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Note from Steve Phinney: What this shows is that uric acid goes up promptly in the same time frame that ketones go up, but after 4-6 weeks, despite ketones staying up, uric acid starts to come back down. Based on these data and my clinical observations in thousands of patients, uric acid returns to or below pre-diet baseline within 6-12 weeks despite the person remaining is a state of nutritional ketosis. Thus, when I’m asked how long ketoadaptation aks, I generally respond that some aspects of it take 6 weeks or more.
This graph, by the way, shows blood uric acid levels from the untrained subjects (VT) and bicycle racers (MIT) at various times over 4-6 weeks of sustained carbohydrate restriction (aka keto-adaptation). |
LISTEN (50 Minutes)
EDITOR’S NOTE: Sometimes, the divide between experts who advise against a high-fat, low-carb diet and those who recommend it seems larger than the Grand Canyon.
But occasionally, top thinkers from both sides break through to discover common ground, along with new paths for exploration. With that in mind, here’s a discussion between two nationally recognized health researchers which refers to the uric data in this chart . . . and more. To see the charts in larger format, click on them, and they should enlarge.
Before going to the transcripts of this interview, here’s more background: Dr. Steve Phinney is emeritus professor of medicine at UC-Davis and a world-renowned expert on high fat diets, including how they affect uric acid levels. Dr. RIck Johnson is a professor of medicine at the University of Colorado who’s an expert on fructose metabolism (fructose accounts for much of the sweetness in table sugar and in high fructose corn syrup). Johnson’s expertise on fructose ties him back to uric acid. Johnson writes: “Our work focuses on how diet (and in particular fructose) as well as serum uric acid may have a role in the epidemics of obesity, diabetes, hypertension, and kidney disease. Our work includes studies in cell culture, animal models, epidemiological studies and clinical trials. Recent studies include studies of fructose induced obesity, insulin resistance, leptin resistance, and fatty liver. We also are interested in the subcellular, and especially effects on the mitochondria in response to fructose and uric acid. Most recently our work has focused on how a reduction in ATP generation in response to fructose and uric acid may translate not only into obesity, but also into fatigue and decreased exercise.
Steve Phinney has a long history of knowledge about uric acid as well, which he’ll share in the interview ahead, as these two medical doctor/scientists compare their experiences looking at uric acid levels, ketones, diet and exercise.
This is a special conversation because both of these researchers have demonstrated a willingness to venture outside some predictable boxes, in order to compare what they know and gain insights from each other. As an overview, most medical professionals consider higher uric acid levels to be a sign of danger, and that’s one reason that many warn that a low carb, high-fat diet is a bad idea–because at least at first, transitioning to a high-fat, low-carb diet raises uric acid levels in the blood. But as you’ll see in this discussion, Steve Phinney, who’s an expert on long-term adaptation to high fat diets, can demonstrate that a short-term rise of uric acid is not hazardous for most people, and if someone stays on a low carb diet over time, uric acid levels go down. Currently, it’s also commonplace among medical professionals to say that ketones are bad for health. Ketones are are a type of fat produced when the body is burning lots of fat, and when the body creates ketones, it’s often possible to detect them through urine or blood tests. Many health professionals assume that detectable ketone levels are always a warning sign of ketoacidosis, but that’s not true. Ketoacidosis IS dangerous, but it generally only happens when blood sugar levels are high at the same time ketones are going very high. When blood sugar levels are normal, many experts on low-carb diets report that the presence of ketone bodies in the blood or urine can be an indication that a body is “keto-adapted.” That is, a keto-adapted person’s body may be in a very healthy state that involves burning fats for fuel. It’s worth noting that many conventional health experts still disagree with this opinion.
So, who’s right? And what’s the right thing to do for health? That’s what these two scientists will discuss. A warning — these research scientists are NOT talking to a general audience here. They’re talking with each other, and they’re discovering insights as they go, as they use many technical terms. We’ll try to define those terms occasionally as they go along, but if you don’t like technical discussions , you might want to skip this.
