging you know how how the first measurements were made in the gastrocnemius and then the three Tesla evolved to image the whole bite so I've always kind of pictured it from the context of impaired fatty acid oxidation in the skeletal muscle which is the glucose sync and then that sort of creating the bottleneck which then contributes to the fat oxidation impaired fat oxidation in the liver and de novo fatty acid production in the liver I believe it can I'm not saying it can't but there's one piece of scientific evidence that would argue against that and that is the fat insulin receptor knockout Mouse the ferco mouse as you know uh uh Ron Khan's Lab at Joslin Diabetes Center created eight count them eight separate tissue specific insulin receptor knockouts and the own and so they're all insulin resistant in their own ways but they're insulin resistant in different tissues they are Regio specific insulin resistance and they all have different diseases for instance my favorite Mouse of all time Bar None is the poderco mouse the glomerular podocyte insulin receptor knockout Mouse so this mouse has had its insulin receptor extracted you know by transgenic means by creelocks from the kidney so the animal is completely totally insulin sensitive except for the kidney this animal has normal blood glucose this animal has normal ketones this animal has normal insulin tolerance this animal is not fat but this animal has the worst diabetic nephropathy on the planet even though the animal is euglycemic even though the blood glucoses and and the glucose tolerance is completely normal why is that how can that be how can you have diabetic nephropathy with normal blood glucose and the answer is because it's not the glucose it's the insulin the insulin makes the difference so in Jerry shulman's hands yes there is absolutely uh defective fatty acid oxidation in the muscle no arguments I agree with that the question is is it a cause or effect and I believe I believe in most patients not in all but in most patients it's effect because of the hyperglycemia that's ultimately leading to it and the reason I feel that way is because of the Fertile Mouse which is not fat okay and is not diabetic yeah if it was in the muscle then you know exercise being a very powerful activator of ampk independent of uh pi3k right would would quickly reverse that but maybe not so much in the liver right so um you know it and I do is kind of brings back some questions related to athletes who are consuming you know two 300 grams of sugar a day and their insulin's maintaining low but they're kind of on a different Spectrum right and then actually we just published a study high carb athletes are essentially you know uh pre-diabetic if even if you adjust for calories which surprised me the results really surprised me we just published this well this is the story of Sami inkinen um and he's happy for me to use his name um Sammy you know one of the original founders of Nokia when he was 19 years old he um sold out you know he he cashed in uh took his money moved to the United States um uh went to Stanford Business School started the Real Estate website Trulia which was bought by Zillow for three billion dollars so Sammy's got more money than God all right now Sammy was an amateur triathlete and he would win he actually would win triathlons this guy you know exercised five hours a day and at age 38 all of a sudden he realized his performance was going down and he didn't understand why and so you saw his doctor and the doctor said hey you're pre-diabetic and he didn't understand how can somebody who's a triathlete who's exercising five hours a day be pre-diabetic and so he went to see Steve Finney who is one of the low-carb you know uh physiologists and Physicians uh at UC Davis and Stephen he said well something that's obvious it's the sports drinks stop drinking the sports drinks and sure enough Sammy stopped drinking the sports drinks and his performance went up his type 2 diabetes or pre-diabetes reversed and he said wait a second this is crazy you know and so what did he do he started virta health and virta health now uses the ketogenic diet to reverse type 2 diabetes because he knows that even exercise can't fix this metabolic problem okay you cannot outrun a bad diet and you've got to fix the diet first so yes exercise is important but it's not enough yeah that reminds me I connected with Sammy kind of early on uh maybe about 10 years ago when he was transitioning and uh he had a you know and met him on occasions and we had a lot of emails back and forth and stuff too and uh yeah he dropped his carbs very low but would actually you know add some carbs back in I think in the form of like chocolate or like dark chocolate but a small amount you know like 50 to 100 grams or something when he was doing this crazy sort of rowing uh uh you know feet and uh it was yeah really interesting that was kind of my for I was mostly focused on epilepsy and other neurological disorders but then I you know then verta came along a while after and I met met with him at a meeting related to that and I got more and more interested in the use of you know low carb uh which I thought was kind of a an odd application of using low carb diets in in athletes because at the time I was just hyper focused on uh epilepsy because that was only the only legitimate application of a ketogenic diet you know uh at least from uh randomized controlled trial kind of point of view but then he opened my eyes you know about 10 years ago to the application in athletics as did you know Jeff Olek and and Finney's book so yeah it was kind of really interesting to see that come along and now the problem exists as a pediatric endocrinologist so this problem is not you know it can happen in in adults in athletes but also in the Pediatric population which I guess you know you were practicing in the 80s is that right and did you see well yeah I graduated med school in 80. okay and did fatty liver disease exist in kids in the 90s no did it start to evolve I remember my very first