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#605: Fasting, Nutrient Timing & CGMs: Interpreting the Evidence – Prof. James Betts
00:56:13
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- [00:00]
A
Hello and welcome to Sigma Nutrition Radio. This is episode 605 of the podcast. My name is Danny Lennon. You are very welcome to the show. We're on quite the run of podcasts, if I say so myself, and lots of great feedback over the last couple of weeks on some of our recent episodes. So if you've missed any of those, I think it's worth adding them to your To Listen list. Last week we had Dr. David Allison talking all about some of the aspects that are really important to consider when interpreting nutrition studies for doing better nutrition trial trials in the future and getting better quality answers, and in particular picking up on some of the important statistical concepts that allow us to spot when a study is being misrepresented or if the conclusions don't actually match the data, or if a study is even set up to answer the question that it claims to do. Lots of great feedback on that. So if you haven't listened, I think it's worth listening. For those of you who did listen into that episode, you will note that a few of those themes are going to emerge that today as well, and will overlap with a couple of those ideas which I think will really help solidify those and see examples of where that plays out in other areas. So that will be particularly useful. Previous to that, I had Dr. Andrew Reynolds on the show to talk about his discussions around dietary fiber, whether it could be considered essential or not in the future. This concept of essentiality of nutrients, how we define that, and then some of the evidence we have today on dietary fiber intakes and chronic disease risk. Lots of good feedback on those couple episodes. So worth checking those out if you have yet to listen to those. Today I'm going to be talking with Professor James Betts of the University of Bath, who was previously on the show back in episode 399. There we talked about some of his really important work that related to concepts like intermittent fasting, and would there be any benefit to such setups that are not just directly caused by calorie restriction? And so his group have done some really tightly controlled work in the area that's been really useful. And so in the intervening time, there's been quite a lot of advancement in those fields. And so I wanted to get Professor Betts back on to talk about some of these aspects of intermittent fasting, nutrient timing, chrono nutrition, and see what the current evidence tells us, where his conclusions now lie based on the evidence we have, and, and then some of the interesting areas going forward. We'll also talk a bit about the concept of continuous glucose monitoring. He has carried out extensive amount of work that has used some degree of glucose monitoring across a number of studies, is very familiar with all the different devices out there and has spoken excellently about what they do capture, what they don't capture, how to interpret them properly and then how we might use that, particularly when it's being now used in situations like in sports nutrition. So hopefully we're going to try and cover much of this throughout this episode. As you will see, Professor Betts is excellent at relaying some of these ideas, speaks with precision and nuance and accuracy, all the things that I particularly enjoy when someone discusses science. And so I'm sure that you are going to enjoy this episode. If you wish to get a set of detailed study notes to accompany this episode, then you can do so by joining us as a Sigma Nutrition Premium subscriber. This is the subscription we offer that gives you extra materials to make all your podcasts listening make more sense, to allow you to get more from it, allow you to be able to retain that information and use it in the future. And so if you want to learn about what we offer with our premium subscription, then I will put a link to that in the description box where you're currently listening or over on Sigma Nutrition.com Check that out, see if that might be useful to you. And of course that's the way to support the podcast. It's literally what keeps this podcast running. So thank you for everyone who is a premium subscriber. For those of you who are listening on the premium podcast feed, then remember your study notes. Your edited transcript will be linked up in the description box and you will also be able to hear our Key Idea segment after the interview concludes. So with that, let's dive into this conversation between myself and Professor James Betts. Foreign. Welcome back to the podcast to Professor James Betts. Thank you so much for taking the time to come and talk to me again.
- [04:30]
B
Well, thank you for having me back. I can't have done too bad a job last time if you're willing to talk to me again.
- [04:36]
A
Certainly not. Not only was it, I think, one of my favorite conversations, but after the fact, it turned out to be one of our most popular episodes because of, I think, the way you were able to discuss a topic that is, I think, so often misinterpreted, either intentionally or unintentionally, and able to reference that through the work that you and your colleagues have done, which we will get to and we will maybe revisit that topic in a Bit. But maybe for people who didn't get a chance to listen to that episode, could you maybe just give a very brief introduction to the work that you do, your academic background, where you're based, and anything else you think might be relevant for people before we get into the discussion?
- [05:16]
B
So, yeah, I'm Professor James Betts. I'm professor of Metabolic Physiology at the University of Bath. I'm in our department for health. So we do a wide range of work in the department, but in particular I'm one of the directors of our center for Nutrition, Exercise and Metabolism, or affectionately known as CNEM. I've been at Bath for over 20 years now and this organization, CNEM that we've formed is, I think we have 30 to 40 researchers now working on all things metabolism and physiology. I would say the broad connector between that wide range of studies or the number of connectors are we're exclusively interested in human metabolism and health and physiology. So we don't really do any preclinical studies. We do some cell work with human samples. And I would also say we do what I would describe as integrative physiology. And when I say integrative, I know that word gets used lots of different ways. What I mean here is when you look at the full breadth of science, how it can be basic science that really pure basic biochemistry, biology at that kind of cell, molecular end, right up to applied science, where you're getting practically useful outcomes at a whole body level, the kind of thing that your GP might measure, and we endeavor to incorporate as many of those in one study as possible to translate the evidence. So if you see a whole body outcome, you can kind of explain the mechanism. And if you see a mechanism, you can also say why that's useful. So I would say that's the range of studies that we all work on in my center. And then for my part in particular and relevant to today, I've become very interested in, yes, human metabolism, but particularly in time, the timing of everything, the timing at which different stimuli like nutrition, exercise, sleep affect us and then the various rhythms that exist in the body that then may or may not be affected by those different events that happen on a daily basis.