Uric Acid and Low-Carb Diets
STEVE: The intriguing dynamic we both have an interest in is uric acid metabolism and its role as a possible bioactive material in affecting fuel partitioning in animals and humans, or its role as a biomarker of metabolic state. I’ve been curious about it, because, having done a lot of research in carbohydrate restriction, I’m aware that there’s a very dynamic change in uric acid metabolism as we initially take all carbohydrates out of the diet, but it’s been my understanding that the uric acid levels rise only temporarily on a low carb diet, and then go back to what they were before. I haven’t thought of the uric acid rise as a health problem.
RICK: We’re doing a lot of work on the role of uric acid in biology. Originally, it was thought to be a biomarker of energy crisis. Irving Fox and others would point out that uric acid goes up with a decrease in dietary energy, and the classic situation is during starvation, particularly when protein is broken down. When you starve the first 24 hours or so, glucose in the blood is provided by glycogen (that’s a sort of starch the body makes and stores close to cells that need quick energy, such as liver or muscle cells) that’s broken down by the liver, but then rapidly the body switches to starting to burn fat. During the initial part of burning the fat, the brain still has not adapted to using ketones as a fuel, so in the first part of this second phase, the uric acid goes up in the bloodstream, and that’s probably a reflection of protein breakdown and gluconeogenesis (that’s a way to raise blood sugars in the body by burning glycogen, recycling extra protein, or even sacrificing proteins the body’s been using for building work and building blocks) that the body is undergoing in order to provide more glucose for the brain.
STEVE: Is the rise in uric acid due to protein breakdown that allows a cell to survive, such as proteins within a cell that are recycled or processed to make glycogen, or is it due to cell loss that’s caused by a cell dying, or if you will, being harvested for its protein, leading to the release of the nucleic acid in its DNA, and messenger RNA that are released when a cell actually dies.
RICK: I think it probably is the death–mostly the programmed breakdown of muscle cells with the release of nucleic acid.
STEVE: In humans, when someone is calorie restricted, we see nitrogen loss due to some protein breakdown. But we have thought it’s because some of the contractile proteins within a muscle cell are being harvested, while the cell itself is surviving. In other words, the muscle cell is losing protein mass. We hadn’t thought about the rise in uric acid levels being caused by actual cell death.
RICK: Well, it probably is cell death.
SHELLEY: Just to be clear . . . you’re saying that there are two possibilities for how a body “makes” sugar when someone first cuts back on carbs. One possibility is Steve Phinney’s suggestion of a recycling effort by the body, where it steps up the effort to take any unessential amino acids — meaning protein molecules — and it sends these protein fragments to the liver for production of sugar, or for conversion into the body’s storage form of sugar, which is the stuff called glycogen. While harvesting a lot of protein molecules might weaken some cells, it would conserve cells that are still active and living. The second possibility is Rick Johnson’s suggestion of actual sacrifice — death — of cells with high protein content, such as many of those in muscle and bone, with the cell’s death providing the materials needed to make more glycogen. In this scenario. Either of these scenarios might offer part of the explanation for why uric acid levels initially rise when someone cuts back on carbohydrates. But in this second scenario, it’s the by product of cell death that would explain higher uric acid levels.
RICK: You can synthesize uric acid from amino acids precursors, but a more common way is for cell turnover with nucleic acid release, and then the nucleic acids are broken down and the liver generates the uric acid from those breakdown products.
SHELLEY: Hmm. So the cells die, and as part of the death there’s recycling of the nucleic acid that’s been bound up in the DNA and RNA, and as the liver turns the proteins in that dead cell into glycogen, it gives off the byproduct of uric acid. (NOTE: Right here, the researchers are talking about how the body, itself, can produce uric acid. But it’s worth remembering that some foods, on their own, are high in uric acid. These include foods high in purines, which are the building blocks of the nucleic acids in DNA, RNA and many important enzymes. Purines are especially high in things that have a high proportion of DNA in them, such as foods high in yeast (that includes beer).
So, it seems that you both agree that initially at least, when someone switches from a high carb to a low carb diet, their uric acid levels go up. And that’s whether or not they’re eating purine rich foods. But then, why do uric acid levels in the blood go up? Are you both saying the same thing now, about why uric acid levels rise during the switch from carbohydrate burning to burning fats?
STEVE/RICK: No.
