Dr. Ted Naiman – ‘Insulin Resistance’

Dr. Ted Naiman – ‘Insulin Resistance’

August 8, 2019 100 By William Morgan


all right thanks everybody first of all I want to thank Iver for such a great talk that was awesome my love I’ve ergh okay love you bro Iver just gave my whole talk like slides and everything so anybody wanted to get some skiing and that would be a great time but if you want to hear me beat a dead horse about insulin then you know here we go did anyone catch the CrossFit Greg Glassman talked last year where he talked about the five buckets of death it turns out that anytime somebody dies it could be categorized as one of five things you’ve got up in the top right hand corner thirty percent of deaths toxic kinetic microbial genetic but down in this giant seventy percent of all deaths you’ve got chronic disease and of course the big three cancer cardiovascular disease and chronic neurodegenerative diseases like Alzheimer’s what we know about all this chronic disease is that it’s driven by Seddon tation and malnutrition this is poor diet and lack of exercise and underpinning all of this stuff is insulin resistance and that is why this is such a huge big topic I mean I will never stop talking about this because it’s really that important I just want to say at the top of my talk here that I use home I are a lot in my patients these days this is homeostatic model assessment of insulin resistance this is my favorite way to non-invasively measure insulin resistance to my patients this is something you’ll see most commonly in the medical literature when people are looking at insulin resistance it’s really just your fasting glucose times your fasting insulin divided by 405 and it’s answering the question and how much insulin does it take when I’m fasting to hold my blood sugar and my fat stores where they’re at right now average in this country is 1.75 that’s really a little too high you want to be a 1.0 or lower anything over about two and a half is clearly insulin resistance you could just search the medical literature for Homa IR and any chronic disease you can think of and it’s just a huge linear Association home IR and cardiovascular disease huge linear Association dying of heart attacks huge association cancer huge Association all forms of cancer huge Association I mean it’s just ridiculous Alzheimer’s pathology massive association with insulin and finally just dying all cause mortality and home I are big association there too so this is a really important topic okay so now what causes insulin resistance well we’ve known forever that the more abdominal fat you have the more insulin resistance you are this graph on the right shows insulin levels you’ve got normal in green obese and yellow and abdominal obesity in red so we’ve known that for a long time right but what about this here’s a graph of insulin sensitivity versus body mass index and how do you explain these people way down here they’ve got a BMI less than 20 but their insulin sensitivity is terrible and what’s going on here right well we’ve known for over 50 years that the larger you’re out of a site the more insulin resistant you are right and in fact it’s a perfectly linear Association you’re out of the site’s can expand in diameter about 20 times so if you look at a cross-section of out besides in our microscope they can go from maybe 10 20 microns to 200 microns that means their volume can expand by eight thousand times and as they get bigger they get more insulin resistant and it’s very very linear um it turns out that large outsides are resistant to the antibiotic effects of insulin and it’s harder to shove more fat in there right you can graph out fasting insulin homo IR any marker metabolic syndrome it’s perfectly linear without up sight-size triglycerides go up HDL goes down home IR goes up tinsel in goes up any metabolic syndrome or insulin resistance marker you measure will completely correlate up or down linearly with the size of your adipocytes if you have gastric bypass surgery and you manage to shrink the size of your ateb sites you’ll reverse insulin resistance and diabetes if you lose weight with any mechanism it’s more important how much you shrink your adipocytes rather than how much weight you actually lose in terms of reversing insulin resistance and that’s why people can reverse insulin resistance really rapidly even before they lose a whole lot of weight it turns out that as you get fatter your fat cells can do one of two things you can have adipocyte hypertrophy and that’s where your fat cell gets overstuffed with fat and it’s inflamed and it’s insulin resistant and it doesn’t want anymore fat or or you can have out of the site hyperplasia if you have the right genetics you can sprout cute new little baby fat cells that are very insulin sensitive and they’re happy to suck up more fat and they’re not inflamed and they’re not insulin resistant so not all your fat cells are are like great your ginormous huge overstuffed fat cells are super inflamed they’re sick they’re dying they’re spewing out fat constantly it