Dr. Stephen Phinney - 'Inflammation, Nutritional Ketosis and Metabolic Disease'

it's a delight to be here I'm happy I can still breathe at this altitude just say remember to stay hydrated and if you're on low-carb follow Andrew mentes advice and particularly because of the increased sodium excretion so associated with nutritional ketosis you should get at least 5 grams of sodium a day that's my tip today my talk today is one of the topic I've been kind of developing on my own for about 20 years and that's trying to understand the world in inflammation plays in in health and disease in particular the impact of nutritional ketosis on inflammation and when I go back and look back I actually can see evidence that of enough of a beneficial effect and I'll show you what I think beneficial means as early as far back as my PhD dissertation research which I didn't do which I finished up in 1980 so it gives you a sense of how far back my so the clues of this for me go let me start and I have to make sure I push the right button as soon as the one on the right yeah so by way of disclosure I am heavily conflicted I'll just say that outright I worked in academia for 20 years I maintained a really clean existence no conflicts and I got no funding to do any of the research I wanted to do so in 1999 they went over to the dark side and I've worked in a couple industries and most recently I met a remarkable world-class athlete and interpret internet entrepreneur Sam ink and then he convinced me that we should turn some of this into a scaleable high-quality intervention and that's what Verta is and I'm the only date I'm going to show you from Bertos data that we published in fact what I'm going to try to show you is the only data I'm going to show you is published in the peer-reviewed medical literature for all the stuff I'm going to present today so there should be no conflict if it's gotten past the peer review process so the primary molecule that we have circulating in our blood wimmer and nutritional ketosis is called beta hydroxy butyrate or Bao HB for short or you can call B HB or you could call it Fred I guess but this is a little molecule a little over 100 molecular weight and for most of my career my assumption was this is a really good fuel for the brain in the heart and the body can use it in place of glucose and for the function in those organs and so therefore it could help you get by on a low-carb diet but the science of beta hydroxy butyrate has balloon virgins since 2013 and we now know that it is a very potent inhibitor of enzymes which in turn inhibit our defenses against oxidative stress so you didn't hit something which inhibits us from not being damaged by free radicals or reactive oxygen species and it and we so we know the mechanism size molecular mechanisms through which it does this and it has nothing to do with being a fuel this is functioning at the gene expression level in terms of all basically altering our body's defenses we also know from a subsequent study published by the same group that it's it they called it more than the metabolites but in this discussion eric Vardhan and john newman point out that there's evidence that big hydroxy butyrate directly reduces insulin resistance so it's an anti insulin resistance molecule again the pathway for that is being worked out parallel to that a group at Yale University collaborating with Dominic D'Agostino at University of South Florida characterized the fact that this molecule beta-hydroxybutyrate works at the in the nucleus at the gene expression levels to suppress the function of something called the nlrp3 inflammasome and what you get from the point of view from the term inflammasome this is a male assembled molecule when when it's put together turns on the body's inflammation and this is reduced butyrate so you begin to get a sense that this is not just a fuel this is not just a metabolite this is something which has fundamental effects within the body and specifically it has effects on on the regulation of the body's inflammation now why would be.we be interested in that I mean inflammation we know you know when you have a fever that's that's a high grade of inflammation fever helps your body in this defense against infection you know if you have inflammation at a site that helps Keeling's you know inflam inflammation is a good thing but the question is is there danger from having too much of it and just recently just in the last decade it's become increasingly apparent that inflammation is a primary driver of for the development of type 2 diabetes and so here is a early paper published in 2011 type 2 diabetes as an inflammatory disease by very respected authors and then Gerald Olesky and and co-author from University of California San Diego published in one of the top-tier journals of in medical research pointing out that inflammation is a significant driver of metabolic disease so this is linking us to this signaling molecule to something which is at the root cause and I would say this probably goes much further down into the causation then say insulin per se because insulin said a messenger insulin is not a cause and I don't want to belittle this but when people say well you know isn't insulin the cause I said well that's kind of using insulin and blaming that for type 2 diabetes or for insulin resistance is like blaming your cell phone for robocalls it's just the messenger and you have to get deeper into finding out which drives that and then the other important question is does this this changing and have any impact on the disease and that's what I want to focus most of my I talk on so again the place where this really began to gain traction was not in diabetes but in coronary artery disease and back in actually is earlier the mid-1980s but in the early 1990s there were a number of papers published that examined geological immunologically the relationship with in cohorts of healthy people looking at the total white blood cell count where the number of white blood cells again is probably the earliest known marker of inflammation the looking at the level of total white blood cells in healthy people whose white