 Hello everyone. It's it's good to be back. It's been a long time I think I spoke with the one in Denver or not a Denver in Boulder a few years ago But that and the very first one are the the only ones. Can you hear okay? Am I closing up to the microphone? My wife's down here giving me hand signals Okay, so we're going to talk about Incritons and the evolution of the GI tract Like Aaron said a lot of people don't know about Incritons how many people are aware of Incritons and what they do okay a few hands go but most people don't so it's going to be a Pretty interesting thing because they're powerful little hormones that that do a lot and we're going to learn how we can modulate them Ourselves and and have good results from that. So let's get going First disclosures. I don't really need to do that Because I'm not giving a CME talk, but I don't really have any disclosures. I don't get any money from anyone Unfortunately, so If you want to copy down this this is my website protein power calm backslash Ahs 21 I've got the bibliography for this talk on there So you don't have to furiously scribble down if you see a paper that you want to remember Because you can just go to that side and it's all there And I actually missed out on a couple that I'm gonna have to go back in and add later because I forgot all about them but most of them are there the Only paper that I've ever written scientific paper I wrote with my wife and Lauren Cordain and a lot of you probably know back in the early 2000s and it was about hyperinsulinemia the disease of civilization and in that paper we talked about in pretense gip and GLP won and I was kind of interested in them at the time but for whatever reason I got off on some other track and and didn't really get back to them and A few years ago. I had a friend from Hungary named Gabor er dosi So you may follow him on Twitter and he gave a talk on increased and Europe somewhere I think in Hungary. I mean Hungarian, but the talk was in Europe. I think it was a hungry But anyway, it was a it was a great talk and it sort of reinvigorated my interest and Creighton's and so I am Kind of ripped off part of his talk and added some of my own And I went ahead and put his talk up on the page on my website So you can see that too because it comes at it from a little different perspective Anyway, what are in Creighton's in Creighton's the the one the main one we're going to talk about a gip Lukas dependent insulin insulin ootropic peptide, which is a mouthful So I'm just going to call it gip from now on and it has a it has a Host of functions that we're going to get into in a little bit more detail later The other one is GLP one Lukagon like peptide one It's one that more people are familiar with because a lot of drug companies have gotten into this because they found out that they Can make drugs that affect this this increase in hormone and treat diabetes with it and so Since it takes drugs to do that we can deal with gip ourselves I'm going to spend most of the time talking about gip, but you can see that What the the Lukagon like peptide does it does a bunch to including increasing insulin sensitivity and Increasing increasing the output of insulin, which is why it works better to lower blood sugar and diabetics So if we look at the GI tract this graphic of the GI tract Gip is produced in cells called K cells that are in the in the proximal in the upper end of the GI tract So when food basically carbohydrate foods and lipids go through there It stimulates gip and we'll see what it does in a second in the distal GI tract That's where the GLP one lives these all are made in these cells called either K or L cells Depending on what it is. Some people think it's the same cell It just produces a different hormone depending on where it is in the GI tract but these these little cells when Glucose or carbohydrate or lipid go by them and they get in the brush border It stimulates the release of these things into the bloodstream which travel to the pancreas and do their thing And you may think that these are really nothing deals And this is a minor issue that I can assure you that it's not and people have suspected that there was something to this as far Back as 1880 and then another group kind of worked on it in 19 early 1900s around 1902 And they didn't get anywhere and wasn't really until 1964 the University of Colorado at Denver when people Really got a handle on the power of increased And what they did was they they took Patients and they gave them oral glucose just a standard oral glucose tolerance test Like probably most of you have had some time or another and you see the glucose curve going up and coming down And then they took these same subjects And they gave them IV insulin I mean IV sorry IV glucose To mimic the glucose curve that they got from an oral glucose tolerance test And then here's where it gets interesting They measured insulin levels and what they they found out when they did that is when they measured insulin levels based on The IV glucose Levels which were the same remember it stimulated the same curve as oral glucose But the insulin response was really muted And then when they gave them When they looked at it the other