case of fatty liver disease and it was in Memphis Tennessee and it was 1997. and I was called to see this 13 year old who was pre-diabetic who was obese of course who had this you know these enormously high ALT AST gamma glutamyl transpeptidases and they wanted to know well why is he pre-diabetic and I looked I don't know this is crazy what's wrong with this kid I figured he had hepatitis or something you know you know hep C or something like that but no he was negative for all these things and sure enough they they took them and they didn't liver ultrasound and they saw that he basically had like 30 percent liver fat I said what the hell is this and so that was my very first case of non-alcoholic fatty liver disease he was only 13 years old so he wasn't an alcoholic and well you know that was my index case and then they started rolling in after that and you know we started then looking for it and we realized you know in 2005 that we could use alt alanine Amino transferase off the chem panel for being able to screen for it and of course the other thing that we did was we would do fasting insulins in order to determine the degree of insulin resistance and so the combination of fasting insulin and ALT was very potent in terms of being able to determine what was really going on with these insulin resistant and fatty liver kids and the answer was in two words soft drinks in your practice did you ever come across kids who have inborn errors of metabolism I just came from a lysosomal storage disease conference where we're doing research on mice who have very large livers and we didn't we're going to do the histology on them but one thing that I didn't know going into this is that the mice that have pomp disease or glycogen storage disease type two type two they over produce glycogen and then you know they can't break it down yes so uh and then this causes problems in the muscle but you know we did not I was pretty much focused on the muscle in the brain because it's kind of like our wheelhouse but uh but in communicating with parents who have these kids too the liver is a big problem and their liver is really swollen and and it needs to be you know sort of a focus of attention so I think and but that's now it's it's looked at and I was wondering if you just came across and it also leads to the question are there genetic predispositions to to to this well these these diseases that you're talking about these glycogen storage diseases are actually pretty rare they're not that common and we have GSD zero glycogen storage disease type zero which is glycogen synthase deficiency all the way up to gsd9 so we have 10 10 of these diseases um the point is that they store glycogen now there are certain organs that can store glycogen like for instance the liver that's where your body wants to store glycogen and you can store it in the muscle as long as you can fish it out you know eventually you can pack enough glycogen in so that it becomes a problem but you know there's a there's a glycogen storage disease GSD type 1A also known as Von gierke's disease which you're missing the glucose 6-phosphatase you're missing the ability to get glucose out of glycogen you're not able to release it so these patients are enormously hypoglycemic that's how they present that's why they call us as an endocrinologist because these kids show up with hypoglycemia and then they're in the neonatal or in the early you know postnatal period and they will stuff glycogen into their livers non-stop so they will be you know hypoglycemic like old get out they will be ketotic because they can't use their glycogens they have to end up using fat and so they will be ketotic but the question is do they get liver failure and the answer is no they don't get liver failure so glucose for lack of a better word glycogen for lack of a better word is non-toxic now it's not good to have too much obviously but hey that's what your liver wants to do with excess energy is make glycogen that's why marathoners carb load you know before a race so I don't see glucose and glycogen as being the big problem now a lot of people think glucotoxicity is the big issue in insulin resistance you know bringing it back to insulin resistance and there's some data that supports that but I think that the reason that glucotoxicity is the problem is because what's happening in the liver is the glucose is getting turned into fat by this phenomenon called de novo lipogenesis DNL where you take glucose and turn it into fat or you take fructose more likely and turn it into fat and so it is the lipotoxicity that actually interferes with liver functioning not the glucose and it is because of these patients with Von gerke's disease that I think so so the glycogen storage diseases I think play a very minor role in this uh in this story I don't think it's as big a problem I think the bigger problem is the Turning of glucose into fat I was wondering if it was analogous because we do see in pomp disease gsd2 is that when the glycogen hyper you know there's hyper sores of glycogen and the decrease in autophagy that tends to impair muscle function and it becomes painful and then that leads to an analogous to that that is occurring in the liver but probably we did not think to look in the liver and we haven't really so far but we just see that the livers are quite large you know as we're starting to do necropsy on these animals uh but the histology I guess will determine and the mouse model is new so we don't really have a lot of but I was thinking that it could be somewhat analogous to that and you talked about the fat really being the de novo lipogenesis and the accumulation of fat as being the toxin would the the lipotoxicity be from the swelling and just the could it be just a mechanical swollen liver that's just breaking membranes and releasing inflammatory factors you know I don't think we know the answer to that yet though uh is you know exactly what is the fat doing in the liver that's generating the problem you know we know that for instance there are Pathways that uh