takes a crap-ton of insulin just shove fat in there the fat doesn’t want to stay in there but your cute little baby fat cells are very insulin sensitive and they’re more than happy to suck up more fat slugs right so you can have two people of identical obesity and the person who’s overstuffed their fat cells and had AB side hypertrophy is going to be inflamed and insulin resistant and it takes a ton of insulin to shove anymore fat in there and the fat is constantly spilling back out but somebody you can sprout new little baby fat cells is going to stay insulin sensitive forever if you have the right genetics and you can just sprout new fat cells this hyperplasia you could be 600 pounds and as long as you have some small fat cells around you still suck up more fat you’re going to be totally insulin sensitive this is about 10% of obese people so there’s this concept of limit of adipose tissue expansion basically there’s a limit to how easily you can get fatter either by sprouting new baby fat cells or expanding the ones you’ve got and once you’ve hit this limit your insulin resistant so fat is typically stored in the subcutaneous first and then it spills over into visceral and then it spills over into liver and muscle and pancreas and blood vessels and you’ve got ectopic fat you know fat everywhere and then you’re horribly insulin resistant here’s a sort of a schematic of how it works you still have your SubGenius adipose first it spills over into the visceral that spills over into liver and muscle and now you’ve got ectopic fat and none of your tissues want any fat or glucose and now your insulin resistant my favorite term when it comes to this concept is personal fat threshold PFT this is a genetic limit to how fat you can get before you just can’t get fatter and your insulin resistance this explains people who are Toph I thin on the outside but on the inside I think dr. Berger mentioned that and these are people who look thin but they completely maxed out there for subcutaneous and visceral and they’re horribly insulin resistance or maybe completely diabetic this is why China and India has passed up diabetes prevalence compared to the u.s. at a much lower body mass index right Personals a threshold on this slide it’s just here to remind me that your giant overstuffed hypertrophy fat cells are literally dying these gray things on the right are dead adipocytes and that’s why you have so many macrophages though these cells are not happy they’re sick they’re dying they’re inflamed the little baby fat cells are happiest clams I love this graph right here it takes a ton of insulin to shove that much fat into an adverse it– and hold it there and to pin it there chronically and that fat is constantly trying to speed back out and that’s why people have maxed out their fat cells just have high insulin 24/7 this is a beautiful illustration okay the best example we have of adipose tissue controlling insulin resistance is lipodystrophy lipodystrophy is a series of disorders where you don’t have any subcutaneous fat or hardly any I have a bunch of patients with lipodystrophy there they’re very unique they have they almost look ripped like like a bodybuilder they have very defined arms and legs as very little subcutaneous fat but they have a lot more visceral fat than you would expect if you do cross-sectional imaging on these people the sub-q fat in red here is very very small but the visceral fat is completely maxed out and almost everyone with lipodystrophy has horrible insulin resistance and horrible brittle diabetic diets all of my lab industry patients really bad diabetes it’s the worst insulin resistance um now you can buy a mouse that has Lipa dystrophy right we found mice that lack subcutaneous fat for whatever reason and we’ve bred them and you can actually buy and sell lipodystrophy mice and it’s a great model for insulin resistance and diabetes because no matter what you feed them they just completely max out so cute a nice fat it all goes to this real fat they have fatty liver they have visceral fat their insulin resistant diabetic just like the humans and we did this amazing study on these lipodystrophy mice where we literally surgically implanted little pouches of subcutaneous fat under their skin and connected to blood supply and you instantly magically cure insulin resistance in these mice look at this black line on top here that’s the sham surgery and you’re looking at insulin levels versus fat transplant surgery on the bottom in white you literally instantly magically cheer insulin resistance in these mice by just implanting sub-q fat in the skin this is kind of the final nail in the coffin of anyone who doesn’t buy into the theory that adipose controls insulin resistance right we haven’t done this exact study in humans I don’t think people would really like that but we do have glitter zones glitter zone in this class of diabetes drug that enables you to get a little bit fatter and it they don’t work that grade that you get a little fatter and your insulin resistance and diabetes gets a little bit better