- [07:15]
A
One of the things that later I do want to return to is your approach within your group of the work that you're doing. Because I think, as I've mentioned to you before, we were recording, the quality and rigor of the studies you do is really tremendous. We will save that for later. First I wanted to pick up where maybe we had left off. In our discussion, maybe close to five years ago now, we discussed a lot of the work that up to that point you and your group had done around things like fasting, breakfast, nutrient timing. Obviously there's been a continuation of some of those themes and a development into more specific branches of that in those intervening years. So maybe to lead off with a overly broad question, but to give us a rough idea from that time point. So let's say over the last five to six years, what do you think have been some of the things that have emerged or have been refined in what we're seeing in the general area around either time restricted eating, intermittent fasting, or the timing of those nutrients?
- [08:16]
B
That is a really broad question. I can't remember exactly where we left off, but probably I think there was still some equivocal data out there and some questions left hanging which have been answered. I suspect I was being, as I tend to be a bit more skeptical about whether they were going to show any great benefits. And I think some of that has been borne out that actually some of the effects that were proposed of intermittent fasting and that kind of thing, meal patterns on weight change and health changes, where I would have been skeptical and questioning whether some of these possibilities were likely, I think a lot of studies have more been balancing that out. On the side of there not being such big effects as people once thought in that area, I think there's been more interest in other outcomes that maybe has emerged over the last five years. So whereas people were initially interested in some of the weight change and direct changes in clinical markers, but there's perhaps been a bit more interest in some other more mechanistic or more complex outcomes, like autophagy is a term. People may have heard some of these more basic adaptive responses within the body which may have benefits or harms in the longer run, maybe a bit more focus on inflammation. And the microbiome is a very topical thing that everybody seems to be interested in now. So there's been some shift of focus into what kind of outcomes people might like to study. And then for my part, my research moved a little from looking just purely at the feeding patterns where we were doing these studies on having breakfast, skipping breakfast, five, two, fasting, alternate day fasting, those kind of models. And we've started to look a bit more at rhythms in the body, what I've been calling physiological rhythms, as in doing these studies where we have people in the lab for two or three days measuring their metabolism continuously.
- [10:13]
A
And there's certainly a lot of fascinating work we can look at. I think it's interesting because many of the messages that I think certainly that come if people go on social media or see in mainstream newspaper articles or whatever can be maybe quite divorced from where we currently are with the evidence base. And I think, as you know, for certain things it's become much more clearer. And again, you can correct me if I'm wrong on any of this, but in relation to, let's say the classic time restricted eating windows or some type of intermittent fasting that early on there was a lot of claims around an advantage for weight loss and certain hypotheses put forward, it could be down to increasing energy expenditure or a variety of other hypotheses. And as more workers come out, we can be probably more clear that that's probably not the case. And maybe if there are benefits to those types of setups, it could be more behavioral in nature. First of all, would you agree with that position? And then second, if there are beyond some of those things related to weight loss, if there are potential benefits still there relating to either the timing piece, where do you think there might still be chance of any promise? Or are we completely barking up the wrong tree by even considering whether we need to have a certain eating window or not?
- [11:33]
B
Absolutely. I'd agree with the first point. There was five years to 10 years ago. Over that period there were lots of hypotheses put out there. I think, I think it is fair to say that even the scientists writing the papers maybe inserted a little more hype than was justified in those hypotheses which were then amplified by the journalists and the media. So that what the public actually hear is that these are not hypotheses. This is actually a suggestion you should intermittent fast or follow this eating regime because it will have these effects. So I think there's blame on all sides there that I think the science may be oversold. What was actually being shown, that it was more of a hypothesis, as you say. And then, yeah, I think that's why people have heard that those were more clear findings in the literature rather than a suggestion. And I think, yeah, in the time since, certainly the last five years, the data at least have discounted those hypotheses. This problem of findings being overstated has remained though. So I would not say that the literature is clear because I think if people just go and read the titles of papers and the conclusions of abstracts, you get exactly the opposite message of what the data are truly showing. And of course, most of the public don't even read the title or the abstract, they will read the newspaper article, the website article from a journalist who has probably read just the abstract. That's a big problem that remains that we're still getting conclusions of papers where the actual data in that paper do not support that conclusion. You need some degree of training in critical thinking and scientific reasoning to be able to figure that out. Sorry, what was the second part of that question? Which outcomes have the potential?
- [13:22]
A
Yeah, if there's any areas that do relate to either a fasting setup or time restricted feeding model or certain times when or not to eat, where there might be certain outcomes that do have promise.
