Uric Acid with Dr. Ben Bikman

hello and welcome to this week's episode of the metabolic classroom I am Professor Ben bman a biomedical scientist and professor of Cell Biology thanks for tuning in and joining me today as we learn more about uric acid and in particular its effects on the primary metabolic marker that matters most insulin resistance today we're going to be unraveling the intricacies of uric acid so we're going to be discussing where it comes from why it matters in particular with a focus on metabolism or insulin resistance and inflammation and then ultimately what to do about it so in getting the conversation just started really clearly let's talk about what uric acid is and and then um some of why it matters before we explore its Origins uric acid is generally simply considered a byproduct of the metabolism of a molecule called purines now purines are um this is some kind of deep biochemistry here but there're the purines as a family of molecules are sometimes referred to as a nitrogenous base so they have some of the chemistry that gives them some a nitrogen and they have what's called two rings two chemical Rings you can imagine this complex structure but when the body needs to metabolize pins everything after all has a life cycle it is it is put together and then it is broken apart um uric acid will be a consequence of that and we'll get into more detail on that in just a moment but for now just appreciate the fact that uric acid is a is a byproduct of the metabolism of purines and usually when uric acid is produced it will be flowing through the blood in the plasma and then it will simply be expelled in the urine the kidneys very actively will bind or you know grab that uric acid and move it into what will become the urine if the either the production of the uric acid is too much or the excretion of the uric acid is insufficient we'll start to have uric acid accumulate in the blood and once it starts to get too high we start to get a condition that is in this earlier phase called hyper uremia now just by way of teaching you guys some of the lingo here and I am a professor after all hyper of course means that the thing is elevated and then whenever you hear that suffix that ending of the word emia it means in the blood so hyperuricemia is just high uric acid levels um in the blood and when uric acid levels get too high it can actually start to precipitate out so normally the uric acid is dissolved and if you were looking at a tube of water with uric acid in it you wouldn't see the uric acid it's dissolved it's mixed within the the solvent of the water or the solution however when the levels start to get too high in the blood the uric acid can start to come together and crystalize and then they happen to crystallize often in joints and so then the person can start to have gout so gout is when the uric acid has reached a point that it is crystallizing or literally coming together as these Jagged Little crystals and then making people's joints ache that is gout but high uric acid s can lead to higher uric acid in the in the urine which can give rise to kidney stones that are based that are sort of built on this same Matrix of uric acid crystals so that's uric acid as a general overview now let's get into some other specific questions as we go through this classroom episode the first of the next questions would be us exploring why does uric acid matter why am I taking the time to talk about it and why are you taking the time to listen not only this is becoming an increasingly common problem and to my delight uric acid is becoming an increasingly scrutinized clinical marker it seems that we hear more about it in even direct clinical settings that uric acid is just now more and more considered just part of a normal checkup uh which is really good news it matters so why does it matter I already elaborated it on it a little bit namely that the uric acid will um start to Clump together causing these uric acid crystals um clumps which start to literally poke and aggravate joints now to lesser degree of course that's something that could be that could be happening every anywhere in the blood the uric acid could be crystallizing and damaging blood vessels um as well but that's not going to hurt like a joint is going to ache you know you can't feel something poking into your blood vessel there's just no pain receptors to sense that now in addition to Simply the high levels of uric acid there are additional variables that can cause the uric acid to start to crystallize and start clumping together that can include temperature so as temperature changes and starts to cool off that can increase the crystallization and that might be one of the reasons why our hands can get this because our hands are often colder than the core of the body blood pH can affect it and then of course as I mentioned the concent ation now that is the common way of viewing uric acid but you know me well enough to know by now that I have a metabolic view of disease that was in fact the whole purpose of my book why we get sick over one of my shoulders here this one uh that's why I wrote it I wanted people to appreciate that among all of the chronic diseases and among all of their distinct causes they do share some common cause so let's get into that part of the uric acid discussion one of the things the thing that interested me most over the years in uric acid is its connection to insulin resistance now you have heard me discuss before the this these categories of causes of insulin resistance where at a high level I have what I consider to be primary causes of insulin resistance and secondary causes of insulin resistance the primary causes include chronically elevated insulin stress and inflammation now that last one I put last for a reason because it's a good segue into the secondary causes of insulin resistance what I consider to be some secondary causes among the definitions that I have that will qualify or the criteria I have that will