I don’t like that if patients knew how it worked they probably wouldn’t want to take it okay so here’s how it works so far right you fill up your subcutaneous fat then it spills over to visceral that spills over into liver and muscle now you’ve got a copic fat you’ve got five everywhere none of your cells want fat none of your tissues one side your insulin resistant what’s really going on here is your body is at war with itself right none of your cells want fat none of your tissues want that none of them want glucose either none of them want any of this energy and it’s like this horrible game of musical chairs where insulin just gets louder and louder and louder until you finally shove some fat or glucose into whatever cell or tissue is the least insulin resistant and next time it’ll probably be even more insulin resistant and once your body is at war with itself like this the wheels just fall off your wagon and this is why all of these chronic diseases are driven by insulin resistance okay bottom line so far your insulin resistant because you filled up all your adipocytes right you have no more room for fat flux every time you eat a meal it has nowhere to go the fat or the glucose so you’re just completely filled and that’s why your insulin resistant and that’s why your hyperinsulinemic and you have high insulin all the time but that’s just this is just the beginning I mean the big question is why did you fill up you’re out of sights right why are they all full is it because humans shouldn’t eat fat because we’re should be low fat vegan is it because you’re just a glutton then you eat too much right No you filled up your fat cells with fat because you suck at burning fat because you eat too much glucose an important rating factor for obesity is reduced fat oxidation increase metabolism carbohydrate this is then brought about by shift towards the body’s preference for the oxidizing carbohydrate rather than fat resulting an increased deposition of body fat you’re eating carbs and glucose you’re not burning fat it accumulates you fill up your adipose turns out everybody with obesity insulin resistance ectopic fat has defects in mitochondrial metabolism of fat everyone in this situation has trouble metabolizing fat in the mitochondria obesity insulin resistance type 2 diabetes and aging all associated with impaired skeletal muscle oxidation capacity reduce mitochondrial content and lower rates of oxidative phosphorylation basically you’re not burning fat in your mitochondria mitochondrial now structure function are altered in insulin resistance defects of mitochondria are believed to contribute to impaired fat oxidation and to the accumulation of intracellular lipid intermediates which contribute to the pathogenesis of insulin resistance mitochondrial dysfunction the elderly and in the offspring of diabetic patients is well documented so basically you’re not burning fat well it accumulates you fill up your adipose now only your mitochondria can oxidize fat right it’s all happening the mitochondria and let’s talk about them for a second every nucleated cell in your body has mitochondria in it right and they’re just constantly turning your food into ATP which drives everything in your body and the turnover rate is just enormous every single day you make your entire body mass in ATP molecules if you’re a 70 kilogram male you manufacture 70 kilograms of ATP molecules every day which is ridiculous the the turnover is so fast that at any given second in time you only have six seconds of ATP left in your body or in fact that is what on cyanide does cyanide poisons your electron transport chain and you can’t make ATP in your dead six seconds later so these suckers are constantly performing metabolism and there are three things going into the cell that your mitochondria can burn glucose FFA is free fatty acid dutchess fat or amino acid now amino-acids is sort of a minor player most of the time people are oxidizing glucose or fat and glucose and fat are oxidized reciprocally so anytime you’re bringing more glucose you’re burning less fat and more fat you’re burning less glucose right now you can actually tell what the fuel mixture is in every mitochondria and every cell of your body by measuring a respiratory quotient right you actually breathe out a lot more carbon dioxide if you’re burning glucose in your mitochondria then if you’re burning fat you breathe out less carbon dioxide and because they’re reciprocal you can actually calculate it out if you have a highest respiratory quotient of 1.0 you’re breathing out the most carbon dioxide and you’re burning pure glucose in all yourselves all your mitochondria if you have the lowest respiratory quotient of 0.7 you’re burning pure fat when you’re making the least carbon dioxide and because it’s reciprocal you can just look at that line and tell exactly what you’re feeling extra is based on your respiratory pollution the fascinating thing about respiratory quotient is you could take two people in this room and measure their baseline respiratory quotient and whoever