alter insulin receptors uh irs1 the insulin receptor substrate one that serine phosphorylate that irs1 instead of tyrosine phosphorylating irs1 and there are enzymes that are turning on that are doing that you know this is the hota mashlaguil Harvard School of Public Health story about junk one jnk1 C June and terminal kinase one which is serine phosphorylating IRS one instead of tyrosine phosphorylating it I don't think we really know the uh the pathway to a defective insulin receptor completely yet I think we're still I think we still have to work on that so I don't want to get too far down in the weeds mechanistically but I do I understand that Gerald Shulman and other people are looking at way is to augment fatty acid oxidation perhaps with an uncoupling agent UCP 3 I believe which would be sort of specific to the liver you know more in the liver so that would then address the lipo or the de novo lipogenesis and and sort of augment liver fatty acid oxidation in a way that could do you think that's a good direction to go into obviously we could talk about food and we're going to talk about food but to just address impaired fat oxidation in the liver is that a potential strategy I think I think fixing the liver is hormone I think that that's where the action is now the question is you know food or drugs and um we need both I mean ultimately we need both and I do think that uh going that route uh as Jerry is is right and I think the reason is because there's another group that's also going that route and that's Ron Evans at salka Institute and they've got a compound that activates ppar Alpha proxasone proliferation activated receptor Alpha which is liver specific and this compound called gw1513 it doesn't work the same way but It ultimately does the same thing and that is increases fatty acid oxidation in the liver and by doing so improves metabolic health so every which way you turn the answer comes back to the liver fix the liver and that's one of the reasons why I've been so you know strongly uh uh uh you know advocating for number one protecting the liver as a primary uh preventative and also treatment for chronic metabolic disease and of course that is our entree to food so we're taught you know I mean just from conventional medical educational nutrition and Metabolism that there's really not a specific macronutrient it's just an excess amount of calories and uh yeah I don't know about that yes and I want you to just kind of quickly overview because it would be another you know three-part series of how for example sugar or fructose a hundred grams of or 200 grams of calories from sugar or fructose has a different effect on the liver than for example protein or or fat um and you know just explain how you know redox control in the liver and and you know just just some basic hepatic physiology of handling these things well for the audience look you've been pelted for the last 50 years with calories okay it's all about calories calories and calories out and therefore it's about two behaviors gluttony and sloth and so if you're fat it's your fault you know and therefore diet and exercise you know ultimately all of these are the mantras of the food industry and the reason is because if it's about calories it's your problem not theirs it's their way of assuaging their culpability for what they you know are putting into Ultra processed foods and you have to understand that there's an entire literature that basically pushes back against this notion of calories so let me give you some examples number one there are countries that are diabetic without being obese and there are countries that are obese without being diabetic so obesity and diabetes don't necessarily play the same role number two um obesity is growing at a the rate of 2.78 percent per year worldwide but diabetes is growing at the rate of 4.07 percent per year worldwide if diabetes was just because of obesity how come diabetes is going up faster number three if you look at the rate of increase in diabetes in the general population of the United States it's going up just as fast in the obese as it is in the normal weight population if obesity was the reason that wouldn't be the case number four there are two diseases that we as pediatric endocrinologists take care of that I want to alert you to one of them is called larone dwarfism now Laurent dwarfism is a defect in growth hormone signaling there is a Founder Effect group of Lauren dwarfs in Ecuador they're known as The Little Women of loja and they were written up in the New England Journal of Medicine and the reason was because number one they're very short but they're also very obese and the reason is because they can't lift fat out of their fat cells because the of the fact that their growth hormone doesn't work okay so these Little Women of loja should be very sick shouldn't they turns out they get zero diabetes and they get zero cancer whereas their wild type relatives all get diabetes and cancer so they are fat and they're healthy whereas their relatives who don't have the growth hormone signaling defect are all thin and sick so just being obese doesn't make you sick all right and there is a disease on the other side called lipodystrophy so these people can't put fat into fat cells because they don't have it they don't have the fat cells to do it so they end up having to take excess energy and put it into fat in their muscles and in their liver and so they have the worst diabetes of all even though they don't even have any fat stores so in each of these cases it's not about how fat you are it's not about the calories it's not about the Obesity so the notion that calories are the cause of type 2 diabetes just has to be stricken that is not what's going on yes no question fat in the wrong places definitely the problem and yes your food contributes to that but it's not because of calories per se because not every calorie is the same if we're talking about the general population and you lower the BMI I don't like BMI but and you're not doing a dexa scan if you lower