way With the glucose so this is glucose that you're seeing now the insulin response to IV glucose When they looked at it with the oral glucose tolerance test it was like that So that is a huge difference and that's called the cretin effect It's it's a mega difference And so the the food going through the upper gi tract stimulates this huge insulin response And if you believe like I do That your health is kind of a function of your overall lifetime area under the insulin curve and it pays to keep insulin down as much as you can These become really important. And so we're going to look how uh learn how we can modulate them a bit Uh And as you see I just put up the glucose tolerance there They're the same the glucose levels both IV and oral but a mega difference in insulin response Now this is a guy named Theodosius Dubjansky who wrote a paper back in 1973 called nothing in biology makes sense Except in the light of evolution and the whole paper is about that But he sums it all up in the title of the paper Which is that and I always try to think of things from that perspective when I see things that are a little bit unusual in a study I think you know, what does that mean? What's the evolutionary basis for that? And of course the evolutionary basis for insulin is that it's a storage hormone and it allows us to Not have to eat constantly we can eat a little bit and insulin stores the food away But where do cretins come into the whole picture? Well, if you look at In cretins they're along the gi tract and back in evolutionary times I mean back when we were not recognizable probably even as mammals You can see those little yellow spots and those were the cells That basically became the pancreas and they were in the lumen Of the gi tract Now the gi tract is really outside your body is you think of it as inside your body But it's not there's a hole in one end and a hole on the other end and food travels through And if you eat a penny it's going to come out the other end Maybe a little the worst for where but it's going to come out And the gi tract works on food. So these things were located in the wall of the gi tract and when But it created a little bit of a hazard because since it is outside the body They were subject to toxins that may come through and if you wipe out these cells you're in trouble So ever over evolutionary time These things migrated away from the lining of the gi tract and became The pancreas that was isolated from the gi tract But the cells can still send signals to the pancreas to let it know that food's coming in so the pancreas can respond properly And that's and this axis it's called the enteral insular axis that sends these hormones to the the pancreas The this is a little bit better diagram You can see the lumen and the green cells are the insulin producing cells and they Evolved into this where they had bile ducts and little cells around that and they ultimately evolved so that they formed the pancreas Now when you when you look at at what Gip does it has effects on the brain and increases insulin secretion biosynthesis increases beta cell proliferation keeps beta cells from dying It didn't say in this slide that I ripped off, but it also increases glucagon Which is one reason people don't like to use it or haven't looked at it closely for modulating diabetes It increases lipogenesis, which is not necessarily good if you're trying to lose fat But importantly it works on bone formation and increases bone formation and decreases bone resorption And this is important in hospitalized patients. You all know what tpn is total parenteral nutrition When patients can't eat they they they can't even be fed with the feeding tubes So they have to be fed IV and they're fed this nasty stuff called Entrolipid that has lousy fats in it and there's some protein and there's some vitamins But it keeps them going But these patients have bone loss because there's no food going through the upper GI tracts and they get no gip So even if you exercise them into all the things that you can to Increase their bone health they get bone loss because they don't have gip. So that's an important separate function of gip Then just modulating insulin But it helps insulin Kind of get set up for storage and here's some people who stored fat pretty well And fat is is basically a battery for us And the last statistics I saw were from 2012 but somebody sitting down and watched how long people ate And people eat 1.1 hour at least they did in 1912 1.1 hours per day And that doesn't mean that you only have a meal for 1.1 That's the time you actually spend feeding your face when they did that You know, you might go to dinner and it's two hours But you really just spend 1.1 hour based on this data Feeding your face and in 1.1 hour you can go all day long You couldn't charge your tesla for 1.1 hour and have it run all day. So it's really a pretty efficient mechanism In fact, it's so efficient that if you uh, if you take A 70 kilogram male who isn't all that big it's about 160 pounds And he's got enough stored fat to walk from miami to new york I might be the little the worst for where when he got there But he could still make it based on the fat stores The guys you saw in