- [13:34]
B
Yes. So I would say there's two things to focus on there. One is that while the more maybe obvious but more real world outcomes, when we first looked at weight change just changes in fasted clinical markers haven't responded. The areas where intermittent fasting feeding pattern type interventions have seemed to show greater effects are those more controlled laboratory trials where you look more mechanistically. If a study has actually like used a clamp study where you're infusing glucosin in insulin and you can actually directly test the level of insulin sensitivity. So some of these more regulatory processes in the body do seem to change. So that's less relevant to a person. You can't put that on a cover of a book and say to somebody your blood glucose will fall. But those are interesting from a scientific perspective that we might be able to target regulation. So I think that first part then is a little similar to some of the other things people may have heard me and others talk about. Like kind of research on caffeine or breakfast where the whole system surveys where we do epidemiology seem to suggest one outcome. But the actual controlled laboratory trials are showing you something very different. Like for example, caffeine. At a population level, caffeine consumption seems to correlate with good health. But then you look at it in a lab environment and we find that actually causes insulin insensitivity rather than making you more sensitive to insulin. So that would be the first part, is that there are some more regulatory measures that seem to respond. And the other part, where I think the literature is moving a little, is that rather than just having extended periods without eating per se, which seems to be just a benefit of the caloric restriction and the literature is kind of settling on the fact that's just another way to cut your calories and it's really largely related to calorie restriction and weight loss. There do seem to be a few more shreds of potential in what people would maybe consider under the heading of chrono nutrition strategies. So this means not just not eating for a long time or missing whatever meal, but this is feeds into the kind of more formal time restricted eating when you're doing a certain thing at a certain time. So it's specifically about trying to marry up your eating pattern with entrained rhythms in the body. So to give an example of that, something like the 5:2 regime that many people are familiar with is popular in lots of diet books where you would not eat on two days a week and you do eat on the other five. Arguably that would be the antithesis of chrono nutrition because you're eliciting a big negative energy balance by having a couple of days a week without food. But you are by definition not doing that in every 24 hour cycle. And there seems to be some of the studies that have shown more potential for potentially beneficial health gains. Physiological effects are those where a certain thing happens at a certain time of day repetitively, like not eating in the evening, for example.
- [16:39]
A
I do want to get to some of the chrono nutrition stuff and drill into some of those specifics. One thing I do want to pull back to because I think it's an incredibly important point that you mentioned, is that if people do go and read studies, oftentimes there is some degree of or a lot of degree of spin in the either the abstract or the introduction or the conclusions. And there's a mismatch between that and the actual data. So when it comes to this area that we've just mentioned around fasting, is there any particular examples that you could maybe give people? Or for you, what are some of those examples of the most common types of ways some, maybe causal language is smuggled into those conclusions or abstract that doesn't actually fit with data even within those studies.
- [17:25]
B
I probably have a bunch of these on the tip of my tongue because they're the things that I'm telling our undergraduates all the time. Look out for this. Here's the hallmarks. So the one right off the bat that you've just alluded to then is causal language. So if you're not seeing a study with randomization, and that's not always clear, right. So sometimes it's quite obvious this is a cross sectional study, but other times it looks like it's two groups, but it's just not, it's not immediately apparent even from the abstract, sometimes even from reading the full paper, whether a study was actually randomized. Did Participants get randomly allocated into groups. It's probably too complex to get into all the details of it, but I think that would be the first point of call is just say are people randomly allocated to groups? Because if you're not randomly allocating, you really are not expecting to see any justified causal language. Anything like results in effect of increased impacted. Those words should not be there. This is just an associational study. Another one that people should look for is then, even if the groups are randomized, have the authors actually then made any use of their controlled comparator group? So often the groups get randomized and then the intervention group in this case would be intermittent fasting, some kind of fasting regime. We're just gonna compare their follow up scores to their prescores and you think, well you could have made that same statement if you didn't bother testing the control group. So so often we find that there's just a within group comparison to baseline, it's called. So you take the weight or blood pressure or whatever else of the intermittent fasting group and say hey, they improved. You've got to compare that to the actual control group, either comparing the changes or ideally some kind of more sophisticated statistical test. But whatever test it is, it must make reference to the control group. And then the next step on from that is in particular to this case, it must make reference to the correct control group. There are literally studies in the last couple of years in this area, bless them, they've taken the time to do three a really comprehensive design where you have a control group who get asked to do nothing, an intermittent fasting group and then a lovely group that's actually matched in some way for the caloric deficit. So that's a great comparison. But then the statistics just look at either just within the intermittent fasting group or compare it to the no intervention control. And that's fine to do that comparison. But then if the conclusion of the abstract is literally going to be worded like fasting was better than caloric restriction, you better have found a difference statistically between the intermittent fasting and caloric restriction group. And that often isn't the case. Just as a little sidestep from my checklist here, there's a paper people might want to go and look at I just published end of last year with my colleague Professor Costas Tsinsas at University of Nottingham. It's called minute