qualify something for being considered a secondary it's that it is dependent on one of the primary variables and that's why I put Uric a acid as a secondary cause of insulin resistance now there is an abundance of research showing that uric acid is capable of causing insulin resistance and does so in virtually every experimental model increased uric acid will make isolated cells in a Cell culture become insulin resistance elevated uric acid will make the animal become insulin resistance and the human become insulin resistant but it does so because of its actions on inflammation and as I have alluded to before including very recently in my discussion in classroom about saturated fat when inflammation is turned on that will turn on the the synthesis and the accumulation of a highly bioactive lipid or type of fat within the sphingo lipid family called ceramides and when ceramides accumulate they will directly antagonize the insulin signal making the cell less responsive to insulin so if you were to start imagining a sequence of events which I like to do um and like to teach as a professor you could imagine if we're looking at uric acid on one end and then insulin resistance on the other insulin resistance being the single most common health disorder worldwide and increasing the risk of virtually every chronic disease so it is something worth focusing on then between the IC acid in the insulin resistance the bridge the great mediator is inflammation and then it would be ceramides and then it would be insulin resistance so it is it's worth wondering then um how important is the inflammation and it is massively important so uric acid will increase systemic inflammation so inflammation is occurring throughout the body rather than inflammation coming from a wound or general infection it increases the systemic inflammation by activating Pathways like the nlrp3 inflammasome now anytime you hear that word that suffix oh it means it's a kind of broad encompassing thing and so with inflammosome it's basically referring to this nlrp3 you could imagine it as this big Central switch that when it's turned on power throughout all of these other circuits is being turned on so when nlrp3 is turned on it's activating countless other inflammatory signals so it's really at a Nexus that when it gets activated a lot of things will follow or a lot of things will be turned on as a consequence of that one and again uric acid will turn that on and then there was a good study by zuu Zhu at all zuu at all in 2014 and we'll have this link in the show notes um that is that really explored this found that uric acid was capable of very rapidly causing insulin resistance and then there were there was a substantial inflamatory burden that was a part of that response and indeed I would say an essential part of the response that if you to to be very precise about it if you block the inflammation you block the insulin resistance so in other words uric acid is only causing insulin resistance in the cells or the body because of its effect on inflammation um so that's that's an effect in fact I'll get to some of my own research in a moment that we're about to publish where I can solidify some of those some of that signal and that sequence of events all right now where does uric acid come from at this point you understand generally what uric acid is this molecule in the blood that has the potential to both crystallize together causing gout or just activate inflammation signals you have a better understanding of why that matters in the context of insulin resistance which we're going to revisit when we talk about solutions to this um but then let's move on now to discussing where does uric acid come from I mentioned this right early on describing or mentioning the origins coming from the purines so as I said as a as a term of chemistry so pardon the term getting the terms getting a little technical um but purines are what's what's called nitrogenous bases that are used is the building blocks of nucleic acids like DNA and RNA so of course you've heard of DNA when you start to think about the genetics of every cell on the planet purines are going to be a part of this um so every animal every plant you're the purines are an essential component within the nucleic acids that make up all of our DNA and and then the central dogma of Cell Biology so the idea of what makes our genetics become our body that flow of genetic IC information boy the pines and the nucleic acids are just critical to that process now why or how can this become a problem the the conventional thinking with uric acid still conventional and certainly historical would be is is that foods that are high in purines where you're eating a lot of purines require the body to metabolize and clear a lot of purines and and and thus giving rise to more uric acid which um through a pathway I'll get into in just a moment but foods like this particularly results in the vilification of things like red meat and seafood red meat and fish tend to have a higher purine load and thus the idea is that if you eat more of those purine rich foods your body has to deal with them um as a course of breaking it down if you have more purines than you need um uh than the body needs you're breaking them down so you start to break down the Pines um then they it gives rise to a molecule called xanthine and as xanthine is metabolized as you continue to clear these molecules and break them down at the end of it then as xanthine is acted on by its enzyme it turns into uric acid that's that's one of the products so it is you eat it you metabolize it and it gets turned into uric acid that and that can certainly happen now the conven itional view is that is not only the conventional view is that that is the only thing that happens but also that it is certainly the most important even if someone is considering that there might be another cause but now let's talk about that other cause because it's the one I believe is the more important one which