the BMI we're just kind of you know we just put this into a simple bucket you know you treat insulin resistance just by losing weight you know you lower your BMI and then you maybe switch to drugs after that to help lose weight well the question is where are you losing the weight from yes are you losing the weight from your subcutaneous fat or are you losing the weight from your visceral or liver fat well it's not going to be one or the other right there's going to be a proportion of each and I think you know if the faster we manage insulin this is how I per you know the faster we can suppress the hormone insulin to augment fatty acid oxidation which would occur at the level of the muscle but also at the level level of the liver and on a ketogenic diet the barometer for enhanced fatty acid oxidation is the production of ketones because that's where ketones come from you have you know the ketogenesis is actually driven very site specifically in the liver by accelerated fatty acid oxidation and that involves carbohydrate restriction it could occur with calorie restriction uh it would be quickly reversed with consumption of sugar and we see that in kids with epilepsy who even get a little sugar from a vitamin that can kick them out of ketosis and trigger a seizure so this seems like sort of the low-hanging fruit kind of if you will but then there are other drugs like glp1 kind of Inhibitors and Metformin that people will Tinker with without before even suggesting you know a dietary Intervention which should really be targeting at lowering insulin and then postprandial insulin too the the spikes in insulin uh it kind of leads us back to an early question I don't know if we addressed it but and it's a question we often talk about in nutrition metabolism class is like why are we not measuring and sweating like I actually you know I spent my whole life and it was only when I started you know studying metabolism that was like okay when I go to Quest I'll I'll put the insulin on you know start looking at that so I think that's a problem because if we see hyperinsulinemia you know you have a type 2 diabetic that gets diagnosed because their glucose is above 126. you know could we have caught that uh half a decade earlier if we were just doing you know once a year or a couple times a year insulin measurement so some comments on that as an endocrinologist I couldn't agree more though that's the Holy Grail right there I totally agree so here's the problem we have this thing it's called the American Diabetes Association and I'm not a fan to say the least I'm not a fan and the reason I'm not a fan are twofold the first is that they State categorically that diabetes is a chronic degenerative unremitting chronic metabolic disease with no treatment and no cure that's what they say go to their website that is what they say none of those things are true and virta health has proven it among others I mean you've proven it too and I've proven it the fact of the matter is that type 2 diabetes is eminently reversible you have to fix the diet but they don't say anything about the diet what they said was give all the carbs you want just give enough insulin to cover it which is also not true I mean yes you can cover the glucose rise with insulin but all you're doing is actually fomenting further chronic metabolic disease so you're fixing the glucose but the glucose isn't the problem the insulin is the problem and the more insulin the quicker you die and that's been shown every 50 ways from Sunday also by a zillion different studies uh United Kingdom perspective diabetes study the Accord study the mural Glitters are study the advanced study Etc so the bottom line is we don't need more insulin we need insulin to work better and the American Diabetes Association is basically saying give more insulin which is why I'm not a fan so Rob what you're saying is the American Diabetes Association does not think that insulin is important enough to measure I think the tide is changing on that because some of the you know data even my colleague Barbara Hansen who we teach the med students has you know she has a lot of non-human primate data that clearly shows hyperinsulinemia precedes that and you know so you're saying hey I never heard anyone kind of put it in those terms but essentially what they're saying is that the American is insulin is not important I mean it's a pretty simple hormone to measure I know there's not like a standardized you know I heard that there's maybe not a standardized test for it and I know it's kind of tricky to measure and I've used a variety of different approaches but I don't know if that factors in too no no that's exactly right so the American Diabetes Association very specifically again on their website says do not measure fasting insulin now why do they say this I think it's the most important thing to measure it's the first thing I measure but they say don't measure it why is that they say it for two reasons the first reason is as you just said insulin assays across the country are not standardized that is true now one of the reasons it's not standardized is because certain assays radio aminoassays will pick up other structures that will be confused with insulin the main one being pro-insulin a pro-insulin as you know is the precursor insulin Pro insulin is a single polypeptide that then has to be cleaved by pro-hormone convertase one in two sites in order to liberate a piece of the peptide called c-peptide and then you have the mature insulin when your pancreas is under duress when it's trying to lower the blood glucose and it can't because insulin resistance is so severe it's got to get every molecule of uh that it's making out into the periphery as fast as it can that program on convert Ace one doesn't have enough time to cleave off the c-peptide and generate the mature insulin and so it will release this immature non-cleaved form called pro-insulin and pro-insulin has about five percent of the activity of the mature insulin molecule the problem is that Pro insulin will get picked up