counting, not calorie counting. We were asked in that paper to review the literature in this area. For just the last two years I've written for that journal before it's called Current Opinions in Clinical Nutrition. And I have mixed feelings about that. If you just have to review the last two years, it means what if the last two years don't reflect the totality of the evidence? But I appreciate it's good for kind of practitioners, clinicians just to check in and see if the picture has changed. And we found six papers that had been published on time restricted eating type patterns over the last two years. I won't single any of them out now. But if you go and read that review, there's just so many papers that have been written in that time where the conclusion just simply does not match the data. So people are still getting hints that oh, there are studies still coming out showing potential for these techniques, whereas they're not there. Sorry, back to the story. The one last one I'll give then as a check that people can have that if they're seeing the right thing is that's kind of a two parter. This last one is sometimes you'll find these papers don't find an overall effect of the diet they were hoping to. So you see the kind of disappointed overall conclusion that the fasting diet didn't do what didn't change our primary outcome at a group level. And then you see the kind of all important but or however and there's going to be now a kind of more exploratory analysis. And the couple of things you then see is either if we take just the people who had high scores at baseline, so you know, blood pressure didn't improve overall at a group level when people fasted. However, if we just look at the people who had elevated blood pressure at baseline, it helped them. So that seems to resonate with people that it sounds like it's just good for what ails you, but you know that that really should be a red flag that makes you think, oh this if you're ever gonna just dichotomize the group at baseline, you, you're prone to this artifact called statistical regression where anytime you get a high score it's likely to be lower at the next score. And the kind of secondary related part of that is people looking at responder analysis, they say at a group level we didn't get an effect. But then draw one of these waterfall plots. I don't know if all your listeners will be familiar with those, but one of these plots that kind of takes a waterfall type shape where you've just lined up your participants from the highest to the lowest response and then marvel at the fact that not Everybody scored exactly the same. So that really doesn't tell you that some responded to fasting or not. You'd have to repeat the whole study and see if the people you called responders still did so. Not a long list, but I think an important one, a crucial list.
- [22:58]
A
And I think it highlights some of those really common error. And this is the striking thing of how common those are. If people go and read studies not only in this area, but in others within nutrition as well, that you see these things committed over and over again, that doesn't only become an issue within actual academia, but it's so common to see some of those same things. When people now are turning to social media and they're seeing people who nominally are science communicators of some of this that will commit those same errors. So just as you mentioned that the waterfall plots, I don't know how many times I've seen someone put up one of those on social media from a study and then start saying, look, this shows us about individualization and that some people respond to this and others are non responders to it. And so that means this diet intervention is good for this person and then this one is better for the other people, whereas that study can't tell us that at all. So the crucial fact of understanding some of those really fundamental elements you just mentioned around basic concepts, statistics, basic concepts of randomizations, of how we want to do a trial, how we test a hypothesis, that's when it becomes so important because you can immediately see, well, we can't conclude this from what this person is showing.
- [24:09]
B
Those ones I listed are quite transferable as well, in fact. So if someone's interested in ketogenic diets or high protein diets or a certain type of exercise, you can apply those same principles. They are so common. And especially the one about comparing to baseline, I would say that is the most common in relation to sports nutrition research, that is the most common problem. There are just about every sports supplement you look at. If you stacked up the literature and said, well, X percent of studies show a benefit, a significant number of those are probably studies that didn't, but they have just shown an effect from baseline. If I could just add one more that is specific to the intermittent fasting type literature, again based on those recent studies that are reviewed over the last couple of years, but even before that is, journals generally now seem to be deprioritizing method sections. A lot of the big journals, especially the methods, get relegated to the end of the article. Instead of the classical introduction methods, results Discussion format and often kicked away to a supplementary materials, which doesn't really make sense to me because it's not even like paper and ink is a premium nowadays because everything's online. We should maybe let authors be more thorough. But so many of these papers, the methods are so brief, we don't even know what was done. Really critical things like if somebody is on a time restricted eating or intermittent fasting type pattern where it sounds very simple, right? Just don't eat after 4 o' clock or don't eat every other day or something. Do you not think that every single volunteer in that study would have at least wondered to themselves, but what do I do on the days I am allowed to eat? Should I be eating normally? Am I meant to be losing weight? Should I just allow myself to respond naturally? Am I supposed to try and eat double? So I think aside from all of the nuts and bolts that researchers like to report about exactly how their machines were calibrated and so on, we miss out that critical information of literally putting in quotation marks. This is what participants were told about the expected response. Even if that was to say respond naturally. We need that kind of information. And the problem is, you know, as the years go on, this stuff is lost to history. There'll be papers a few decades old where probably the researchers can't remember or have retired. So if we're going to make use of this information, we really need to know what people are told about what else they're supposed to eat, what they're supposed to do with their physical activity, are they told to take it easy on fasting days or not. So I think a much better description of the human elements of these studies is needed too.