is fructose some of the evidence that I would cite just at a very superficial level to support the idea that if we're worried about the increasing frequency of gout and it is more frequent then how do we square that curve how do we reconcile that with the fact that red meat consumption has been going down generally and fish consumption has always been really low well then how do we how do we reconcile that if one of these variables is going down or at the best staying flat how can the other one be going up there must be something else that explains it and indeed I think that's something else is fructose the consumption of which has been increasing for decades now let's talk about fructose then so fructose is absorbed in the intestine and it is moved into the body and it goes to the liver and the liver is uniquely suited to metabolize fructose because of the the Transporters that allow it to bring in the fructose and as well as the enzyme expression enabling it to break it down so unlike glucose when when you have when you have these monosaccharides these simplest unit of the sugar glucose and fructose when they come into a cell they each have their own sort of respective pathway that they're going to go down fructo in order to be metabolized glucose is heavily regulated these steps are intricately sensitive and responsive to the overall energetic milu of the cell so if the cell has a lot of energy let's think about the liver if the liver cell has a lot of energy it can take that um where it's burning a lot of glucose already that high level of glucose burning will basically start to feed back back and tell the liver cell hey we're burning a lot of glucose right now so let's divert that glucose into something else so it has some regulatory steps that will check its own metabolism however fructose bypasses the main regulatory step of glucose which is an enzyme called phosphofructokinase pfk now pfk has some different varieties but pfk phosphofructokinase is the is one of the more sensitive steps in the burning of glucose that allows the cell to decide what it wants to do with glucose but again fructose bypasses that it does not have it doesn't have to listen to the signal coming from phosphofructokinase like glucose does this means that the liver cell is able to metabolize fructose at a much much higher rate essentially unchecked compared to glucose levels now then within the liver um as the fructose is getting metabol ized it's getting acted on by an enzyme called fructokinase or sometimes called ketohexokinase now that has nothing to do with Ketone bodies but rather it's more of a term of specific chemistry where there's a ketone Bond within these molecules so let's just call it fructokinase um to avoid any potential confusion so this fructokinase enzyme turns the fructose into an enzyme into a molecule called fructose 1 phosphate but whenever you have a molecule that has gone from one form to a phosphate form or a phosphorilated form it has to it has to have used ATP in order to do that so fructokinase will grab the fructose molecule it will grab an ATP molecule and mesh them together one of the phosphates at least from the ATP and give rise to fructose one phosphate but that means that what what was an ATP with three phosphates adenosin triphosphate has become broken down Lo having lost one phosphate and now it's adenosine D phosphate ADP and this reaction just keeps happening we keep just breaking ATP just to handle the fructose load because we're metabolizing so much fructose and essentially the liver can't stop there's no way for it to regulate its own fructose burning the net effect of this is that as we start to try to recreate ATP in order to continue to fuel the fructokinase reaction we end up getting a lot of a molecule called adenosine mono phosphate that is an important development in this process when we start to get a lot of a lot of now we're just a couple steps away from um the uric acid because amm starts to turn through a series of events and I'll spare you you're already thinking I'm getting too specific I could be a lot more specific where the is now basically turning breaking down through a few steps back into xanthine which you recall because I just mentioned it and then give zantin another step and it's turned into uric acid so we've now completed this journey again where the fructose just to recount it perhaps with some degree of brevity the liver can't stop burning fructose there's no way to really turn it off unlike other metabolic pathways and this means that the cell is burning through a lot of ATP and through the course of trying to continue to recreate ATP we end up getting a lot of am and then the am after a handful of metabolic steps becomes uric acid this I think is the singular pathway mattering more than any other when it comes to explaining why the liver cell in particular is pumping out is creating so much uric acid like G hang Busters it can't stop so the more uric acid coming in the mouth or the more fructose the more fructose coming in the mouth in whatever form whether it's fruit juice or or sugar or high fructose corn syrup is going to give rise to more uric acid production by necessity all those molecules of fructose you just can't stop burning gives rise to a lot of uric acid now before I move on to the final part I should encourage I need to encourage all of you if this is a topic that you're getting more and more interested in I strongly recommend you look up the work of Dr Rick Johnson a friend and colleague colleague in research and collaborator that I'll share the project we're doing in a moment but he has written a book called The Fat switch or nature wants us to be fat and it's all about how then the uric acid as it accumulates starts to drive more hunger and then ends up becom BEC a primary contributor to obesity in the long term now with all of this having been said we move on to the Happy Ending which is what can you do about it thankfully you can do a lot about