cells are in what was considered a normal range and looking at their subsequent risk of developing type I'm sorry developing coronary artery disease and what both these papers pointed out is that for people who had lower levels of applied blood cell count in the normal range that they had a lower risk of developing heart disease and if you look at the numbers here for the bottom paper this one by William canal who headed the Framingham project for about two decades they followed almost 1400 men and women their white counts were in the normal range at baseline but when they then looked at their risk of developing type or developing coronary artery disease that it was increased 34 percent in men and I'm sorry 32 percent in men and 17 percent in women per one unit and we measure white blood cells as 1 times 10 to the ninth normal range is roughly between four and a half and ten so for each one increase in that normal range there is something around a 20 25% on average between men and women increase in coronary risk so if you have a number of five versus a number of eight that's three times that number you're essentially looking at that doubling the increased risk of heart disease strictly around white blood cell count independent of total cholesterol or its distribution and lipoproteins so this is something that is not a cholesterol driven aspect of coronary risk then the question is does changing it make a difference now we don't until recently we haven't had any medications that are safely used chronically in people to lower biomarkers of inflammation they say well you can use aspirin you could use motrin and those are anti-inflammatories but they only work through the eicosanoids pathway not through other inflammation pathways and they don't really significantly drop these biomarkers so it turns out that the modern statin drugs rosuvastatin and atorvastatin which were developed to lower LDL cholesterol by releasing reducing liver catchment cholesterol production that they also lower biomarkers of inflammation particularly one called c-reactive protein and again there's potentially a bit of conflict of interest here because the guy who developed the high sensitivity CRP c-reactive protein test paul ricoeur is the one who's been doing the studies looking at what happens when you change it so he has a certain bit of interest in having a patent on the assay that said they did a massive study where they took 17,000 people who were selected for having not having a marker the elevated LDL so the LDL was under 130 but they screened them and screened out people who had elevated c-reactive protein values so normally you give theoretically you would give a statin to somebody with high LDL and they were picking people with high CRP s and they intended this to be I think a four-year study and they randomized into two groups they either got the super statin or they got or they got placebo and they ended the study after 1.9 years when the risk of primary coronary events was cut almost in half in the people who got receive a stat it was a dramatic effect but the problem was although they selected people for relatively low LDL LDL was further reduced by 50% and but their CRP was true dropped by was reduced by 37% and so you know both of them went down and you can't ascribe which of the which which of these are to what extent either one of them reduce the coronary events so you know it's very promising study in terms of maybe the reduction in inflammation was important but you really can't tell from that study and then along came a monoclonal antibody it was developed for people with rheumatoid arthritis so this is a targeted monoclonal antibody against interleukin-1 beta which is one of the many biomarkers but also inflammatory mediators that we look at and so this is an injected drug it's very expensive you inject it every three months and they gave it at one of three doses versus placebo in a group of people who were otherwise healthy and looking to see what what would happen to their coronary event rate and what they found was that there was a dose respect a dose response effect on coronary risk that went from 0.93 that 0.80 that's the relative risk so if you got the dose thick that that took you down 2.80 you had a 20% reduction in coronary risk and this is with a monoclonal antibody directed at a single protein and had no effect on cholesterol or lipids so the good news it pries it proved that lowering inflammation will can in this case lower coronary events so there is now we're very confident that this is a causal relationship the problem is that when you target a single component of your body's defenses against infection guess what happens now you should say it's like taking the manhole cover off of a manhole in the middle of a street and you know people disappear and so they saw an increased death rate from sepsis that counteracted the beneficial effect of this in terms of reducing heart disease but that's a really important thing to understand that inflammation is not just a Associated factor it's a causal factor in coronary risk now you say well why don't we use nutrients to modulate inflammation as we know there are lots of anti-inflammatory nutrients and you heard some of them mentioned today and fish oil or DHA is is is touted as a anti-inflammatory and indeed it is and we know the pathway but when you look at measured biomarkers like white cell count or CRP or some of the other biomarkers its effect is very very modest there's a naturally occurring omega-6 fatty acid called gamma linolenic acid that you can get from evening primrose oil or borage oil and it has a it boosts the body's production of what are called class-one prostaglandins it has anti-inflammatory effects but again they're very modest and not of the caliber that we were looking at here with reductions in CRP of 30 or 40 percent and then the the much touted resveratrol which you know is found in in dark fruits including dark red grapes and found in wine again given in very high doses the animals can have concern to have effects but it's very hard to show anything like this kind of effect in humans I do want to mention