STEVE: As an internist I was trained to treat hyperuricemia, which is defined as high levels of uric acid in the blood, and I’m aware of the benefits of reducing those levels. But as someone who’s done a lot to treat people with low carb, ketogenic or calorie restricted diets, I’ve considered the transient initial rise in uric acid that occurs in the first few weeks of ketoadaption as inherently benign in the long run. Except in the case of someone prone to gout. In these people, both high uric acid spikes upward or sudden drops downward can trigger a gout attack, and we take steps to reduce that risk in gout-prone people. Overall, I’ve thought of the fluctuating uric acid levels that occur when switching into fat burning as transient and inherently benign in the long run, and I’ve not thought the uric acid level changes require medical intervention. But I’m certainly open to being reeducated if that was a misconception.
RICK: Uric acid definitely has a lot of biologic effects. We can show that it’s kind of an alarm signal with biologic function attached. It can activate inflammatory cells. It can induce inflammation of a wide variety of cell types. It can cause vaso constriction, that is, narrowing of blood vessels, and raise blood pressure. I know that Dr. Fine has found, for instance, that following bariatric surgery, which is surgery to shrink the size of the stomach or some other digestive organs, there’s an early rise in uric acid and blood pressure. The more we learn, the more we realize that uric acid is probably not just a marker but a player in this whole series of events involving starvation, fat and carbohydrate storage and inflammation and so forth. So we’re actively studying a lot of these processes, and your viewpoint will change with time.
Uric Acid, Keto-Adaptation (Healthy) vs. Ketoacidosis (Dangerous)
STEVE: I’m aware of the bariatric changes. When I did my clinical fellowship in nutrition, I worked once with a group of physicians where many felt that in gastric bypass surgery, any calories you got into those people was good, to get them re-fed and out of the hospital, and the primary food to give them was simple carbs. But at the Deaconess Hospital (now Beth Israel Deaconess Medical Center) at Harvard, George Blackburn and Bruce Bistrian were strong advocates of low-carb, ketogenic diets. Some of their post-operative gastric bypass patients had difficultly with avoiding foods that caused them problems, such as fresh milk that caused obstructing curds in their digestive tract after surgery. They would come into the ER, and Dr. Blackburn would admit them into MIT’s metabolic ward where I became the lieutenant to whip them into shape in terms of food choices. So I got to deal with a lot of these people in a metabolic ward. We used diets that when we kept them in nutritional ketosis (about 3 millimolars beta hydroxybutyrate — that’s a log order lower than ketoacidosis, by the way). In patients with nutritional ketosis, if anything, we saw improved blood pressure, and we saw very good metabolic tolerance — even in the first few weeks of carbohydrate restriction. It seemed to be quite different from the pattern we saw with gastric bypass patients eating the more typical high carb diet of sugars and starches. And that’s not all. We were studying metabolic adaptations to carbohydrate restriction. So we also had people who were not post-operative but were simply eating ketogenic diets in a metabolic ward. Drs. Bistrian and Blackburn together published 50 papers on that. I got to be part of 5 or six of those during my fellowship.
RICK: Did the patients in your ward get any glucose at all.
STEVE: We fed one of two diets. One of meat, fish, and poultry with about 600 – 800 calories per day, with about 100 grams of protein, basically 1.5 grams per kilogram reference body weight per day. The meat, fish and poultry diet was problematic for early gastric bypass patients. For gastric bypass patients we’d use a commercial liquid weight loss ketogenic formula of mostly protein with about one-third of calories from carbohydrate, usually as maltodextrin, not as sucrose.
RICK: Perhaps you did not see the rise in uric acid during the acute phase, or did you?
STEVE: We saw a rise in uric acid, but it didn’t matter whether we were feeding our patients the meat protein sources that contained nucleic acid or the purified liquid diet proteins that contained no nucleic acids,. For instance, when we were feeding dairy-origin proteins such as whey or casein, we didn’t see any difference compared to meat. Nor did I see any differences in blood uric acid levels when I was at University of Minnesota and we were making comparisons between ketogenic, meat-based diets and formula-based diets in cohorts of 40 people per group. The metabolic profiles of the patients, in regards to uric acid and ketone levels, were pretty much the same, independent of the protein source, which leads me to think that the rise in uric acid was not determined by purines in the diet. More likely, it was due to the competition between ketones filtered from the blood and uric acid in the kidney. I don’t know if it’s still politically correct to talk about the organic acid secretary pathway. But the competition between ketones and uric acid has always been thought to be the classic reason for the rise of uric acid following the induction of the ketogenic state.