that last picture could probably work walk to peru and bag But it's it's a really effective means of fat storage Now let's get into oh, sorry about that Too quick on the trigger. Okay. Now. This is an interesting study So now we're going to get into to what these ingredients really do And this is a study that they use the same subjects as their own controls And they started out and they had these subjects eat a pound of apples And it took them 15 16 minutes to choke down a pound of apples And then they gave them some time some wash out time and then they gave them apple puree Aka applesauce That the apples were you know made into applesauce and then they gave them the apple juice equivalent And then they did it slow and fast So in the fast one they just wolf down this applesauce or drink the juice as quick as they could And in the slow one they made them stretch it out over the length of time that it actually took them to eat the apples And so you can see that in all this that the glucose doesn't change much And if you look at that the glycemic index of apple juice is 41 the glycemic index of an apple is 38 There's not that much difference now if you've read any of my stuff You know, I'm not a big fan of the glycemic index this makes me even less of a fan But the glycemic index shows that these should have about the same Blood sugar levels and they do But when you look at insulin levels, you see a huge difference and ignore that thing over on the side because the way this paper is written It's kind of screwed up but the the So this is a fairly narrow range This is insulin equivalent You can see the major differences in insulin and that big peak on the top Is the apple juice and the peaks in the middle or the apple puree and the peaks down on the bottom are the apples themselves and so what you can That's the juice and that's the apple so what you can see for that from that It's when the structure of the food is broken down Even though it's the same amount of carb the same amount of sugar essentially The increase in response is much different So this is one of the things that makes me a little iffy about and we're going to see a few more of these Looking at different things makes me a little iffy About people crowing about how great they are on a on a continuous glucose monitor, which I myself have worn for a few months But because you can see what the glucose is and right here You don't know what the insulin level is so you can be eating something that that doesn't really affect your glucose much But can have a real whopping lot of insulin So this is uh, this is done with apples. Now this next one is particle size versus glucose and insulin response and they did this with fine flour and coarse flour And whole grains and cracked grains and you can see the same thing. There's not much difference in glucose response but there's a A pretty huge difference in insulin response just based on the integrity Of the grain whether it's ground or whether it's cracked or whether it's a whole grain Same amount of carbohydrate same glass semi-candex just a big difference In the grain and you can see down here the area under the glucose curve Almost doubles when you have the wheat refined Kind of hate to be old If here's another interesting one. This is a wheat bread A whole kernel rye and then the thinking was that it's the fiber in there that kind of blunts the increase in response So we're going to take some of this whole kernel rye and we're going to substitute beta-glucan for it and beta-glucan is a soluble fiber And then you've got this whole meal pasta and we'll see what happens there Well, what ends up happening Is that the insulin level runs the highest of course with the wheat bread Which is ground, but number two is the beta-glucan bread So it didn't make any difference at all anything it made it worse So it's not really a function of fiber that causes this incretin response or this incretin blunting with uh, the whole foods And you can see over there that What is that? That's the oh, that's the incretin response itself You can see the gip went way up with that And that's the gp went okay Now we can look at this one in this god. It's the same one. What's going on? I hit the wrong bell What they say about it is that they suggest that the structural And compositional properties of fiber play more of a role in the regulation of the insulin response And does the amount of fiber consumed because the rye bed and beta-glucan contain more fiber than did the whole wheat bread And so basically that's a roundabout way of saying that The fiber didn't do it. It's the structure of the grains the president showed Study showed that the lord insulin response was not dependent on the type of cereal consumed Because pasta made from wheat and bread made from rye lord insulin responses as well It's a functional a function of the structural integrity of the food. Now. Here's a great paper This is jerald raven syndrome x guy He got into this back in the 1980s and wrote a bunch of Handful of papers on it. I really like this one because he used white beans and DC means damaged cells you see means undamaged cells and so what he did on the left these are undamaged Kind of starch