that I was involved in research it was a compound called gamma tocopherol and you all know that took off halls are a class of vitamin E and the class that work with one that we're all told us is the most partners how important is alpha tocopheryl and so when you buy vitamin E you're getting alpha tocopheryl but it and that's because it in the test tube it is the most potent antioxidant but it has almost no anti-inflammatory effect whereas gamma tocopherol is a quite potent anti-inflammatory and working in a previous setting I did research and we publish data on people with end-stage renal disease who have high CRP levels and we showed that gamma tocopherol alone or in combination with DHA can dramatically reduce CRP levels it would be great if we could be studying that but unfortunately we filed for a patent on on that compound and that formulation and then the startup I was working for didn't want to do dietary supplement work they won't do pharmaceuticals so they didn't weren't worried about doing anything with that and they went bankrupt trying to come up with a drug to do something like that and then Johnson & Johnson bought that patent they've been paying this is not a conspiracy this is just normal business they've been paying the maintenance fee on that patent for since 2005 and they've done nothing with it and by the way you know they own the the brand names of town hall and motrin so there's a nutrient combination and have this kind of fact that we aren't gonna have access to for a while because it's blocked under patent so let me then then share with you what we can do with a well formulated ketogenic diet in terms of biomarkers of inflammation and this is a study that Jeff Wallach did with his graduate student Cassandra Forsythe and my name's on the paper because I was kind of the old advisor flying in the wall guy fun to watch them do this they took 40 people with metabolic syndrome which is essentially pre-diabetes and they randomized them to one of two dietary interventions one dietary intervention was a a low-fat relatively high carbohydrate diet that was restricted to 1,500 calories a day the other one was a high-fat low-carbohydrate diet moderate and protein and they ate that to satiety and the reason that they ended up being the same amount of calories intake and the two diets is because that was a satiating diet for the people on the on the low carb diet so they matched caloric intakes one by restriction and one by just led restricting restricting total calories one by restricting carbs and they filed this for three months and they looked at a whole bunch of factors I just want to show you weight loss and metabolic syndrome data so this is weight loss and so you see the two curves so the upper one is the people on the high carb diet and this is typical when you compare side-by-side high carbon low-carb diets in match groups of people so about double the weight loss for the people in the ketogenic diet and there were a couple on the ketogenic diet who had market weight losses but you can see that the average weight loss for the low-carb group was slightly greater than the greatest weight loss than any other group so it wasn't just a couple outliers who skewed this this was a consistent pattern of greater weight loss and again we're told but you know it's mostly body water you know it's only about one kilo of water and that's water associated with the glycogen that's in muscles which is reduced about in half when people initially follow a well formulated ketogenic diet so significant weight loss but they're both still losing weight at the end of 12 weeks and that's important because you know they're still in a negative calorie balance for each group the boxes here in green this is a complex slide but the boxes here in green this is abdominal fat so central obesity blood triglyceride it's HDL cholesterol and blood glucose these are all all parameters for which we define metabolic syndrome and you can see that in all cases the results from the high fat low carb diet significantly were significant improved compared to the high carb low fat diet and so there was a very significant effect on on metabolic syndrome in these individuals but we also measured a panel of 14 different biomarkers we basically took everything in this alphabet soup of biomarkers of inflammation every one we could find a test to measure and measured all 14 in both groups and for seven of them there was no difference in the response to the two groups now this isn't response from baseline this is difference in response at the end of the study and so the none of the the from none of these biomarkers were the was there a superior result for the high carbohydrate group but for seven of the biomarkers there was a significantly greater benefit against these biomarkers of inflammation for the low carbohydrate high-fat group so statistically that's that's a very powerful result indicating a superior anti-inflammatory effect in the context of weight loss done into two well matched groups in parallel and that's where we were up until a couple years ago when I met a remarkable person and you'll meet her tomorrow speak to you tomorrow dr. Sarah Hallberg who is a physician in Lafayette Indiana and she had switched her practice in Lafayette from a standard internal medicine practice to a predominantly low-carb practice for dealing with severe obesity and type 2 diabetes and she approached me two years ago and said you know I this is amazing this is having great results but some of my patients LDL levels are going way up and we got to figure out what's what's wrong with them and so we decided to do a study the study was roughly 500 people recruited in the Lafayette area and 400 of them had either type 2 diabetes or metabolic syndrome the majority had type 2 diabetes and close to a hundred of them were recruited it from the usual a group from their diabetes clinic and I'm we're going to show you a little bit of data from 262 of the people who had type 2 diabetes who we followed for the first year so dr. Hamburg is the PI on the study to do this the our protocol is a very intense either in-person hands-on or very