RICK: One possibility is that the ketones are blocking the uric acid secretion and so you become hyperuricemic. But the problem is that ketones continue but uric acid levels go down. So there either is then an adaptation or another mechanism for the rise in uric acid. The question is, I was thinking it is related to the fact that the brain may not adapts to the beta-hydroxybutyrate rapidly and there may be a desire to help maintain glucose levels, in which case, the question is, could you do gluconeogenesis from the proteins administered through dietary feeding, or would you have to break muscle down. And breaking down muscle would be an explanation for the uric acid rise.
Protein Balance in Bike Racers Who Ate Low Carb, High-Fat
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Comment from Phinney: This graph shows nitrogen (aka protein) ‘balance’ in the bike racer study. What this slide demonstrates is that taking away all carbs while holding protein and energy intake constant causes a mild inefficiency in the body’s use of protein. This inefficiency takes about 3 weeks to fully resolve to the point that the body gets back to its original ‘balance’ despite maintaining the very low carb intake and stable blood ketone levels. |
STEVE: Good question. I thought it would come up, so I brought these diagrams along for data. We did a study in a group of lean healthy males, some of whom were bicycle racers, and we locked them up in a metabolic research ward and gave them seven days of a low-fat, high carb diet, which is pretty much what they usually ate. This diagram shows nitrogen balance calculated by taking measured nitrogen intake where we were feeding them precise amounts of food, then we collected all urine and all stools and did total urine nitrogen and stool nitrogen analysis. We fed them 1.7 grams of protein per kilo reference body weight per day with a eucaloric diet, so it was weight maintenance for then lean healthy mails. Then we changed the diet, giving the same amount of protein and no visible carbs (that is, no carbs except in the glycogen in the meat they were fed). Based on their nitrogen balance response, there is a transient period of lean body mass loss, but since each gram of nitrogen excretion roughly equates to 1 ounce of muscle loss, they were losing less than a quarter pound of lean tissue for the first 3-4 days.
RICK: So muscle loss acutely. This is what I think is driving the uric acid up.
STEVE: But their average total loss was at most a pound based on area under the curve for the typical subject in a group of 9 subjects. And at the end of the first week of the low carb diet, they were back at baseline for nitrogen metabolism. This metabolic ward at MIT was set up by Nevin Scrimshaw, Vernon Young and Hamish Monroe, who were literally the Gods of nitrogen metabolism in the 1960s and 70s, They said that true protein maintenance occurs at about +1 gram of nitrogen per kilo per day, maybe due to loss of hair fingernails, etc. But this diagram shows in the final week of the study, they were recovering back what little they had lost here in the first week of the low carb diet.
RICK: So the prediction is the uric acid would only be high during this phase and then would come down.
STEVE: The light blue bars are the uric acid levels of this group of lean healthy males. They started out with values under six, they went to values over 12, Week two 11, and by week four they’re heading back down though not yet at baseline. This other bar is at the University of Vermont with five females, one male in a metabolic ward. They were on a very low calorie ketogenic diet in order to lose weight, very low calorie ketogenic diet. These guys from MIT, the bike racers . . . They’re riding over 100, 200 miles per week. This group from Vermont. . . . they’re sedentary. They only exercised twice. Their response in terms of nitrogen balance and ketones and uric acid was similar to the bike racers. My clinical experience using this as a weight loss tool in over 2,000 patients, is we did labs on them once a month in those subject, and by the third month, most of these people were down to their baseline uric acid levels. Many people actually went somewhat lower by four, five six months. The mean duration on the diet was 6 months, which was monitored through ketone levels. So I had a fair amount of clinical experience.
SHELLEY: Rick Johnson you’re interested in what happens to people’s blood pressure and what happens to them in ketosis and with their uric acid level variations.
RICK: It sounds like you’re saying the blood pressure really didn’t change very much in these people.