- [26:51]
A
Yeah, absolutely. I mean, let's put all the detail we can into the methods and results and let other people be able to see that and draw their own conclusions from that. Certainly that would be a step towards better quality science to maybe finish off on some of this stuff around the timing piece and to touch on the chrono nutrition. This has been an area where fitting in what we've said already about things related to time restricted eating, there's obviously other elements around chrono nutrition that don't specifically look at eating windows, as you mentioned. It could be to do with specifically when meals are going to occur. We could look at the distribution of maybe calories across the day, things like that. There's been some really nice work done over the last couple of years that has answered some of that. And again, some of the things that early on had a lot of promise, seem to have not played out others where there does seem to be some utility. Notably I think on the podcast we've discussed some of the work that Alex Johnston's group up in Aberdeen did with the big breakfast study and their colleagues in Surrey as well were part of that. That has informed some of that over the last couple of years. And so from your perspective, when we think about this field now of corona nutrition and we look at those circadian rhythms or any real rhythms in biology and how some of these interactions with a stimulus like eating or nutrient ingestion could play a role for you, what are the things that are currently being looked at that deal are interesting research questions to you that have shown some degree of utility.
- [28:22]
B
It maybe does transition from what we've just been talking about in terms of just when you absolutely don't eat to maybe a more subtle rebalance of just when certain things arrive. So the fasting feeding cycle is one thing and generally we humans are just feeding all day long and the fasting is at night. So yes, there's some studies where you could look at that. But generally the thinking there is that eating at night is probably that kind of misalignment is not great. So I think more, there's becoming greater interest in more subtle shift in where things are balanced. So instead of just there are still the time restricted eating full on studies. But I think moving macronutrients and just moving the where the predominance of something arrives is very interesting. So we know just to list a few of them relevant to let's say the macronutrients so we get clear rhythmicity and carbohydrate related outcomes. So blood glucose being highest in the morning, but us having greatest sensitivity so that we can control our sugars greatest in the morning, which also happens to be when a very high carbohydrate meal arrives. Whereas our blood lipids are going to increase progressively through the day, a similar thing for amino acids. And then we know that protein synthesis might peak in the afternoon and some of these things are related to when the food arrives. But we also know that some of those are true kind of intrinsic rhythms. So even if you put somebody on a more constant protocol and remove the external stimulus of diet, they are still there. So I think there's still a lot of legs in that area of just the actual pattern whether things are distributed evenly or so on, because we know there's this uneven distribution. As I mentioned, we have very rich carbohydrate breakfasts, very little protein at breakfast and almost all our protein in the evening. So whether just slightly adjusting some of those things, we could synchronize things slightly better to get health effects. Again, these are going to be, though arguably more subtle effects than you'd see with the more kind of sledgehammer approach of just skipping whole meals and completely restricting feeding. But that doesn't mean to say they're not important.
- [30:37]
A
I suppose, speaking to some of those, the postprandial responses we might see to meals at different times of the day seems to be different. And certainly if you look during the night, if someone consumes a meal with a lot of dietary fat and or dietary carbohydrate, those responses are different to what we might see at other times of the day. So there could be specific applications there, thinking about shift work, for example. But by and large they are going to be relegated to those specific contexts as opposed to maybe these big broad global claims that early on were more calling people's attention. There's also been a kind of similar pattern, I suppose, over time within the context of exercise adaptation, sports nutrition broadly, where nutrient timing has always been a hot topic. And perhaps there is a bit more relevance there, especially as we go up different levels within sport. It's been another area where there's been a lot of hypotheses, ideas that maybe didn't play out, or maybe there were some truth to them, but end up being refined over time or positions modified. And as more workers come out, there's been some type of change from your perspective, related to feeding as that relates to exercise adaptations. What have been some of those changes? Has there been a big shift in generally ideas that were popular or promising that didn't play out, others that have been confirmed, or where does that kind
- [32:00]
B
of leave us when we think about nutrient timing? And that really comes down to when nutrients arrive relative to what. And that can be all sorts, could be the clock time or time of waking or other meals. But one of those is exercise. That makes a lot of sense because nutrition is the arrival of the nutrients and exercise is something which can turn on the taps to use those nutrients. So we know that there's rhythms, a kind of periodic arrival of these nutrients on a daily basis, which varies per person and per meal per nutrient. But we also know that people prefer to be active and not at different times of day. And there's an older literature really quite clearly showing us that our ability to do some exercises, if we're thinking about sport, varies over the day, where we might be better at Strength and explosive stuff, kind of mid afternoon, early evening, maybe some hints at aerobic activity in the morning. But we know these things vary and there's this kind of questionable concept of chronotype. I'm not a huge fan of it, but I wouldn't debate the fact there are some people who, we can't argue with them, they would like to be doing certain things at different times of day to other people. So yes, there's continued to be interesting in that kind of area. We've done studies here at work. My colleague, Professor Javier Gonzalez, has done a lot of that work as well on carbohydrates. And if you look at changing when your carbohydrates arrive, so they may or may not be fueling you before your activity, we know that that can have some clear effects on human physiology. So that your response to training might be greater, perhaps you might be able to burn more lipids, say, if you haven't had the carbohydrate before. I think protein is a, is an area that's just asking to be looked at more in, in this sense, whether we rebalance that throughout the day or whether you should have. You know, there was some classic studies from the late Kevin Tipton that really pointed towards the timing of protein around an exercise bout. And I know he was always saying, I'd love for more people to go back and look at that area. So I think for me, even after exercise, in fact, there's been many more studies looking at protein, whether you need it very soon after or can just be spread over the day. And I think there's still some equivocal data there. So from a sports nutrition perspective, I think the timing of pre, during post and how long post all sorts of nutrients arrive is important. For my part, the study we are currently running, and the one that's kind of killing me at the moment because it's such a tricky one to run, is we are now looking at whether you move the exercise relative to nutrition in the day. So we're currently doing a randomized control trial with either complete bed rest or morning exercise versus evening exercise. And we're going to be looking at a kind of daily diurnal rhythm, if you like, in protein synthesis and whether that can be affected by when you exercise in the day. And I know that these are fields where we know a lot more from animal models, particularly from rodents, but we would not necessarily expect that to relate to humans. So I'm very excited to get a bit more understanding of the physiological rhythms in things like protein synthesis in humans.