has the higher one meaning they’re burning more glucose and less fat at baseline will literally be significantly fatter three years down the road that’s what this study was measured based on our cue whoever is burning more glucose and less fat is literally going to be sadder later defective fat oxidation remains the likely explanation for this point yeah I couldn’t agree more it turns out you can take two people of the same obesity whoever has the higher or whoever has the lower respiratory quotient meaning they’re burning more fat is going to be metabolically healthier they’re going to have lower insulin let’s metabolic syndrome if your insulin resistant you have a hierarchy if you’re diabetic you have a hierarchy if you’re obese you have a higher RQ if you have family members with diabetes you have a hierarchy anything bad metabolically you have a higher R Q and that’s just not good there’s also this concept of metabolic flexibility metabolic flexibility is the ability to drop your RQ if you’re eating more fat so if I’m thin and healthy and I have tons of really good mitochondria and I’m good it brings out if I eat a high fat diet I will immediately drop my our cue and burn more fat also if I’m fasting and I’m just living off of fat my RQ goes way down people with poor metabolic flexibility can’t do that they if they eat a higher fat diet they end up just storing that if they if they are fasting they have a struggle to meet their metabolic needs just from that you can draw a graph of metabolic flexibility and insulin sensitivity and it’s just a straight line right now okay this is a really important point if you’re on a mixed diet and you eat a bunch more carbs you will immediately raise your RQ in anybody you can drive up anyone’s RQ by feeding them more carbs and glucose because glucose completely controls metabolism and substrate oxidation it has to because you don’t have anywhere for that glucose to go so if I feed anyone more carbs there are Q goes up the same isn’t true on a mixed diet if you’re eating just a regular standard American diet and you add more fat to it you just throw stick of butter on top you will not drop your RQ you’ll just store all that butter I’m reading in this box here excess carbohydrate results in increased carbohydrate oxidation a lower fat oxidation increased our – this is not the case for fat excess fat intake on a mixed diet does not stimulate cell oxidation but enhance its fat storage um that’s because glucose rather than fat completely controls substrate oxidation right glucose control oxidation and here’s why glucose has to control metabolism and substrate choice professor flat drew this diagram this hydraulic mechanical model of metabolism like 60 years ago and you’ve got this giant fat reservoir over here on the right that’s 200 times bigger than this tiny little glucose carbohydrate reservoir so when I dump a bunch of fat into the system nothing has to change I don’t have to change my fuel mixture I can do that all day long on the other hand you only have a tiny little carb glucose reservoir it’s it’s really small you know you can have what 5 grams of glucose in your bloodstream maybe a couple hundred grams and your liver and your muscle and that’s it so when you dump in a bunch of carbs in blue coats you literally have to switch your metabolism over and burn more glucose I’ve made a fancier little hydraulic model of metabolism here and again you’ve got a fat reservoir on the right so when you dump more fat in nothing has to change but as you add carbohydrates and raise glucose you literally have to switch your metabolism over and burn more glucose just to get rid of it you just have no other choice that’s how it has to work in fact if you need enough carbohydrates in glucose you literally have to convert it to fat via de novo lipogenesis to store it and get rid of it only when carbohydrates and glucose are absent can you switch your fuel mixture over and burn fat again there’s another concept here and that’s glucose hysteresis there’s an inertia to your metabolism a general feature of metabolic regulation is that substrate typically induce the metabolic machinery necessary for their own metabolism what does that mean if you’re good at burning fat you have epigenetic changes that up regulate your fat burning pathways and you’ll stay good at burning fat for a period of time it’s like an inertia to your memory to your metabolism on the other hand if you’re a glucose burner you operate you have epigenetic changes you have to regulate glucose burning and you sort of stay good at that that’s why it takes you know one to three weeks to switch over from a high carb diet to a low carb diet ok this this study sums it up so well I’m just going to quote directly from it the development of insulin resistance is the impaired ability of skeletal muscle to oxidize fatty acids as the consequence of the elevated glucose oxidation and the situation of hyperglycemia hyperinsulinemia and the impaired ability to switch easily between glucose and fat oxidation and response to homeostatic