in the insulin assay so when you measure insulin especially within a radio amino acid you're not just measuring insulin you're measuring pro-insulin too and sometimes you'll even measure igf-1 so depending on the assay your assay may not be specific for insulin that is true who cares who cares yeah I mean it's the relative changes over time longitudinally yeah right exactly the point is in any given patient if the insulin is going up it's a problem and if it's going down it's good that's all you need to know within any given patient not how the patient fares against any other patient but within the same patient who cares as long as the insulin assay is being done in the same place each time who cares so that's problem number one with the Ada's stance problem number two with the Ada stance they say fasting insulin does not correlate with obesity that's correct I agree does not it correlates with metabolic health and for all the reasons that we just talked about just a few minutes ago okay because subcutaneous fat is protective well subcutaneous fat is the majority of the BMI so in fact you can be metabolically healthy obese and have a low insulin but still be obese because fasting insulin does not correlate with obesity that's right it doesn't that's not why you draw it you draw it to determine metabolic health and the thing is a fasting insulin will change way before finishing glucose way before glucose tolerance way before hemoglobin A1c so it is a much earlier Arbiter of metabolic dysfunction and by the way this is why fasting insulin is part of levels Health's Labs 2.0 and the reason it's theirs because I made sure it was my decision it's like unfathomable to even think I mean we are accepting that insulin resistance is a problem and insulin is the most important metabolic hormone and that even other investigators and people who teach this subject at medical schools are you know know enough about the data to know that insulin starts to go up before type 2 diabetes becomes diagnosed so it just seems like unfathomable that this is not part of a standard you know that someone needs to step up and put this I mean there's some historical baggage there with the assays and everything but uh but jeez uh so you know it's kind of like what do we do moving forward something's got to change uh to acknowledge this and then I guess most importantly I mean we should probably discuss you know what are evidence based because in school we have to teach about evidence-based therapeutic interventions to treat and also to reverse like what should be taught you know from an evidence-based perspective in my view having done this for 40 some odd years what I say is that we need to get the insulin down any way we can what range so let's talk about like what the ideal ranges should be and what to do once it starts creeping up right so ideally the fasting insulin should be less than 10 Micro units per milliliter ideally the lower the better okay marathon runners who eat well will have fasting insulins of two or three I would say anything less than 10 is fine once you get above 15 you've got insulin resistance and that's sort of like the the break point and if you have insulin resistance you're not going to be able to lose weight until that insulin comes down because that fasting insulin is always there and it's always pushing on your fat cell it's always telling your fat cell more store more and you can't reverse that you can't get lipolysis you can't get the fat out of that fat cell until that insulin goes down you got to get insulin down any way you can now in my life there are four ways to do that diet exercise drugs surgery those are the four ways okay diet is where you start fix the diet fix the diet how do you get insulin down very simple don't let it go up well what makes it go up really only two things refined carbohydrate and sugar those are the two things that make insulin go up fat does not make insulin go up amino acids do make insulin go up but you need amino acids I mean you have 15 protein you can go up to 20 and you know but the the amino acid that really makes insulin go up as leucine branched chain amino acids and so you know branched chain amino acids are what's in corn corn-fed beef chicken and fish so that's one of the reasons why we also say you know uh you know Skip the ultra processed foods because that's basically um you know what corn fed beef chicken and fish is so those foods are high in leucine and leucine is used as a branched chain amino acid supplement for many people who lift weights but I think maybe you have to view this in context right so you're saying if I do blood work and I measure high levels of leucine and I don't work out that that's driving insulin resistance is that what you're saying because you know the fitness community that I'm familiar with they're all about throw as much leucine in as possible in your meals because it's stimulating muscle protein synthesis and uh but you're saying that could may not be a good good idea or in the context of a sedentary person well I was going to say in the contents of a sedentary person so if you're if you're a bodybuilder you know you need muscle and you can't build muscle without losing in fact you can't build muscle without all three branched chain amino acids leucine isoleucine valine they are 20 of muscle and they are essential amino acids you can't make them you have to eat them so if the goal is muscle mass if the goal is bulking up if that's what you're doing then you have to consume them and that's why you know the they scoop the protein powder into their smoothies you know and you know why they have big tubs of this at GNC I I get it I get it and that's okay if you're building muscle but what if you're not building muscle what if you're mere mortal like me you know and you're consuming excess Branch chain amino acids well what happens to them is there any place to store them well muscle but if you're not building it then you can't store it there can you so what happens to the excess goes to the liver liver takes