- [35:20]
A
If we focus in on that particular trial, just as you mentioned, can you maybe touch on some of the considerations that went into maybe the design of that trial and some of those methodological challenges we have in doing those types of trials to detect the types of effect sizes that we may or may not see for some of these?
- [35:38]
B
That study I just mentioned is actually the third iteration of that experiment. So probably when I was last on the show, I would have been talking about our first one and maybe the second. So this was 10 years ago. I think at first, in thinking almost, we talk a lot about clocks, this, these kind of circadian rhythms where we have clocks in peripheral tissues and how important skeletal muscle is. It's so important for our metabolic health. But I realized no one had really taken skeletal muscles around the clock in a human participant. So back then we established this model of taking muscle biopsies every four hours. And I can tell you that the early kind of grant proposals I put in were met with some firm resistance from the established chronobiologists saying this just simply isn't frequent enough. You need two hourly samples or one hourly samples, which I think further illustrated that all the research to date have been in rodents where you can do that kind of time resolution. But with humans you've limited to how many muscle biopsies you can take in a 24 hour period. And so we did that first study and provided some of the first data of the transcriptomic analysis of the genome and lipidomic analysis of what's going on in skeletal muscle over a 24 hour period where we fed continuously during the day. Then we moved on to a second study where we randomized people to receive their nutrition either continuously day and night. So we started using a nasogastric drip to feed them. So that was doubly exciting because now we were taking muscle samples from a human while they're asleep and while they're eating at the same time, which is kind of a novel model to have. But comparing that with bolus feeding, which, I mean, maybe we can talk later, but that's, that has some really clinical implications there because people in intensive care units are generally fed continuously. And I don't see a lot of strong reason to be doing that. And then, yes, onto this current study, then we've layered on top of the nasogastric feed now multiple stable isotope traces so that we can look at some of the fluxes in metabolism. Having done omics, which is great because you get this big shotgun approach of hints at what might be happening. We're now really keen to look at physiological endpoints. And when I say endpoints now, I don't mean, like I mentioned at the start of this, this call about the kind of thing that your GP might be looking at. I mean endpoints as an even a cellular endpoint. It's one thing to just see gene expression, but we actually want to see what's a physiological change that actually occurs, what's the response to food arriving at a certain time of day. But yeah, very challenging protocols to do. But you know, when it's 4 o' clock in the morning and we're trying to take a sample, I remind myself that this is why it hasn't been done. It's not that it was an idea nobody had had, I think it was just an idea that no one was stupid enough to try and answer.
- [38:33]
A
One other area that is not specifically related to what we've discussed so far, but is certainly a huge topic right now, and I know it's one that you have tackled both directly in terms of your communication about it, but have also done so many trials have actually used monitoring of glucose. And of course that topic is the use of continuous glucose monitors, which not only now are becoming very popular for people without diabetes that are just looking to improve their health, has now even spread to areas within sports performance as well. And people are trying to use these devices to take in all this data with the idea, well, this is great. I can get this real time data of my blood glucose and then I can do all sorts of things like this to inform choices I'm going to make around my nutrition for health or performance reasons. Now there's a lot to discuss in this area. We might not get to all of this, but first, before I get to how we should interpret this, maybe to get clear, because I think this is the part that's maybe skipped a lot and that's what we're actually doing with a cgm. What are we measuring? What is actually important for? Why it's important to understand what we are measuring in terms of how we're going to interpret that.