signals the decreased out oxidation results in the accumulation of intermediates of fatty acid metabolism glucose around you can’t burn fat the fat accumulates now your insulin resistance this concept of metabolic flexibility goes all the way down to the mitochondrial level so here’s your mitochondria with the two inputs glucose and fat and a healthy mitochondria can easily flex back and forth glucose fat glucose set but if you have an inflexible mitochondria you’re one of these damaged mitochondria it’s really bad at doing that it really struggles what’s going on inside your mitochondria as you’ve got glucose and long-chain fatty acids the to input into the cell right glucose inside glucose goes into the mitochondria and when you dump in a bunch of extra glucose you have increased citrate and citrate gets exported to the cell and because there’s extra citrate your body knows it’s time to make fat instead of burning fat so you’re still going to make that it converts it into melon Alcoa that literally blocks carnitine pummelled transfers one CPD one and fat actually physically cannot enter your mitochondria to be burned when melon Alcoa is elevated in other words when you’re making fat you don’t want to burn fat that would be wasteful so all your fat gets rerouted as triglycerides to be stored I’m reading the caption here mechanism of inhibition of fatty acid oxidation by glucose basically melon okole inhibits the entry of long-chain fatty acids into the mitochondria this effect reroutes fatty acids toward the certification so when there’s a bunch of glucose present you can’t burn fat here’s another illustration the same thing you dump in a bunch of glucose you export citrate melon elko a first committed step to making fat so you don’t want to burn fat and you block entry of fat into the mitochondria and all your fat accumulates as triglycerides to be exported and stored what’s really going on here is your body is way too efficient to make fat and burn fat at the same time so when you dump a bunch of glucose into your cell your body knows it’s going to make fat right fatty acid synthesis and melon elko is the first committed step to fatty acid synthesis block cpt 1 because you don’t want to be making fat on one side here on the right and then burning fat on the other side but just that would be a futile cycle right that your body’s not going to do that that’s why glucose inside our burn reciprocally all the way down at your mitochondrial level because when you’re burning glucose and you’re going to be making fat you don’t want to be burning fat we’ve proven that this happened here’s a brilliant study that literally proves us they are measured oxidation of glucose and fat in the mitochondria baseline they infuse people with glucose and insulin and bam immediately glucose oxidation goes way up fat oxidation goes way down this is just how it works this is why if you eat carbs all day long you’re not burning fat any fat at all rather the intracellular availability of glucose not fatty acid is a prime determinant of the substrate mix ie glucose versus that is our size for energy in other words you dump in glucose you literally have to burn glucose not fat that’s just how the whole system works here’s a cuter picture of it right insulin binds to the cell up in the upper left-hand corner the glut for transporter goes to the service glucose comes in it’s converted to nominal Co a because you’re going to turn it into fat so that blocks CP t1 so you don’t burn any fat and then all your fat accumulates there in yellow now what let’s say I eat just a diet of pure glucose right I’m some crazy low fat vegan and all I eat is just sugar I’m on a sugar diet I’m on some sort of kempner rice diet okay I only glucose but I don’t overeat and I’m careful with calories yes I’m blocking entry of fat into the mitochondria but I don’t eat any fat so fat isn’t accumulating I actually won’t gain weight you can eat a diet of pure sugar and you will not gain weight you’re horribly locked into glucose dependence so I don’t recommend it at all now if I dump a bunch of butter on top of that oh yeah well then I’ll gain a thousand pounds right because you’re blocking oxidation of that with all the glucose and then all the fat accumulates and next thing you know your insulin resistant and in fact what happens is your cell sees what’s going on here all this fat is accumulating and the accumulated fat shuts off insulin signaling so the blood floor transfer goes back inside the cell and your cells refusing glucose right your cell doesn’t wanting more glucose look at all this fat that accumulated your cell doesn’t want glucose right your cells smarter than you are what could you do with your diet when your cell doesn’t want more glucose I can’t think of anything but that’s probably something now if we take it even one layer deeper and look at the electron transport chain which we saw earlier thanks to dr. Eid electron transport rates so you’ve got you know you’re pumping all these protons across this membrane it’s like a little battery that