the amino group off now you have a branch chain organic acid like oxaloacetate which then enters the tricarboxylic acid cycle overwhelms the TCA cycle Vmax you know the maximum velocity can't turn fast enough throws off the excesses citrate the citrate leaves the mitochondria for a process called the citrate shuttle now the citrates in the cytoplasm and then those three enzymes ATP citrate liaise acetylchoic carboxylase one fatty acid synthase these three enzymes which we call De novo lipogenesis new fat making take that citrate to acetyl-coa to malonyl COA and then finally to fatty acyl COA which then gets packaged and now you've got triglyceride and that triglyceride either makes it out of the liver in which case your serum triglyceride goes up which is a you know potential nitus for cardiovascular disease or obesity or it doesn't make it out and it precipitates in the liver now you've got a lipid droplet and now you got fatty liver disease and now you got more insulin resistance Rob are you are you saying that this is specific to Lucy Lucian is a purely leucine and lysine are purely ketogenic amino acids and I think valine and isoleucine are maybe mixed gluconeogenic ketogenic amino acids so the scenario that you described because I'm telling you leucine is such a Hot Topic in the fitness Community the scenario that you described in the liver with leucine is that specific to leucine yeah it's specific to leucine but isolucine and valine do it too but leucine you're saying okay leucine is disproportionately high in certain you know food products especially if they're over consumed and you have excess calories then you have a scenario with a surplus amount of leucine and that Surplus amount of leucine same thing could happen you know it's driving you know Surplus calories in the form of sugar and stuff too are detrimental but it's that Surplus amount of leucine that is really uh inish because I you know this is I haven't really heard this that much and I remember reading about it in your book this is work from Christopher newgaard at Duke okay so leucine then it's almost like a biomarker if you have excess amounts of leucine and you're not working out that that's that's really driving and fueling okay yeah I mean interest we don't we don't tend to draw serum leucine levels but um you know you could I just got mine measured so it was uh it was mid to Upper range of normal so um entry but but yeah I do I do eat a lot of eggs and you know meat and things like that so in regards to you know you went through nicely four different sort of scenarios with diet being the low-hanging fruit of that but also in your book you talk about you know the role of fiber too and gut health and you know from you know the the fiber perhaps delaying gastric emptying the phytonutrients and fiber um the the mucin layer of the the gut uh you touch on a lot of different topics you know and I encourage people listening to this to if you want a real deep dive and references and everything check out metabolical so a little bit about fiber because fiber is a contentious topic I don't know why it is but it's a conscientious Topic in the nutrition Community especially from the context of like a carnivore diet where they say fiber is not important with fiber is not essential you have people eating zero fiber and claiming you know that it's curing their autoimmune diseases and things like that so uh so so what's your take on fiber and why is it important if it's important yeah so your intestine is outside your body okay I mean it's inside but functionally the Lumen is outside your body and it presents a barrier okay it's a sewer in there okay and the goal is to extract the nutrients from what you eat without letting the bacteria or the cytokines the lipopolysaccharides get across into the bloodstream because if they get across into the bloodstream then they go via the portal vein straight to the liver and induce inflammation so keeping your intestinal barrier functional and uh optimal is absolutely essential to metabolic health now there are three barriers in the intestine one is physical that's the mucin layer and the mucin layer is this mucopolysaccharide coating on top of the intestinal epithelial cells and that basically forms a physical barrier to the Sewer that doesn't let all the stuff in now the bacteria in the intestine they got to live they got to eat something they eat what you eat but the question is how much did you eat versus how much did they eat if you are absorbing everything early in the duodenum and therefore not presenting anything for them to eat in the jejuna minilium then they're starving those that microbiome those bacteria and they're not they don't they get unhappy and what will happen is if they get unhappy because you're starving them they will eat the mucin layer right off your intestinal epithelial cells they will use it for energy they will Denude your intestinal epithelial cells and in doing so they will then increase opposition of bacteria to the intestinal epithelial cell which you can see on electron microscopy and that can ultimately lead to degradation of that epithelial cell layer and what we call leaky gut and also transport of bad stuff across into the portal system and therefore the liver and generates systemic inflammation so fiber is the food for the bacteria the bacteria will be able to chew it up we can't break the bond of fiber we can't break that beta-glucam Bond but the bacteria can so that ultimate means that fiber is the food for your microbiome and we know that increasing the fiber content of food increases microbial diversity it lets the good bacteria battle off the bad bacteria which is good from an inflammation and chronic metabolic disease and autoimmune disease standpoint so that's one reason then there's the second barrier which is the biochemical barrier okay there are proteins in the intestinal epithelial cells called tight junctions and what they do is they bind cells to each other and don't let stuff get through the pores okay and so these tight junctions