it let's start with the pharmacological approach and then we'll move into the nutritional approach which you can already guess where that's going to go the pharmac the pharmacological approaches include very common drugs like alop purinol alop purinol is the most common and it will effectively reduce uric acid um uh and in so doing it will improve gout as is expected and that's usually what people are looking for they want resolution of their gout that being the most commonly acknowledged consequence of huric acid but there are metabolic effects as well that are beneficial so a study by Madero at all 2015 Madero at all um they published a Clin iCal trial so this is good that's the highest quality of Interventional research and they looked at overweight and prehypertensive um subjects so these are men and women and they put them on alopurinol and they found um that the alopurinol not only resulted in uric acid reductions but also a significant Improvement in metabolic Health now a confounding variable including weight loss and improvements in insulin sensitivity so all very very good things um One Challenge though is that I have been unable to find a study that did this in the absence of any other intervention so this study by Madero at all 2015 they they gave the people alopurinol and looked at these metabolic outcomes but they also had a low fructose diet So based on what I just said you can see how that's a bit of a confounding variable even still generally certainly in clinical practice from what I've gathered from Clinical teams alopurinol will often result in some degree of weight loss and general improvements in metabolic markers that are connected to insulin resistance now however before you just jump into taking alopurinol every drug has side effects that you don't want and so I just feel inclined to mention them just to Curb Your Enthusiasm for this drug lest you ask for a prescription from your Clin a little too readily there can be some significant skin reactions um like an exfoliative dermatitis as well as some even more serious skin problems there is the common GI issues like diarrhea and nausea and even some liver and kidney problems as well so it is a drug to be careful with like all drugs are even though it does have some metabolic benefits because of the lowering of uric acid now let's move into allulose as I mentioned at the beginning alos is a rare sugar and it really has emerged as a pretty promising agent to improve uric acid to reduce uric acid and that might be one of the mechanisms whereby allulose has been shown so extensively in humans and rodents to improve metabolic outcomes now just as a disclosure I am finishing an alilo study now we're just about to submit this for publication in animals and we're doing a human study soon um but the effects were substantial and it's these are unpublished results that I'll mention so I need to describe them cautiously or just with some you need to hear them cautiously because they've not gone through a peer review process but among the groups we had was one group of animals on a western diet so high fat high sugar and unexpectedly they gained a lot of weight if we gave them alos in their drinking water they gained substantially less weight less than half of what the other animals ate and they ate less they just were not as hungry they had much better satiety so alose is important U it matters and uric acid could be one of the key changes that are that's helping the metabolic health of the animal now how does this happen um it could be twofold one with regards to absorption and the other with regards to excretion of uric acid now let me also say um I regularly get my blood tested through a company called BLS and I encourage you to look them up I really a fan of their service my uric acid levels have always been in the normal range um however when I as just a matter of experiment started taking much more of the RX sugar products of the allulose um my uric acid levels went below the normal range and nothing really changed but they went down so much that it got below the normal range I don't think that's a problem I continued to feel fine but I've seen this happen in many other people as as well who despite changing their diet and becoming healthier they still have persistently high uric acid levels and it just concerns them they start taking alos and it drops very very quickly so now I appreciate what I'm saying these are unpublished results so please appreciate that I want you to appreciate that as a scientist what I'm citing to you or sharing with you is anecdotal my own and those I've seen of others but I have seen enough that I am inclined to mention it even even though I would rather just be citing a peer reviewed study until we have some peer reviewed studies um I'm happy to mention the anecdote now how can it work all right the first thing I mentioned was the uric acid interestingly alos is the good twin to fructose now and a lot of people nowadays are trying to say fructose is good and you should eat a lot of it I'm not trying to suggest that fructose is uniformally bad but I do think we eat it in a way that we never did before honey would have been a very uncommon occurrence and we would have had to fight off bees in order to run away from it so it's something we as humans would have enjoyed infrequently and moreover the the fruit that we would have had ancestrally would have not only we not only would not have been drinking it we would have been eating it but also would have had very very low levels of fructose um just as a case in point do yourself a favor as an educational tool and look up the change in apples over the past 100 years um what was once these small bitter sour little things that become these big fat juicy and delicious fructose sugar bombs so we eat a lot of fructose now back to alos alos is a twin it has One Singular alteration in in one of the carbons but it other compared to fructose but it is otherwise identical to fructose but