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Steve Phinney: This graph shows the blood ketones from my bike racer study, and illustrates the prompt rise in ketones by the first week of the diet. |
STEVE: But realize these were bike racers. Five of the nine were riding up to 200 miles a week. That degree of physical effort and training can probably overwhelm a great degree of incipient pathology in the normal person. These were the actual measured serum ketones in the light blue bar subjects. By the first week, they’re 2 milimolars. There seemed to be a trend down. We were interested in that. It wasn’t statistically significant. But because the bike racers were going to do both a maximum performance test and an endurance test to exhaustion at week four, we asked them in the middle of week three to stop exercising. We know that exercise drives ketogenesis. So the dip down is probably not a trend down. It was probably just because we took away the exercise driver, and that’s the affect of exercise on ketone values These people here in the Vermont Study, who were more sedentary, on the blue bars averaged 1 1/2 or 2 mmol ketones, across a six week controlled diet period.
RICK: Are you saying you believe that the ketones are why the uric acid is high and there’s some kind of adaptation that occurs. Because the urinary ketones stay high throughout.
Keto-Adaptation can take 6 weeks
STEVE: I’ve had people who’s blood ketones remain high for months. They appear to make a full recovery from that initial transient hyperuricemia. There appears to be some delayed adaptation. I call that human keto-adaptation. My interest has been the adaptation of physical performance. All the studies that led to carbohydrate loading as benefiting competitive athletes were done by comparing low and high carbohydrate diets athletes . That is, they were only switched to a high fat, low carb diet for a few days and certainly for less than two weeks. When we put sedentary obese people on the low carb diet and tested them after one week they could walk just under 3 hours of walking uphill at 65% of peak aerobic power until they couldn’t keep going. It’s a cruel test to do! After one week, on the ketogenic diet, they’re down to just two hours of walking before exhaustion. That’s a pretty significant reduction in their ability to keep going. But after six weeks of adaptation to the ketogenic diet, we put them back on the uphill treadmill, and now they walked on the uphill treadmill for over four hours. That’s significantly more than when they started. In case you’re wondering, while on the ketogenic diet, they had lost, on average 25 pounds. Now, we adjusted for that somewhat, because at week number four, we put 25 pound backpacks on them , so that they still had to carry the same amount of weight that they started with. But, based on oxygen consumption, which we measured, it turns out that carrying weight in a backpack is more efficient than carrying weight on your body. So we can’t prove an improvement in their performance after four weeks on a ketogenic diet. But at least we can say there’s a significant recovery in performance.
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Steve Phinney: This shows the treadmill times of my untrained subjects at baseline, then at one week and 6 weeks into the ketogenic diet. |
RICK: DId the bike racers show a decrease in performance after one week?
STEVE: In the bike racers, we were using very invasive studies that required two catheters and needle biopsies before and after exercise to measure muscle glycogen. To reduce the chance that they would walk out of the ward and never come back, we did only two studies, baseline and four weeks in the bike racers. Thus, we don’t have one-week data. But we do have beginning and end point data that show, before switching to a low-carb, high fat diet, endurance time to exhaustion in the bike racers was 147 minutes at 65% of peak aerobic power. By the way, their peak aerobic capacity is 1,500 calories an hour, so two thirds of that means they were exercising at 1,000 calories per hour. Now, most research of athletes who switch to a low-carb, high fat diet follows them for less than two weeks, and that research indicates a drop in their performance ability, similar to the drop in performance we saw at one-week in our Vermont non-athletes. As I mentioned, we don’t have that one-week data for our bike racers, due to our concerns about the rigor of our testing. But to me, the key is what happens further out in time anyway. And here it is. Despite four weeks of eating no visible carbs, in the four week test of the bike racers, their VO2 max was unimpaired, and their endurance to exhaustion was pretty much the same as it had been initially, on the high-carb diet. But their was a change, and that involved what their cells used for fuel. At the start, when they were eating mostly carbs, the muscle cells of those bicycle racers were burning 50-50 carbs to fats. After four weeks, they’re doing the same amount of work but almost 95% of the energy is coming from fat. This is quintessential evidence for keto-adaptation. Meanwhile, in the muscle glycogen, they drop the total amount of glycogen in the muscles, compared to when they started. But doing exercise, they use far less of the glycogen for fuel.