present a complete barrier against the stuff in the sewer so it doesn't make it into the bloodstream so those tight junctions have to work now the most famous of the tight Junction proteins are zonulins which are the ones that go defective in the celiac disease well that's if they're immunologically targeted but you can nitrate tight Junction proteins and they will become dysfunctional and allow stuff to seep through also and so what nitrates type Junction proteins will have about fructose fructose nitrates tight Junction proteins so you increase your gut permeability with sugar so that's another problem and then finally the third part of the barrier is the immunologic barrier so as you probably know there are more immune cells in your gut than there are immune cells in the rest of your body all these pyres patches Etc there's I mean basically there's an entire immune system running around your intestine trying to keep things out all right and those immune cells for the most part are th17 cells and those th17 cells are presenting an immunologic barrier and preventing stuff from getting across as well but they get depleted on a high sugar high fat diet and that allows for uh entry of stuff that you don't want to get in either so bottom line inflammation is in the gut and the goal is to control the inflammation there are different things that will control that inflammation so obviously getting rid of fructose which of course carnivores do controlling this th17 cells which carnivores do but fiber is an important one too and yes it's true carnivores don't do that yeah fantastic overview I need to incorporate some of that my lectures but uh you know the things that that we teach that fiber is you know fuels the production uh and I think you touched on it of the short chain fatty acids like butyrate and then butyrate then is one of the primary fuels for the colonocytes so that by increasing the availability of butyrate then which also not only functions as a fuel that it has important signaling properties we're looking at beta hydroxybutyrate yeah and butyrate functions as a histone the acetylase inhibitor has epigenetic function on top of that and uh and actually really helps to preserve that brush border membrane the barrier function uh just by you know its own antioxidant or its own anti-inflammatory effects and functioning kind of as a fuel too but it's interesting that P people for example with crohn's disease and other diseases can be on a fi a diet completely void of fiber and they seem to do well on just eating meat and I would have not predicted that and I don't you know it's more anecdotal reports and and things but I mean there's I think some research now on Carnivore diet and looking at you know uh permeability but it could be just from eliminating things that were toxic or irritating to the gut and triggering a breakdown of zonulin and and the tight junctions and it's just it's not what you're eating it's what you're not eating could be the therapeutic effects right so that's likely true I will also tell you that carbohydrate often makes the wrong bacteria grow so this is work that may be related to Crohn's disease it's definitely related to autoimmune disease this is work from Alan ebbringer immunologist from the University of Oxford and what he showed years and years ago was that patients with Ankylosing Spondylitis a classic autoimmune disease had antibodies against an intestinal bacteria called klebsiella and it turned out that the klebsiella was making the enzyme that we use alpha 1 6 glucosidase now starch as sure the audience knows okay our alpha 1 4 and Alpha 1 6 linkages they are if they're Alpha One four linkages they're amylose which are lungs linear strings of starch and if they have Alpha One four and Alpha 1 6 then they look more like a tree because of all the branching and so that's why glycemic index is important because it chops up the glucose is off the starch quicker because there are more branches so you can absorb it faster Well turns out that Alpha 1 6 is not ours it's the klebsiellers and so when you feed starch to a patient with autoimmune disease they get worse because you're actually generating more klebsiella and more klebsiella means more antibody production against it which then as an anti-idiotypic antibody affects the bone and causes the Ankylosing Spondylitis this is also true for rheumatoid arthritis different bacteria Proteus instead so the bottom line is what we put in our intestine has enormous ramifications for how well our immune function Works based on what we're doing to our bacteria so this is not a little issue this is a big issue and we've ignored it uh in general medicine up to this point and so even another reason why we have to watch the refined carbohydrate in sugar so what you're talking about too would also be termed small intestinal bacterial overgrowth from excess carbohydrates that's that's one issue but I know I teach the the fructose is transported in the gut by the glut 5 and that's in energy dependent mechanism and I and I know that there's some evidence that you know if you bolus a lot of fructose and sugar that it's not it's not purely diffusion it's a facilitated energy dependent Fusion so it could in some ways de-energize the gut in a way like if you drink you know consume a lot of fructose that could cause you know bloating and intestinal basically you're really stressing out the intestinal uh energetic systems by maximize trying to over produce it that's right you're depleting the intestine of ATP and those zonulans are ATV dependent so they're going to become dysfunctional in the presence of excess sugar another reason why sports drinks really don't make sense yeah and I think that's really not discussed that you know these things especially fructose is sort of an energy dependent transport process so if you overwhelm it especially in the context of you know exercising where you have blood flow diverted from the then it's it can contribute to a lot of performance related GI disruption and things like that so