granules within the bean and on the right hand slide The or the right hand graphic those have been crunched up mechanically So that the starch granules which you can see over there have escaped So it's the same exact bean Same glycemic index same everything and you get essentially the same plasma glucose response You should get a markedly different insulin response So just from damaging just from processing the food And this is a this is a study that shows the decrease in fiber content over time And if you look at that the black dots are carbohydrate intake Over time from all the way back around 1900 I'm not real crazy about this slide because we got a lot of food wastage now that we didn't have then But nonetheless You can see that fiber has has dropped off dramatically and not that fiber Itself is is a a good thing that stops anything But the fiber is basically a proxy or a surrogate for Food processing so when you get the lord fiber ratio to total carbohydrate ratio You know that you're eating more processed foods And it's interesting looking at this over time because the green line up there that just went up That's during world war two so you can see that they were starting to eat processed food I mean world war one starting to eat processed foods before world war one Then when the war came and you had rationing and all that then they started eating unprocessed foods Then when the war was over and you're back into the roaring 20s here came the processed foods Then world war two came on and bam you're back to unprocessed foods And then from that point on it's just been a slow slide to more and more and more processed foods Now let's take a look At what happens what's the the incretin response to lipids now there's a response An incretin response to proteins, but it's not very much Even if you hydrolyze the proteins, you know kind of like pre-digest them There's not a big incretin response to proteins But there aren't a lipids and it's interesting because this study is done What you see on the left is basically the same thing that they did with glucose. They had people drink Intra lipid Which I can't think of anything worse, but anyway, they drank intralipid and they got an IV And they did it just like they did before they they drank it They measured their tribe blood triglyceride levels Then they gave them an IV amount that would mimic that and then they looked at what happened and you can see That there's not a a big response Uh in glucose Which you wouldn't think And there's not even really a big response and free fatty acids And what uh what you see though Is that when you look at gip It really runs it up So when you take lipids it runs up your gip. Those are the dark Dots and the lower ones are the IV lipids So it really runs it up and if you look at glp one it runs it up too And if you look over here you notice that the uh that the the insulin is elevated a little bit So fat does elevate insulin levels And why does fat elevate insulin levels you always hear that it doesn't but it does elevate insulin levels because Your body's trying to store and it's got to have insulin to store it And it also elevates glucagon. You said well, why would it elevate glucagon? Well, it elevates glucagon gip does because if you run insulin up When you're not taking any carbohydrates, you're going to become hypoglycemic So you have this little spurt of glucagon that helps you maintain Your blood sugar level. So it does both of those with lipids Now this is a really interesting and kind of weird study They took I think nine how many there's no six obese males And they put them on a diet and I mean a real diet they fasted them for three weeks And under supervision and they lost 10.8 kilograms, which is what 23 24 pounds in three weeks And what you what you see on this is that the uh that the god Is that What they did if you can see the lines above they gave them ibic glucose And then they gave them oral fat and you can see that the oral fat had the highest response Really of glucose and of insulin and almost of everything. So glucose in the presence I mean fat oral fat in the presence of glucose Really runs your insulin levels up and even can run your blood sugar up And if you look on the right, this is after they had lost weight You can see how when they lost their 25 pounds or so in six weeks that they had a sort of a moderation of that effect Now what aggravates me about this study is I wish that it had gotten six normal people and done it too So that we could see what a normal is and what a Obese one is and then what the one is where they've lost the weight But you can definitely see that uh that losing weight losing fat modulates all these responses These people drank corn oil which god bless them Uh This is uh, this is an increasing response to mixed meals. I'm not crazy about this study because it's a uh The what do you call that thing god? I just want to blank on it A clamp. Yeah a glucose clamp study, which is non physiologic So I'm not really crazy about those but what they did is they had people eat sandwiches And made with butter and dried meat Uh, and so they clamped it so that their glucose stayed the same And then they looked at what happened to the