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Steve Phinney: This graph shows the performance and metabolic data from the bike racers, demonstrating no loss of peak aerobic power or endurance performance after 4 weeks on the very low carb diet. The RQ value of 0.72 during exercise at 900 kcal per hour demonstrates how effectively their bodies have converted to using fat as an exercise fuel. |
RICK: They’re conserving their glycogen as much as they can and using fat more often.
STEVE: Their cells are becoming extremely efficient at sipping glycogen instead of gulping it. We didn’t do CRPs (C-Reactive Protein is a common measure today of inflammation in the body) in those days, but these athletes had lower white blood cell count over the four weeks, which may be another marker for lower inflammation.
RICK: They’re still hyperuricemic here at four weeks.
STEVE: They’re higher than they were at baseline.
RICK: It’s clear that a ketotic diet is leading to a more efficient fat utilization. Maybe associated with an initial drop in performance, but over time it recovers. We’re learning more and more about how beta-hydroxybutyrate is giving benefit to organs with a high mitochondrial content. (Note to readers – mitochondria are sort of like the batteries inside of a cell, that help the cell burn and use energy. Mitochondria are actually separate, living cells that are housed inside our cells, and if one of our cells need more energy, the number of mitochondria in that cell can increase. Cells that typically are high in mitochondria are muscle cells, including among other muscles, the heart.) Ketones may offer benefits in the heart, in the kidney and certainly in the brain. You wonder about the benefits of beta-hydroxybutyrate in these states and how it affects mitochondrial function. The uric acid is very confusing, because it’s certainly going up acutely and then it comes down. And mostly we think of it as not a good thing. But uric acid can be beneficial in some cases.
STEVE: When you look at the ORAC test in human cells (Note to listeners, the ORAC is the Oxygen Radical Absorbance Capacity test. It’s a test tube evaluation of how human cells respond to oxidative stress), the biggest variable in anti-oxidant status is not alpha tocopheral in the blood or vitamin C in the blood, It’s uric acid in the blood.
SHELLEY: Are you both saying that uric acid in the blood can be protective from an antioxidant standpoint, but inside the cell, it may be causing problems, and the level in the blood may be a hint at what’s going on in the cell.
RICK: Inside the cell uric acid is a pro-oxidant, and outside the cell it’s an antioxidant. But is a pro-oxidant in the cell always bad? Well, it depends on the biologic content in terms of starving the cell or trying to load fat in the cell or burning fat. Obviously the most interesting thing would be to do a randomized trial and give some of the bikers allopurinol (note to readers–allopurinol is a medication that blocks uric acid production by the liver, and in this way, keeps circulating uric acid levels lower) to see what happens when you block uric acid rise in the blood and see how it would affect their performance.
STEVE: Working with Dr. Jeff Volek at the University of Connecticut, my collaborator there, we looked at some affects of carb restriction on people with metabolic syndrome. After all, arachidonic acid is bandied about as being inflammatory within cells, whereas Omega 3’s are considered to be anti-inflammatory. I’m very interested in what happens to these fatty acids when a person is restricting carbs. So we took 40 people with metabolic syndrome, who were on average somewhat inflamed, as evidenced by high blood pressure or central obesity (fat around the tummy), or high triglycerides or low HDL cholesterols. Half of them were put on a 1500 calorie energy restricted high carb diet, the others put on the same calories but high fat, very low carb. They were out-patients, and we followed them for 12 weeks. After 12 weeks the mean weight loss in the high carb group was 5 kilos, and the mean weight loss in the high fat group was more like 8 kilos. Some of that was water, but still, they lost more fat than the high carb group. The most important data in this is that Jeff measured 14 different markers for inflammation, and both groups had some reduction in inflammation, but the reduction in inflammation was significantly greater in the high fat, low carb group. There was also more reduction of insulin resistance in the high fat, low carb group.