intense through a online app where people are having contact with their coach daily sometimes up to three times per day and so the coaches that work with the patients are intimately involved in their management by the way two of our coaches are here in the audience Bobby Glahn and Brittany Volk and you know this was a really intensive intervention in order to generate these results the first thing we demonstrated we've been told over and over again yeah you can put people on the ketogenic diet but in the real world nobody can stay on a ketogenic diet long term so these are the data for blood ketones measured by finger stick glucose and and monitored through our app and you can see that the the group initially was above at or above 0.5 out to six months and then the second six months as we added back as because we personalize the carb tolerance or carbine take two the tolerance of the individual but they're still maintaining an average of 0.4 millimolar they do a direction butyrate where point five is the use we used to think was the threshold of impact and we think is actually better than or lower than that now so again we had remarkable adherence to carbohydrate restriction for this group of people over that duration of time our focus was not weight loss these people were told from the outset to eat their eat this diet to satiety and it was a high fat moderate protein where we started to have about 30 grams of total carbs per day and some of the people progressed upwards from there after the three to six months and you can see the weight loss continued out past about out to about nine months and then plateaued for the last three months so not the usual u-shaped curve of losing game back and we had a whole bunch of things that we monitored including their diabetes status and dr. Harbor would report that tomorrow but this shows the white tone white blood cell count for the usual care group up on top at baseline and at one year and for the intervention group started at a in the normal range of value of points or 7.0 dropped to 6.5 and then down to about six point two and that doesn't look like a big change but that's over that would be equivalent to about a 10 to 20 percent reduction in coronary risk based on the published data from from previous epidemiological studies and the other thing is the consistency of this change and you can tell the consistency from the p value and the p value here is not 2001 or 0.005 but it's 1 times 10 to the minus 16th this is a very consistent change for people following a well formulated ketogenic diet so really looks like something this is hardwired into our biology take away the carbs and you reduce the inflammation we got more dramatic results with C reactive protein and again remember 2 is above 2 considered where the threat where rich risk begins and these people started both groups started above 8 and then there was no significant change for the intervention group at the 3 months but at 1 year we cut their value down by about 35% which is a really big change so this is the same magnitude of change that you when we get with the the monoclonal antibody or with a statin drug but we're doing this just by changing macronutrient intake and optimizing mineral neutral and I don't want to minimize that we pay a lot of attention not just to restricting carbs but the providing adequate sodium potassium attack potassium and providing adequate magnesium so this is a very potent this is a drug like effect you know if we could put this in a pill and solid it's a billion-dollar drug but the neat thing is you can do it just by eating real food and it doesn't have to be expensive somebody asked in the previous panel you know what do you do for people of low income and my favorite source of fat is good quality olive oil I buy it in bulk from my local big-box store name but I was mentioning to some folks over lunch the the cost of a thousand calories of good olive oil I don't drink it I mix it it's really anxious and delicious and in foods and sauces a thousand calories price has gone up recently and it's up to 65 cents a thousand calories who can't afford that and you buy a 395 latte I'll get off my high horse so one of my conclusions Siri what's to say you know this there's no drugs it's approved for chronic use it doesn't have side effects you can do this and yes there can be side effects to a well formulated ketogenic diet but they're manageable if you maintain adequate hydration sodium and minerals as some of the key associated factors you need to deal with you know someday down the road we may get access to this gamma tocopherol DHA combination that be putting three pills per day and cost about a dollar a day but till that comes along it looks like our best hope is a well formulated ketogenic diet and this is something that pretty much you know many people use we could guess more than half our population would benefit from doing it's not for everybody and this available any to anybody who either wants to find the materials or seek out the coaching to be able to do it and let me leave it at that and thank you [Music]

Channel: Low Carb Down Under

Views: 91,207

Rating: 4.891892 out of 5

Keywords: Low Carb Down Under, LCDU, www.lowcarbdownunder.com.au, Low Carb Breckenridge 2018, #LowCarbBreck, #LCB18, Steve Phinney, Jeff Volek, Virta Health, Inflammation, Nutritional Ketosis, Well Formulated Ketogenic Diet, WFKD, LCHF, Low Carb High Fat, Metabolic Syndrome, Low Carb Denver 2019

Id: A5_R13Luit0

Length: 25min 49sec (1549 seconds)

Published: Sat Jun 23 2018

Reddit Comments

[u/Ricosss]

is it possible to put a little summary with youtube videos? I don't always have time to watch so it would be great to read a couple of key points mentioned during the presentation.

[u/MediaManXL]

Is inflammation in this context the same thing as joint inflammation (like swollen knees)? I know my joints feel tremendously better, but I don’t know if that is entirely attributable to losing 50 lbs, or if there is a more direct effect of keto via this inflammation issue. I think even non-weight bearing joints like my wrists and jaw feel better, but that could be imagined.