insulin response and when they ate the mixed meal with the sandwich The the insulin loving the insulin levels really went up But when they just the butter they still went up because in the presence of glucose, which you get with a clamp Fat oral fat makes your blood sugar make your insulin go up and They had when they gave them the meat it went up a little bit Like I say dried proteins as a lot. I mean dried meat is a lot of protein and protein doesn't have a big effect on ingredients. So that's interesting from that perspective And you can see on this uh, what happened with the uh, god, I can't even read this Oh, that's a glp one and then that's the gip But you can see what the gip really went up in the air with the mixed meal under this clamp study And when you look at the area under the curve, you can see that the area under the curve with the mixed meal Is about three times what it was with just the dried meat and of course That's the increting effect right there Now this next study is one of my favorite studies of all times and I liked it so much. I actually took the time to Do it to make it legible. So you're not reading these black lines in a journal Usually I haven't either the time or the will to do this, but I love this study so much that I did And what this is a mouse study and it's c 57 bl mice which are kind of Metabolically broken anyway, but it doesn't matter in terms of this study and they fed these mice a chow diet And then they fed them a high-fat diet and this is weight gained along the bottom and Or I'm sorry body weight on the top and time of feeding along the bottom So you can see they gained much more weight with a high fat diet and they gave them a western diet And it was kind of intermediate Now most people would have just stopped there and said well That proves that a chow diet is best a You know a A high carb low fat diet is best at least at least for mice. So that's That's good, but this reminds me how many people have heard Richard Feynman's lecture about cargo cult science God if you haven't you ought to because he has a story about a guy Trying to learn about rat running in a maze and all the different things He does to figure out how the rats find the right door and he just keeps going and going and going until he finally realizes It's the sound of the floor and he puts sand on it and then the rats are confused and can't do it But it's just it goes to extraordinary links in that to come up with the answer Whereas most people would have stopped early on and this most people stop here But these guys took it one step further and what they did was they ground up the food They completely grounded out all these different foods into a powder and then when they looked Here was the chow diet Here was the high fat diet And here was the western diet So a huge huge differences made in the structural integrity of the food And I got to go fast. I've been getting the sign here This this is pretty interesting too. This is the japanese day. They had, you know, vegetables Carb and meat and they should have done this in six different studies But they chose these three they had the potential to do six and they gave them at different times in different orders And what they discovered is that if you if you look at the response The the lowest insulin response or I guess is that glucose? I can't read from over here I think there's another one. That's the insulin response But the lowest insulin and glucose responses came when they gave the carbs last the vegetable first and the and the meat in the middle and Another study looking at grayland, which is the hunger hormone and they did this with the sandwich broken down to its components The blue is if they eat the carbs first and you see it goes down and then it goes back above baseline So those people are hungry the full sandwich or the Eating the carbs last kept kept the line low And so the you know The take-home message from this is life is short. Do not eat dessert first No no Now we know that that Glucose fluctuations influence what happens to foods that go down Secondary to gip Here's a doctor friend of mine that sent me this he had patient that came in that had blood sugars all over the place was diabetic You can see the date on this thing is back in january 2018 Put him on a mainly meat very low carb diet in the very next week You can see the glucose excursions went way way down So if you keep your glucose down your excursions down, you're not going to experience Just like these overweight guys did the fasted for three you're not going to experience increase in effect as much And i've got to mention this stage just because kevin hall did and it got a whole bunch of attention And he put people on an ultra processed and unprocessed diet and you can see that the They gained weight on the ultra processed and lost weight on the unprocessed These were same people using their themselves as controls And the thing that makes me Question this is if you look at the top and you see the glucose response It's about the same what you'd probably expect that but understanding what you do about in cretins now You look at the bottom and that doesn't really make sense You've got this little bit of insulin