since we're on the topic of gut health and I get this question a lot uh it does make sense from the perspective of eating within a restricted window to give your gut a rest time so it can rejuvenate make the stem cells and you know and just kind of sleep and then also ties in with sleep too right uh so sleep being super important uh and also this time restricted feeding as a way to restore gut health and also to lower insulin as fast and as low as possible restricting the feeding window a paper came out two years ago that suggested that time restricted eating was very important but it worked only in those patients with liver fat and that made sense to me I haven't seen a follow-up on that but that made a lot of sense to me because what that suggested was that the reason time restricted eating works is because they're giving your liver a chance to get rid of the fat that accumulated over the previous 16 hours which I think is the right thing to do so I'm for intermittent fasting but I'm four for the right patient I'm not necessarily for it for everybody makes sense yep Rob another topic that I really wanted to cover because I get a lot of questions about this and there's of course a lot of discussion because people want something easy to enhance insulin resistance and facilitate glucose disposal is uh the use of supplements that could potentially enhance so we know about berberine and alpha lipoic acid uh and other things that are on on the market and uh you know there's not a whole lot of evidence behind many of these things at least for insulin resistance but you know in some cases they may work but I'd like to get your uh opinion and experience with these things and patience what you've seen yeah I mean there are a whole bunch of supplements out on the market and they're advertising on TV you know golo and what have you um you know show me the data is the way I look at at it they all work in the dish but I have not seen any of them work in people yet now maybe there'll be a combination that'll work but individual uh components you know they're just no strong pieces of data yet that demonstrate in a randomized controlled trial that the any of these have any specific and durable effects on fixing insulin resistance I mean we have chromium we have alpha lipoic acid berberine as you said turmeric and you know a whole host of other compounds but uh uh you know the reason that they can put them on the Shelf is because you know they're supplements they're quote nutraceuticals they don't have to demonstrate efficacy well I'm a scientist I'm a clinician and you do have to demonstrate efficacy and I don't see it yeah good point yeah I know there's a debate you know with berberine and comparing it to it's like the herbal form of metformin and and some maybe some small studies out there that compare the two um but you know and I've used these things and I think maybe in the context of someone with uh you know used with postprandial glucose excursions it may like maybe knock down the peak of that but but what's it doing long term and are there side effects to it and and and also I don't think anyone's measured insulin you know which we're talking about so I think we just have a lot to learn before these things can be suggested you know for patients to use I agree the Hot Topic now and we're talking about it sort of in class is uh the implications of these glp-1 Inhibitors so they're glp-1 analogs not Inhibitors but yeah I don't think we know the answer to that what we do know is that they cause insulin release that's why they work for diabetes but more importantly they work at the level of the brain stem to actually tell your brain that you're full uh so they are part of the satiety signal they always have been we've known that for a long time but basically we're telling the brain we're full all the time which is one of the reasons for the weight loss is because of the reduction in food intake so whether or not it's a direct effect on insulin resistance or an indirect effect because you're actually getting rid of the things in the diet that are causing the insulin resistance I think is still unknown yeah I mean it's a little bit counter-intuitive because the glp analogs do cause a a release of insulin or an augmented release of insulin so are they working centrally and in in some way enhancing insulin sensitivity where prolonged Administration it's hard to look at this independent of weight loss because that's just you know a side effect of these drugs mostly through nausea and things that are kind of unpleasant more or less right to be determined I guess at this point I don't think we have the answers for that yet thanks for the discussion Rob I've learned a tremendous amount and you just further shown that your Encyclopedia of information on this topic from the clinical perspective from the actionable things that people can do and I just you know commend you for what you're doing and the information that you're putting out your books your podcasts and everything and I just think you're helping so many people through the Outreach that you're doing and I really appreciate that well thank you and um you are uh you know shall we say at The Cutting Edge of this entire you know metabolic Health movement that is now at the precipice you know it is we are we are at the Tipping Point uh but I hope that this has been helpful and useful to the general public in terms of understanding why this insulin resistance phenomenon exists why it's so important why you know we uh as metabolic physiologists focus on trying to understand it and also ameliorate it this is this is where the action is [Music] oh [Music]

Channel: Levels

Views: 407,301

Keywords: metabolic fitness, metabolism, metabolic health, metabolic, cgm, continuous glucose monitoring, glucose monitoring, cgm life, biowearables, biohacking, cgm sensor, cgm glucose monitor, glucose, glucose test, levels, insulin resistance, blood glucose, nutrition, levels kitchen

Id: dFOaBrujDHo

Length: 77min 18sec (4638 seconds)

Published: Thu Apr 20 2023