it is different enough that it can't get metabolized but it still can it still can compete with those same absorption Pathways so the same doorway that lets fructose come in can let alose come in and so that we believe is most especially relevant at the gut that if you have competition for the uptake of any fructose alos is fighting now what used to be an uncomp entrance for fructose to just come right into the gut now has to fight and with the alose if you're taking an alose so it stands to reason that less fructose is getting absorbed that means less has to get metabolized now let's say that there is fructose that has been absorbed and it is getting metabolized that now we look at the back end of it where uric acid if there's more allulose this is theoretical this hasn't been published but we're hoping to confirm this in our upcoming human study when alilo gets consumed it's because we don't burn it as an energy source its main exit is through the urine and there's this idea that Dr Rick Johnson at University of Colorado the resident the global expert on fructose and uric acid metabolism he has posited this idea that the alose could be increasing this pull effect on the uric acid enhancing the kidney's ability to remove the uric acid from the blood and dumping it into the urine and I already shared with you my own experience and that of others now let's transition as a final Point into the ketogenic diet the ketogenic diet is calorie for calorie probably the best way to improve insulin sensitivity and I would even say weight loss in the body um interestingly uh a ketogenic diet uh often but not surprisingly will be high in meat including red meat and even fish so those are foods that are high in purines now typically this person's not eating a lot of fructose of course that would be antithetical to the ketogenic diet and as we mentioned before when purine metabol metabolism is high uric acid production goes up now there are studies to show that that that uric acid levels can stay high or even climb with the adoption of a ketogenic diet this is documented it's published and I'm and I have no qualms in sharing that so how do we reconcile that with the fact that I just mentioned how I believe based on the evidence that calorie for calorie the ketogenic diet is the best way to improve insulin sensitivity well we just got done talking about how uric acid will increase inflammation and thereby cause insulin resistance interestingly the ketogenic diet even if some of the studies show an increase in uric acid levels uniformly show a reduction in inflammatory signals so when you look at something like C reactive protein it is always down in the group on a ketogenic diet and yet sometimes uric acid is up so what is going on how do we reconcile all of this the reconciliation I believe is explained in the study that we've just finished with Dr Johnson as a collaborator the Dr Johnson I've alluded to a couple times now these are once again unpublished I have at this point in time recording this podcast a handful I I think I have three studies that I need to finish and get published or submitted for review to publish this is one of them we wanted to answer this question and so we conducted a series of cell culture-based experiments so the simplest model right to cells growing in Petri dishes where we found if the cells were treated with uric acid inflammation was up and insulin resistance occurred when we treated with uric acid and an anti-inflammatory agent insulin resistance was better when we treated even further one more step with uric acid and an inhibitor of camide production the cells were in insin sensitive so you can see that we addressed it at each of these subsequent steps remember the pathway that I outlined earlier uric acid causing inflammation causing camide a cruel causing insulin resistance if we increase the uric acid we get insulin resistance if we increase the uric acid but block the inflammation the cells are insulin sensitive if we increase uric acid but block the ceramide production the cells are insulin sensitive now however where do the ketones come in earlier on I had mentioned that uric acid activates the nlrp3 inflammosome well guess who inhibits the nlrp3 inflammosome ketones and so it could be that in the ketogenic diet despite the increase in uric acid the ketones are sufficient in order to keep the consequences of the uric acid in check now as an interesting Next Step here that that one of the possible explanations for why a ketogenic diet can increase uric acid may be the high consumption of meat it may also be the fact that when ketones are getting excreted at in the urine at the kidney they actually compete with uric acid and so if you have more ketones in the blood it could be not that you're making more uric acid but just the very Act of clearing the ketones means the uric acid levels have to wait a little bit the uric acid molecules need to wait until they can get in line to finally be excreted potentially giving rise to the higher uric acid levels um you could look up an old study published in 1965 by Loke leq at all Loke um 1965 L CQ we'll put this in the show notes like all of them um but you can look that up there and they detail this pathway of this competition for excretion anyway that could be a part of it but again the evidence does suggest that if you are in a ketogenic diet you don't need to be as concerned about the U acid because you're also making molecules that are inhibiting the inflammation that's it that's today's metabolic classroom I hope by this point now you feel much more confident conversing about uric acid what it is why it matters where it comes from and even what to do about it thanks for tuning in thanks for listening as ever nothing Thrills a professor more than having a new bunch of students to teach a principle to thanks for joining me

Channel: Insulin IQ

Views: 72,855

Keywords:

Id: Eh6pg3jBPEk

Length: 33min 57sec (2037 seconds)

Published: Wed May 15 2024