- [39:47]
B
Yeah, there's a lot to say on this, right? I mean, so some of the stuff we definitely can say very objectively, what, what are they doing? There's. They're about, if people haven't seen them, they're about the size of a 50 pence piece, generally stuck on the back of the tricep, although older monitors used to be stuck on the abdomen and you can put them other parts on the body and incidentally can get some very different results from other parts of the body. But they're stuck onto somewhere, say the back of the arm and there's a small filament that goes into the interstitial space there. So it's not like when you have your doctor or a nurse put a needle into the vein and actually measure your blood glucose. But we know that some of the glucose molecules are then outside of the blood vessel in that space there in the fluid that's surrounding. And that's what it's sampling now. So that's a fact, that's what it is measuring then. You see people call them kind of continuous blood glucose monitors. And some people, I've probably done it kind of cleverly, pull people up and say, hey, don't call it blood glucose because it's measuring interstitial glucose. But actually, I think I've come full circle on that because it is often calibrated to blood glucose. So if somebody does a lot of the modern monitors do to say they don't need a calibration, increasingly wearable technology is advertised, is easy to use by saying doesn't need calibration when we scientists love calibration, but nonetheless, if it is calibrated. So if the interstitial reading is saying my glucose is 4.5, but I take a finger prick that says no, in fact, my blood values are 5.5, some of these systems will then adjust that value and say, okay, well, if I'm seeing 4.5 in the interstitial space, but you're telling me blood glucose is 5.5, it will adjust the readout. So for me, actually it is telling you it's measuring interstitial, but it's telling you a blood glucose value. So maybe they are giving you blood glucose data even if they're an interstitial glucose monitor. So that's what they're doing. I'm wary not to always just be like Mr. Cynical on these things. There are problems with them, but mainly just because of how they're used. Right. Like to the point earlier about waterfall plots, I've got nothing against the poor waterfall plot itself. It's how they're used or misused. So I actually think it's a wonderful technology to be able to get real time glucose data. I remember when I first had access to one of these commercially and I stuck it on my son and he doesn't have diabetes, but I just thought, my goodness, if I had a child who did this would be a godsend. Being able to actually see Real time data. So I'm absolutely in favor of having the information. And as someone who studies patterns and rhythms in physiology, I think it's incredible that we get that kind of time resolution. I just think they've been misinterpreted and oversold so that we now have people running around getting incredibly panicked when they see, if they see what they would call a spike in their glucose, they get very upset that it's no longer in what they were told was the normal range. And that word normal is always very dangerous. In medicine and health, it is absolutely normal. If you eat sugar, the normal physiology is for your sugars to increase. If you exercise hard without eating, then your glucose could go up to a level where most of these systems would be flashing lights at you and saying, be careful, what have you eaten? So it's just in how we use the information. And the kind of mantra I'd been trying to tell people is it's about patterns, not peaks. So don't just focus on what my highest glucose value was after the meal, but try and take into account the totality of information. Which of course is the big benefit of these monitors is that they're measuring glucose so frequently to be almost continuous. It's kind of ironic that we've now got this tool that can measure every few seconds and people just report, what's my average for the day? Well, you could have taken just five fingerprick samples at random times and get an average for the day that at a population level would be the same as your average from the cgm. So I just think we need to be a bit more sophisticated in looking at what the important variables are there, whether it's to do with variability in blood glucose or, you know, these common time in range. Type values can be useful too.
- [44:01]
A
One of the huge issues is how people misuse them, misinterpret them. Sometimes that's through listening to someone who doesn't have sufficient expertise, who talks about this online and tells people that if a reading goes above a certain arbitrary number, this is quote unquote bad, or that they then jump to conclusions about whether this person can quote unquote, tolerate this type of food or not. All the this type of nonsense, which are huge issues if we park those for one moment, because there's a lot that could be said. But I think a lot of people are starting to become a bit more aware of those. One of the other areas is if people accept those, there's still some specifics that maybe are not talked about as much. So in terms of the actual precision and accuracy of these measurements, there's a lot that they can do well. And so maybe could you talk about where they do best in terms of the precision and accuracy of these measurements? Maybe some areas where some more noise might be brought into some of these measurements or where someone might need to be wary and anything else that relates to the actual use of them for getting that data in an objective sense without thinking about some of those narratives, if that makes any sense.
- [45:13]
B
Yeah, that makes sense. So when we're thinking about validity and reliability in different situations, I would say that I think the literature shows. So I've used almost all of the monitors that are available. There's counted them up recently. I think there's 8 to 10 different kind of well known commercial monitors available around the world. I've used a large number of those and they vary in kind of strengths and weaknesses on different factors, usability and so on. But a key one is of course, the precision. Are these giving us precise, accurate values? And some of them are just, I would say some are better than others. There's some issues that are suffered by different monitors where there can be other parameters that are in that interstitial fluid that can interfere. So some of the things that I've heard that is that some, some vitamins can be detected as glucose, maybe ketones can be detected. And these are relevant things, right? Because a paper published by Katie Hutchins in our group when she was working with Professor Javier Gonzalez looked last year and this was in American Journal of Clinical Nutrition looking at the effect of drinking fruit smoothies and how that can affect the glucose values. So you can get some misreads there. But yeah, also things like ketones where if someone's fasting, just briefly, these are metabolites that would increase to feed your brain largely. And if those were detected, again, that's a problem. These are exactly the kind of activities that people who are trying to think about their metabolism and might be inclined to buy a glucose monitor might be going on ketogenic diets or ingesting lots of vitamins. And we need to know that those things don't interfere. And I know there's a big push with the technology to try and adjust those things. I think across the literature there's certain things that these are going to do better and perform better with. So I think if someone's using it, like I alluded to earlier, if it was for a family member or a person who has very impaired glycemic control, if you're using that because it's going to tell you that your glucose values have gone from the normal range of around 5. If they've increased fourfold up to 20, then if there's a 10% error on that, you probably don't really need to know if the score was actually 18 or 22, it probably means it's elevated. But now we've got the worried, well, healthy individuals who are getting very upset if their glucose is 7.9. And then the kind of errors in there might mean that they're actually overestimating how bad the problem was. And some of these, you then layer on the things I just mentioned. If there's some other parameter in the circulation that's interfering, you might be thinking you're above a certain threshold for a long time when in fact you were below it. And I believe that then the low values are where you really can get some further issues. So if you're seeing very prolonged periods of very stable and low glucose, that often is a misread. Sometimes if you've laid on the monitor, I know the ones we used to use on the abdomen at nighttime, you used to see people with extended periods of 2 millimole per liter, which would be very worrying if it was true. But I don't think that is. I think sometimes you get these artifacts in the measurement at certain times.