RICK: My interpretation of your data is that when you go on a low-carb diet, you will have a tendency to deplete glycogen in the liver more rapidly and since glycogen retains more water with it than fat does, per gram, you lose a lot of the water that’s attracted to the glycogen. That accounts for the greater water loss. And then the body has to start utilizing fat more often as its energy source. My guess is that’s why you see more reduction in water and fat on that diet. As for the improvement in insulin resistance and inflammatory markers . . . in people with insulin resistance, most of the reduction of insulin resistance and inflammation is more likely to be due to the reduction of fructose intake rather than the reduction in carbs. The evidence that fructose drives more insulin resistance and inflammation getting quite significant. We have a paper in press right now where giving less fructose to people with kidney disease made for greater reduction in inflammatory markers and insulin resistance and blood pressure. We also have a study in press with low fructose but it was with caloric restriction so it’s a little trickier. Nevertheless, the evidence of the role of fructose is getting more significant.
New Study to Determine the Role of Glucose & Fructose in Disease
STEVE: There’s a potential of going back to look at the fructose content of subjects who were on the carb containing part of our recent study. And this summer, we hope to be doing another study that gets everybody keto-adapted, getting them off the sugar-and-starch roller coaster and then we will incrementally add back carbs until we get them all out of ketosis. We’re doing this because as a clinician, I have seen that in some people, you can feed them 50 grams of carbs and they’ve got huge amounts of ketones, whereas another person given the same amount of carbs will have ketones levels that are very low — it’s like they’re eating 4 bagels a day. And we don’t know why different people respond in these different ways. We have the potential of looking at blood and urine uric acid levels.
RICK: Uric acid does affect glycogen. We have some beautiful data. In fact, if you acutely raise it, uric acid blocks glycogen degradation in the liver. This was actually published in JBC in vitro (note to reader-in vitro means in a test tube), but we have in vivo (in a living body) data. There is a uric acid glycogen story.
STEVE: Is it due to lack of degradation of the glycogen, or is it increasing glycogen production because the metabolic trauma or stress of uric acid is driving gluconeogenic carbon from the periphery to the liver? When you stress somebody, the peripheral musculature gives up what it’s got to help out the central viscera.
RICK: We loaded animals with glycogen then looked at the removal of glycogen over time during starvation. So it’s more a removal of glycogen. We do think there could be effects on glycogen synthetase, but we haven’t looked into it in great detail yet.
STEVE: Since we haven’t started collecting samples yet . . .
RICK: Collaboration would be wonderful. And the other possibility is that the low carb diets improve insulin resistance in part because of reduction of dietary glucose that reduces endogenous fructose. When you become insulin resistant, your aldose reductase goes up and so you start making endogenous fructose. We’re doing studies right now with fructokinase knockout animals to specifically check that pathway.
STEVE: I hadn’t considered endogenous fructose production.
RICK: It’s very important.
STEVE: The pathways for disposal of dietary fructose are very different from the disposal in the fructose 6-phosphate pathway. They don’t cross. But endogenous fructose? Is there a place I can read about that.
RICK: There will be some papers coming out on that, so stay tuned. Fructose is used to help increase fat stores. It’s all meant for a purpose, just as all animals, including us, have machinery to raise fat, and machinery to lower fat.
Fatty Acids in Health and Disease
STEVE: Dr. Forsythe is the first author on Jeff’s study in Lipids in 2008.
RICK: I think I have a copy. It’s a beautiful study.
STEVE: We looked at phospholipid fatty acid profiles of these people before and after, this is baseline, week zero and at 12 weeks out. We saw a consistent rise in arachidonic acid overall, which is surprising because arachidonate is something that we normally see is tightly regulated over time. And it’s not because they ate more arachidonic acid. An Australian group that published a study in the New England Journal of Medicine in 1993 was interested in membrane fatty acids and insulin sensitivity. They did muscle biopsies that indicate that membrane arachidonic acid is positively correlated with insulin sensitivity. They’re talking, not about protein receptors embedded in the membrane but the membrane fatty acids themselves, that seem to be affecting the sensitivity. We are going to look at that in more detail in this upcoming study.
RICK: Did you measure prostaglandins, or thromboxine derivatives to see if there was a change in patterns.
STEVE: We measured urinary isoprostanes, but it’s very hard to get a snapshot of them, because they’re so bioactive. And yes, prostaglandins are a byproduct of arachidonic acid, but there’s another possibility. Everybody up to now has looked at membrane composition from the view of dietary input, but membrane fatty acids are prone to peroxidation, and so they might be affected by degradation instead, in essence becoming victims of reactive oxygen species.
