the other thing that has been characterized is there is a regulatory entity within our cells that's called the nlrp3 inflammosome and this is a basically like a master sergeant it oversees a platoon of inflammatory soldiers and this regulates multiple down Downstream inflammatory Pathways and this this when this inflammosome comes together it works if it doesn't come together it doesn't work and B hydroxate blocks the Assembly of the nlrp3 inflammosome uh a study that was uh published by Jeff V's graduate student cassander for uh she got three or four papers out of this and then got her PhD this paper is highly cited I think it's been cited over 200 times since 2007 um and basically what Cassandra and Jeff did was they recruited 40 people with metabolic syndrome and half of them they gave a lowfat diet restricted in calories to 1500 calories per day so metabolic syndrome includes obesity these are people who would like to lose weight so they recruited and said we're going to give you a really nice flavored good real food diet and Dr Zen would be very happy with with the fact that this is all real foods we didn't use any highly processed foods we are almost none in putting it together and um they they ate this they were given this diet for for three months the other group uh were randomized to the ketogenic diet um but they gave them the the freedom to eat as much as they want and the reason why we did that is we know that when you take people like this and give them a a well formulated ketogenic diet they undereat calories by about a th000 calories per day so these two groups are actually matched in caloric intake one group was calorie restricted and one group was eating to satiety ate about the same number of calories and you'll notice in red at the bottom that the ones on the lowfat diet got 12 gram of saturated fat per day and the ones on the high fat diet got three times as much 36 grams of saturated fat per day what do you think is going to happen to their blood saturated fat levels you know you are what you eat every eating three times as much saturated fat we'll come back to that two more slides uh weight loss um the group that got the ketogenic diet lost twice as much weight as the group that followed the the control diet ostensibly they were eating the same number of calories but these were outpatients and they had the opportunity to eat other stuff um so we don't know you know we did not have 24/7 cameras mounted on on these people then the question is how much of that is you when you go on a ketogenic diet you lose quite a bit of body water well you lose water associated with glycogen in muscles but if you don't have edema you're not going to lose that much more water or if you do you're going to reduce your circulating volume and your cortisol level is going to go up but the result was that when we did body composition with dexa dual x-ray absorb geometry the group on the ketogenic diet one kilogram of their 10 kilograms of weight loss was due to to ex extra body water loss and the other 9 kgs was what they wanted to lose and you notice that the range the median weight loss in the ketogenic diet group the the um bars coming down on the on the right hand side there then the Red Bar there for the or line for the the people on the ketogenic diet um the average value of weight loss was greater than the greatest weight loss in the other other group but the most important thing is these people were people with metabolic syndrome and the metab components of metabolic syndrome um are outlined in green there and you can see that the red bars um were uh dramatically better than the blue bars the blue bars are being the lowfat diet and the red bars of the ketogenic dot um and then the other really interesting thing on the far right hand side outlined in Orange Is The Blood triglyceride levels of saturated fat so this is the fuel triglyceride circulating through your blood and the ones who got the got the ketogenic diet with 36 gr of saturated fat had more than double the reduction in blood saturated fat so if you have a little card that you carry with you you say you are what you eat tear it up you are what you sa from what you eat and one of the the resilient and robust metabol characteristics of of nutritional ketosis is you give the body the permission to burn at least twice as much fat as when they're not on a ketogenic diet and that's whether they're at rest or exercise and it clearly one of the F the SAT the fats that the body prefers to burn when you give it permission to burn twice as much fat is saturated fat it only hurts you if it builds up in your blood if you're keto adapted you can eat saturated fat I won't say to abandon but as a significant proportion of your fat coming from um U uh coconut oil from animal fats wherever uh and you will burn it for fuel turn it into CO2 and water and contribute to global warming but speaking about warming and inflammation we measured 14 biomarkers bioactive compounds associated with inflammation in these patients it was a three-month long study and of the of the 14 seven of them came down significantly in the group great to a greater degree in the group on the ketogenic diet compared to the control diet and those are little alphabet salad here but