- [48:28]
A
This is a topic we could spend a long time on. And for the sake of time, I'll maybe keep it to one more question and to try and maybe connect it to something we mentioned earlier. Not the exact same point, but I think it is relatively similar to when we were discussing people taking those waterfall plots and making claims about responders and non responders in relation to CGMs. We see some type of parallel where someone will say, hey, look at this CGM data that I have and that you have. You respond in this way to this type of food, or I respond in this way to this type of food. And so therefore it's good for me or bad for you or some type of message like that. And so then this kind of brings us back to that question of how much of this is a true individualization of response that relates to biology and how much of this might just be a variability within that person. Because there's, I mean, as far as I'm aware, there's some data actually showing this where that you have these repeated measures of the same meal and you see this huge variation within the same person. But yet now we're seeing people make decisions based on one reading in response to A certain meal of that they can or can't tolerate a certain type of food. And I think it's the same type of error maybe we mentioned earlier. Is that something you've been seeing as well of the conclusions people may jump to if they misuse the data that they're actually getting from these?
- [49:49]
B
Yes. So on that front, absolutely. The test retest can show that actually that there probably is less into individual true inter individual variability than we think. But actually to be positive about it, these wearables, that's the opportunity. It's a great opportunity now that if we truly want to start thinking about inter individual differences and let's just take the number of waterfall plots we see, at least the one thing they do show us is that people are interested in individual differences. Scientists seem to want to talk about it and the public are very receptive to the idea that they're special and that everyone might be different. So people clearly want to know about individual differences. And bluntly, the way to do that is to do these what would be officially called like a replica crossover trial, where you essentially just repeat the study over and over and see if the person you have labeled as a responder is consistently doing so. And so actually that is, there's always a lot of work. I've always got a huge respect when I see one of these replicate crossover trials come out because it means a scientist has essentially decided to do their study at least twice instead of moving on to the next study with their time. But these kind of monitors give us the opportunity to do that without killing ourselves to do repeated lab visits. You could say, well, and as you allude to, has been done so researchers have said, well, let's just keep giving the same meal to that person and they can do it every day. And we can see because we can now get under free living conditions, repeat exposure to the same stimulus and see if this person is continuously being the kind of person that they're labeled as. And yeah, but as you mentioned, more often than not, from what I've seen, that hasn't come through in a lot of areas where we thought there was inter individual variability. Actually we find that people are more similar than they are different. But there are cases where that's going to be supported and then you might want to know what type of person you are.
- [51:47]
A
We are coming just close to time. So before I get to the very final question that we always end the show on for people who are maybe interested in keeping up with the work that you and your colleagues are doing, where are the best places for them to go on the Internet. Is there anywhere you would recommend that you'd like to send their attention?
- [52:02]
B
We do have social media accounts for our center for Nutrition, Exercise and Metabolism. I will confess that our website is not the best, but we are currently working on that. So I would hope by the time this comes out, people can go there and see all the things we're doing. There is a small short list of journals that we tend to publish in, in the area of nutrition, American Journal of Clinical Nutrition I just mentioned. But increasingly these are more basic physiology
- [52:27]
A
studies we focus on now in Description. I will put a link to all of that for everyone listening as you can go and check those out as well as I'll maybe list up some of the specific publications that relate to the topics we've discussed today. So with that, Professor James Betts, I'll leave you with the final question that I always end the podcast on. And it's simply if you could advise people to do one thing each day that might have a positive impact on any area of their life, what might that one thing be?
- [52:57]
B
I think because I've got my kind of physiology hat on here, I'm thinking exercise. It has to be go and be active. But then there's parts of me thinking of deeper, more meaningful things. But I'm probably not the best qualified person to. To advise people on the kind of more meaningful, mindful parts of life. So if we're giving practical advice, I would say get up and get moving and ignore all of the complexities we've talked about, baseline comparisons and responder analysis and all of that stuff. Just know that if you get up and get moving and do anything is better than doing nothing.
- [53:31]
A
Professor James Betts, thank you so much for taking all the time to come and do this. And as I've mentioned to you before, I have a lot of respect for the quality of work that you do and I value it a lot. So thank you for giving up your time to come and talk to me.
- [53:43]
B
Oh, that's very kind. Thank you for having me on here again. Foreign.
- [53:59]
A
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