RICK: The other thing is comparing a ketotic diet to one where there’s calorie restriction leading to ketosis, where you’re not getting fats fed to you and how that affects fat metabolism differences.
A Healthier, High-Fat Chow for Research Mice and Rats
SHELLEY: Have you told Rick Johnson about the high fat chow you’ve made that isn’t runny?
STEVE: I’ve worked with Craig Warden on his obesity prone C57/black mice6 to produce a healthier ketogenic diet than Bioserve’s F3666. Rodents are quite keto resistant. F366 is 94% fat, 5% protein, and it does produce ketones, but it also makes rodent livers fatty, and liver enzymes go up, if you keep them on the diet for a month. Our healthy ketogenic diet is 15% protein, 76% fat and only 5% is carbs, using the sugar alcohol xylitol, which unlikes sorbitol or manitol, yields energy but is not insulinogenic, and so they get moderately ketotic without getting fatty liver. In contrast, the F3666 fed rats have fatty livers.
SHELLEY: What about the Zucker rats that are prone to metabolic syndrome?
STEVE: They’re leptin resistant rats.
RICK: Sprague Dawley rat? That’s a regular rat. So what about the ketotic diet for rats again?
STEVE: The F3666 diet has been used for a decade to create rodent models to explain why a ketogenic diet helps kids with epilepsy.
RICK: You’re saying two different ketogenic diets have major differences on fatty liver. What’s the difference?
STEVE: The F3666 is very low in protein, so the animals don’t gain weight as fast, but we think it’s inducing sarcopenia. It’s so low in protein that the animals are protein starved. We think it’s making their liver very sick.
RICK: Kwashiorkor.
STEVE: Yes, and it’s preventing, we presume, lipoprotein production in the liver so you entrap fat in the liver because you can’t efficiently produce adequate surface proteins to get it out of the liver and into circulation.
SHELLEY: With humans, do they get fatty liver on a high fat, low carb diet?
STEVE: They get fatty liver on a high carb, low protein diet. That’s Kwashiorkor. When you feed children pure starch diets because there is not protein, such as just manioc, they develop bloated bellies with big, fatty livers. That’s the classic field diagnosis in developing nations of Kwashiorkor.
SHELLEY: But in people eating a high fat diet, generally does that reduce fatty liver or increase it.
STEVE: Eric Westman has attempted to do a small study using ultrasound, which seems to indicate it reduces liver fat on an Atkins diet, by which I mean the version that Eric Westman, Jeff Volek and I have described in the New Atkins diet book which we published a year ago as co-authors. In it, we encourage people to continue eating low-carb, high fat diets long term to provide complete remission from high blood pressure and Type II diabetes. I’ve seen it work as a clinician. We’ve seen complete remission for people of Type II diabetes when they stay with this diet. And I think it’s feasible for people to eat this way in the long term, as shown in this nearly century old pastel drawing of three Caucasians talking with native people of the Arctic, the Inuit people. The Caucasians traveled with the natives overland in the Arctic, and Lieutenant Schwatka, a US Army surgeon, said in his diary that the first two weeks on the native diet were hard, but after that, they could do great . . . for 3,000 miles of hard travel. So it wasn’t that the inuits had a unique genetic ability. They had the ability to live in a hostile environment and do prestigious feats of physical activity on a diet without carbohydrate.
RICK: Fascinating. If you have the tissue from the mice who got the ketotic diet and developed fatty liver, I think we can help you with our assays to identify mechanisms.
STEVE: The graduate student who did the studies for us may not have saved enough tissue. But next year, Craig and I might put some C57/black mice, or better yet, some Zucker diabetic male rats on a three-arm dietary study. Could you use tissue and serum from that.
RICK: It’d be a little more complicated, but yeah. You’re doing great work. Well, it’s complicated. I was thinking the rise in uric acid was from gluconeogenesis and muscle breakdown, but it can’t be strictly that.
STEVE: Perhaps you mentioned this interesting possibility, that it may be that the positive interaction with the circulating ketones is counteracting the initial transient problems with increased circulating uric acid.
RICK: I did say that.
STEVE: It once again confirms that Nature is an elegant beast.
Very informative! And I liked the way you discuss. Great synergy.