what I want to point out is interestingly over on the right hand side those are the column that in that column was the things that didn't come down and one was white blood cell count one was CRP and it turns out that all things all these different keys on the keyboard don't respond in lock step in the early phases of Keto adaptation and C reactive protein in particular is one of the slow responders so I've seen multiple papers of people doing well done ketogenic diet studies and they measure C reactive protein and say see inflammation doesn't come down you know it's like you know running a really really fast quarter mile but you never you never get the Gold Cup at the at the one mile mark on a one mile race you got to run the whole race it takes longer than than three months for CRP to respond to this this type of intervention so cutting to the chase most more recently the study we did with Dr Sarah halberg in Indiana we're now we've completed 5 years by the way and she survived through the the final um uh patient visits at the 5year time Point um and that was part of her commitment to to this process so we recruited 262 people actually we recruited close to 500 there was a about a 100 people in a a a non-randomized parallel usual Care Group and then of almost 400 people total 262 had diabetes and the remainder of them had pre-diabetes so focusing on the people with diabetes um they were about 2/3 female average age 54 um very overweight average BMI was 41 had lots of weight to lose um and importantly the average duration of time since diagnosis was over eight years these are not not new onset you know uh um uh uh early stage people with diabetes some of these people had diabetes for 20 years the majority of them were on two or more drugs um metform and plus something else and some of them were on multiple drugs um um and they were managed through a um a basically a remote Continuous Care app uh across the full two years of the study uh and the patients um had access to a coach and to a physician in the case of study to Dr halberg on a continuous basis seven days a week they could they could reach out through the app and get in contact with someone um they got um most of their education through video and and and printed materials um they monitored their blood glucose and their blood ketones they stood on the scale every day um they couldn't um U misreport their weight because it was a cell phone connected scale the only way you could mess it best with it is hold on to a bunch of helium balloons while standing on the scale um and then and these were a very committed group of people because all of them had met and interacted with Dr halberg and her ability to connect with people and convey the sense of benefit to them and the sense of the mission was just absolutely incredible for this study um this is an older slide we we've published at this point 11 papers from from this one study um but these are the papers that demonstrated one year and two-year data uh on diabetes and also cardiovascular risk I'll Focus just on the two-year data so this is a paper published uh uh in frontiers of endocrinology and we presented it at obesity week in 2018 so it's not brand new the blue line across the top shows retention in the study and um you can see at one year we had 83% retention uh in the people with type 2 diabetes in two years 74% retention uh and I'm not bragging you can go look um in lifestyle studies maintaining half the people in a study at one year is considered good and having this this level of retention at two years is remarkable and then the embedded graph there on the lower left hand side side shows the daily blood ketones in patients uh over a oneyear period of time and you can see that uh out to 8 months on that of that one year time frame the group mean value for beta hydroxy be was 0.5 Millar so people tell you that patients can't say maintain this wrong people can maintain it you just have give them permission to do it and proper information in terms of how to do it and it can be done uh at at uh two years our our mean value was was down to about3 but it was still statistically significantly above their Baseline value so the ketogen tiddes can be maintained they're really hard to do and it takes a really robust support system to allow the majority of people to do this when they did that the the blue line here shows the weight loss at at um U one year was about 35 pounds of weight loss and that's with the 80 plus per retention and it two years the there was a 5B weight regain but they still maintained a 30 PB weight loss which is truly remarkable among non-drug assisted or surgery assisted uh lifestyle interventions and then the the usual Care Group you can say that that their weight went up over the two-year period of time um and on the right hand side you can see that hemoglobin A1c dropped about 1.2 units at one year and we maintained a 0.9 unit reduction and 0. N unit reduction is more is the same or more than you would expect from one full you know powerful type two diabetes um intervention drug the other thing that occurred in the first um over this time period is we reduced and maintained the patients off more than half of their diabetes medications and uh for the people who started on