response, but not nearly like we've seen in all these other studies and so the The And then I read a press release of the study And this is an ultra processed breakfast might consist of a bagel with cream cheese and turkey bacon That's the ultra processed while the unprocessed was oatmeal with bananas walnut and skin milk If you were given an unlimited amount Which would you eat the most off and i'm not so certain that the uh that the bagel with cream cheese and turkey bacon Isn't less processed than the other one, but anyway, that's just an interesting study And i'm going to skip over this because you don't need to talk about it I'm getting the sign of it running out of time I want to go through the take-home lessons of this whole thing And the first one is that if you want to lose weight and you want to improve your health It's pretty obvious what you need to do. Don't eat Which this Brings to mind a conversation my wife related to me that she overheard in the women's locker room of a country club We used to belong to When these she heard these two overweight women talking one less overweight than the other one The overweight woman says to the lesser overweight woman. Wow You look great. How did you lose all that weight? And the woman says I quit drinking wine and the other one says well, that's just too extreme So if you find not eating too extreme then don't eat carbs If you find not eating carbs too extreme don't eat processed carbs If you find eating processed carbs not eating processed carbs too extreme don't eat them first And don't graze give your Your liver and your ingredients and your packers a chance to rest Eat fewer larger meals instead of the whole thing about eating all these little meals all through the day And eat mainly meat And there you go. Thank you very much We have about eight minutes for questions So please come and use the mics on either side of the room Michael thank you. Great talk You mentioned gebor adosi early on and i'm sure most of us follow his work along with ivor cummins and others That are available quickly on the internet Um And i'm wondering if you're familiar with because i mean the world of wearables are continuing to develop and As you mentioned the cgm technology is ever more available It's not quite there for a wearable insulin assay or wearable insulin test, but Gabor is working on a project along with eric smith And i'm wondering if you're familiar with this project metabolic is what it's called and it's a a point of care a point of yeah point of care real-time insulin assay Along with an app that they're developing No, it sounds great provides the blood data and and plots curves So glucose and and insulin so you can see those other than off to the lab and three days later So it's an exciting. Yeah, and i'm going to mention this talk to gabor. Yeah, you know, I read just a few days ago that In a paper a peer reviewed paper that people were working on a keto monitor that was like a continuous glucose monitor But i don't think it's made it beyond Into the commercial phase yet But it's interesting to be nice to have that too, but it would really be nice to have an insulin monitor Right and I think the first step that they're working on is really trying to get it to clinicians to work with patients And again to plot their blood blood data in real time. That's great. Thanks I've seen you know the debates as to whether High insulin leads to insulin resistance or it's the other way around or it's some combination And i'm wondering if this Encretin Factor plays into that do any of these studies look at this effect in insulin resistant versus Insulin sensitive people and also does eating more structured food Reduce your your chance of getting insulin resistance Well, based on I mean, I just showed you the tip of the iceberg in these studies I mean there are a lot of studies that show All this same stuff and not just these that I picked out and they seem to it would imply that it would But I don't know. I've not seen a study that was Encretin's an insulin resistance looked at at the same time But they know it runs it up and since uh The higher your insulin is the more they're the less sensitive your receptors become you would think it would just logically My question's a bit related. So you were talking about the effective fat on insulin in the presence of glucose Presumably it's less when there's lower glucose Do you know if there's a difference in the ketogenic or fasting condition compared to The other non I had not seen that I mean not that it doesn't exist. I've just not seen a paper looking at that It would be interesting to see I'd love to know Yeah, so would I I don't know what effect if any ketones would have on I mean circulating ketones would have on Encretin's or just the glucose sparing effect. Yeah, yeah, the uh, yeah, I don't know. I've not seen that Thank you All right, I think that's uh all the questions and so let's thank dr. Mike eads once again Now we know what in Cretan's are And how important they are and so with that knowledge we can all go and make an appropriate choice for lunch during our lunch break And uh, we'll be back here for the afternoon sessions at kickoff at 11. I mean at 1 40 p.m