powers your ATP synthase motor and it spring loads all your ATP molecules bla bla bla when you’re just doing beta oxidation of fat everything runs really smoothly your level loading your electron transport chain the membrane potential is perfect everything’s nice your body is designed to just live off of stored body fat so just burning fat has to be worked perfectly but you dumped a bunch of glucose on top of this and you overdrive plus one and you get too much membrane potential in too many reactive oxygen species and you literally get something called glucose toxicity in your mitochondria you can basically bust those suckers by trying to burn sugar on top of beta-oxidation okay let’s take this into the real world right real world here’s a company that specializes in obesogenic rat chow this is what they do they make an obesogenic rat chow that people pay money for this stuff it’s supposed to make you as fat as possible as fast as possible I’m talking visceral obesity liver fat insulin resistance diabetes the whole thing this this obesogenic rat chow is very low in protein it’s high in fat and carbs it’s really high in carbs if you look at the ground it’s vaguely eerily similar to the standard American diet it’s pretty sad right yeah so we know how to make we know how to make both animals and healings as fat fat as possible as rapidly as possible it’s sugar and fat together right the obg undergrad Chow is a refined process concentrated fat and sugar mixed together it’s usually cornstarch and vegetable oil or something like that but it’s low in protein low in nutrients it’s just sugar and fat and that is how you get anything as fat as possible as rapidly as possible you can feed humans donuts it’s pretty much the same thing so we know how to get the very highest insulin levels the most overfilled out of the sides the worst body composition the highest fat mouth the lowest lean mass you do that by feeding high carb and high fat right and you keep everything else low sugar and fat this is a absolute worst we also know how to get your adipocytes the very smallest and how to get the very lowest infant levels and we note that thanks to natural bodybuilders and fitness models and aesthetic athletes and they accomplish this by either going well they usually go high in protein very low in carbs and sort of low issue in fat we have studies that document how this is done this is female fitness competitors they achieve this low body fat reducing carbohydrate intake while maintaining a high level of protein resistance training and moderate fat so it’s basically very low carb high protein moderate fat and lifting so we also know what calories got dumped into the American diet to cause the obesity epidemic over the past six years right grains oils and sugars this is flour sugar and oil or as I call it the processed food trifecta right flour sugar and oil in 2010 60% of all the American calories were flour sugar and oil we’re literally eating obesogenic rat chow and we’re just maxing out all our fat cells right ok I’m almost done I just have like two slides left I just want to point out that your adipocytes are there for daily fat flux you’re out of cites are supposed to expand during the day when you’re eating shrink at night when you’re fasting and living off of stores that and as long as you have plenty of room for fat flux you know as long as you’re out of the sights are empty enough that you have plenty of room for this flux everything’s fine that’s how it’s supposed to work there’s also a seasonal component to this fat flux piece all energy on earth comes from the Sun and the summertime there’s more sunlight plants make more sugar herbivores eat more sugar and they get fatter carnivores eat more fat from sadr herbivores and they get fatter omnivores like humans come along we more sugar and more fat and we get really fatter the classic example is a bear right this is a classic omnivore and these are actual bear out of the site’s in the summer they’ve got sugar they’ve fruit and honey and berries and they’re also eating more fat because the animals are salary in the summer so they’re any more sugar in fact they’re expanding our episodes they become insulin resistant and then in the winter time everything changes right no more glucose at all there’s no plant sugars at all in the winter time so they’re just eating protein in fact there’s also less fat because animals are leaner in the winter time so that’s really the end of my talk but I just want to end by saying that in this country we’ve made it summer time the peak of summer time 24 hours a day 365 days a year is just sure if that together day after day after day we’ve all maxed out or out of the site’s half the planet insulin resistant and I think it’s time a lot of us made it autumn you know we’re there a lot less plant sugars and way less glucose so we can finally burn some sod for a change and for some of it it’s may be time to make it the dead of winter where we know glucose at all and you know maybe even less fat so yeah that concludes my talk yeah [Applause]