on on um insulin half of them stopped their insulin in the first month and you heard Dr Penny fig tree mention that and she also uh and I was delighted to hear her say that this is not an easy thing to do in a monitor and the way that we can do this safely in a very large number of people and we now have tens of thousands of people in whom we're doing this is because we have the app and they have continuous access to a trained physician and working with a a trade coach this is now um a graph of the uh um 12 different biomarkers that are associated with coronary disease risk that has been formerly um uh um uh proposed as a way of measuring U long-term uh disease risk tenure disease risk uh and um that this the overall disease score is reduced by 12% the only fly in the ointment is there in the middle that downward poting pointing arrow with a red core is LDL cholesterol and if blue goes up it's because of ketogenic diet improved it if Blue Goes Down ketogenic diet made it worse on average LDL went went up but the the thing pointed down there LDL went up about 10% 9% in in this population but the HDL cholesterol went up markedly um so pretty much everything else improved uh and the result is that the this calculated disease score where we don't look at just one on the keyboard but we look at the whole keyboard it's getting better cutting to the chase inflammation we measured 16 biomarkers um two of them were not significant the one on the right where it goes up which is uh vcam one is not actually a a risk is not associated with diabetes risk but and over on the left hand side the the IAM one was reduced at one year in blue and further reduced at two years in in red but it wasn't statistically significant all the other reductions were significant if you look at the far left hand side the well formated ketogenic diet at one year reduced C reactive protein uh by um over 30% and it wasn't significantly reduced further but the two years we had an even greater reduction than CRP um but the important thing is we changed the level of inflam atory stimulus across the whole keyboard so there is a balanced effect of this but realize we've evolved with this molecule since the liver was invented this is a this is an evolutionarily um longlasting thing that that through Evolution the body has figured out you how do we how do we play this music where we respond when necessary to challenges like inflammation or like infection and or trauma and then how do we shut it back down into to the normal resting range where it's not doing us harm and then clearly we're doing this in a balanced manner so coming back to this picture here um you know there are multiple roles for this this molecule as you can guess there are people who are trying to figure out how we get this molecule into people without having to go into ketogenic and the folks at the buck Institute are working on a um one of a a class of compounds one of a class compounds called ketoesters where you're not eating Ketone salts but you're actually getting these in a where you don't have to have a lot of of uh sodium and potassium and magnesium those are good things to take in moderation but if you want to get 75 or 100 grams of ketones into someone you can't give them that much as Ketone salts so they're working on these these things called Ketone Esters U where exogenous ketones may be able to achieve some of these effects and as I mentioned when they Infuse beta hydroxate into for one day they got a measurable effect on on gene expression so don't discount exogenous ketones but my liver probably makes 75 to 100 grams of of ketones per day currently ketones of various forms probably cost the US about a dollar per gram so my liver is making 75 to $100 worth of of good stuff every day and all I have to do is eat good food so terms of other inflammatory diseases this is just a a wish list you know if you say oh Steve finny says it works for multiple sclerosis and and depression and arthritis and Asthma we have lots of anecdotes of that I could have come up with 10 or 20 cases but until we study it in a prospective randomized way and demonstrate that it is is robust that is it last it it'll work for a long period of time and it's safe um these are this this is of our our wish list of what we want to do do and you know my conclusion is there's no drug in chronic use that can deliver these POS potent effect safely this is a truly unique tool and um um I think we came up with an interesting acronym we call noodle and that's not a carbohydrate food it's NE wle it's nutrients with drug-like effects and this is the poster child for that concept the the diet um is is potent and both both broadly based it um requires giving people adequate support um and and INF inflammation information and that's not easy for PE people to do not everybody can do it and there are times in people's lives when they're ready for Change and times when they're not so it's not something you tell people you need to do this now you say this is available when you're ready we're here for you um and then as I mentioned we have lots of future targets to study and with that I'll brag about the fact that once upon a time I climbed a mountain that was 14,000 ft high with no curbs and thank [Music] you for