Bewegung zur richtigen Zeit: Chronotyp und Stoffwechsel | Expertentalk (englische Folge)

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00:00:06: Today we are talking about chrono-exercising, the idea that not only the type and amount of physical activity but also timing may affect our metabolic health.

00:00:16: Our guest is Professor Patrick Schrollen a metabolic researcher at The Deutsche Diabetes Centre in Düsseldorf.

00:00:22: Welcome!

00:00:23: Thank you for joining us.

00:00:25: Your work focuses on insulin resistance type two diabetes mitochondrial energy metabolism exercise And the body's internal clock.

00:00:35: But in the past, you have worked for many years on human translational studies and energy and substrate metabolism.

00:00:42: Which scientific questions has been most important to shaping your research career back then?

00:00:49: Thank-you very much!

00:00:52: My interest is always understanding how type two diabetes develops.

00:01:01: Determinants of the disease are and if I go way back during my PhD.

00:01:06: I worked on a certain protein mitochondrial and coupling protein, try to understand that role.

00:01:12: And then after several years i came into The field of diabetes because I think now almost twenty years ago it was discovered that people with type two diabetes have a reduced function of the mitochondria, especially in their muscle but later also shown on other tissues.

00:01:31: And yeah really intrigued me to see why is this?

00:01:35: Why do they have lower mitochondrial functions?

00:01:38: and of course exercise.

00:01:40: we know one of the main effects exercises improves mitochondrial.

00:01:46: That brought us also to exercise intervention, so see can we improve the metabolism of people with diabetes?

00:01:53: The risk for developing further diabetes by doing exercises and what is the role of mitochondria in there.

00:02:02: And again I think almost fifteen years later... We came into a field of Grona biology that had to do among others, with the fact that the Nobel Prize was given to the fields of chronobiology.

00:02:17: So a lot people started getting interested in it and also because the mitochondria are really regulated by the biological clock.

00:02:28: so all these things came together And yeah... That's how my work developed.

00:02:33: but In the end our aim is really to understand How does diabetes develop?

00:02:40: Especially muscle and liver, how can we with lifestyle interventions prevent diabetes or treat it?

00:03:11: And how did your work on mitochondrial function and metabolic flexibility lead to investigate this circadian biology, the timing of exercise?

00:03:20: Can you go a little bit more about that?

00:03:22: why the timing is crucial.

00:03:28: I think it was in twenty seventeen, the Nobel Prize giving and a PhD student of me at that time had really interest.

00:03:35: He said can we do project?

00:03:36: where will study the mitochondrial function different times during today?

00:03:43: In first instance healthy people.

00:03:45: so he did initiated this project.

00:03:48: The mitochondrial function is not constant over the day, but it fluctuates over-the-day.

00:03:53: So what we call a circadian rhythm which has been driven by this biological clock and then thought okay that's interesting.

00:04:04: We know type II diabetes have lower mitochondrial functions.

00:04:07: What about their rhythmicity?

00:04:11: Then we did the same study again, measured mitochondrial function at different time points.

00:04:15: And then we found exactly that this rhythm or healthy people have... ...the type two diabetes people do not have there.

00:04:22: they basically a flat rhythm or lack of rhythm.

00:04:29: and then we thought okay That's interesting!

00:04:30: That might mean something and it might mean if we try to get that rhythm back that this might be good for the patient.

00:04:39: Then we know that exercise can boost your mitochondrial function, but exercise also resets the biological clock.

00:04:49: so not only for mitochondrial functions but also other functions in the body.

00:04:53: and then we thought okay maybe if you time the excise on right moment of a day than it's better to improve.

00:05:04: That is where DRDs came from not only by us, but the field also was getting into that direction.

00:05:13: Can you determine chrono-exercising or using chronobiology?

00:05:17: Can you elaborate on precise scientific terms how you can distinguish a clinical meaningful exercise timing effect from an incidental difference and metabolic measurements?

00:05:31: Yeah!

00:05:31: That's good question.

00:05:33: So first of all maybe to the basis is that a lot of our functions in our body are regular, have a twenty-four hour rhythm, circadian rhythm and they're regulated by biological clock.

00:05:45: That's not only mitochondrial function but it has blood pressure or blood temperature off course.

00:05:52: how sleepy and awake we feel.

00:05:54: this is best known rhythm And it's also quite clear that people who have disturbances in their metabolism, such as diabetes patients or insulin resistance patients.

00:06:09: Also have deviations of these rhythms.

00:06:14: and I think what grown-up exercise is you time the moment when doing an exercise which fits with your with your rhythm and so you do to maximize the beneficial effects of this exercise.

00:06:35: And that holds true for exercises, it also holds through food intake as well discussions about how much we eat in the morning or evening.

00:06:46: all has to be done by setting a biological clock on one hand.

00:06:52: On the other hand, we have this biological clock and we don't have it for nothing.

00:06:55: It has a function.

00:06:57: This biological clock in its rhythm of functions means that at certain periods of the day We are active And on certain periods or they we should rest and recover.

00:07:07: like during the night your body recovers.

00:07:10: During today you're active and nobody should be prepared to be active.

00:07:15: The problem off course nowadays is that?

00:07:21: because we have light all day.

00:07:24: I mean, we don't have dark and light outside still but inside of course we can have artificial light.

00:07:31: We have food twenty-four hours per day.

00:07:33: So then you get this balance between your circadian clock Your circadian function And our behavior.

00:07:41: That's where the misalignment starts Where you start to get these metabolic complications.

00:07:48: If we try reverse that by eating at the right time, then we might reset this system.

00:07:58: So when we talk about in the same exercise session on a twenty-four hour day and morning or night why exactly have they different metabolic effects?

00:08:12: Which physiological processes changed it?

00:08:15: I think its individual for each human isn't.

00:08:18: So it's not something you can say for all the same?

00:08:22: No, no.

00:08:22: That's true.

00:08:23: and well.

00:08:24: first of all let me say that exercise is always better than no exercise independent off-the time.

00:08:33: And its important to say because sometimes people forget this then they say okay if I cannot do the exercise on a right time Then i'd rather do it now.

00:08:41: Well thats not good.

00:08:43: Maybe its an excuse...I don't know.

00:08:48: But the reason why it works, we don't know actually.

00:08:53: We don't exactly and that is still ongoing research.

00:08:56: but what my research group have shown at least As you know, we all have a feeding fasting rhythm.

00:09:05: So... We are normally fed during the day and then switch to fasting stage during night.

00:09:10: And this fasting state comes with certain biological processes that allow you to basically survive during the night.

00:09:17: You should still have substrates for your organs available during tonight.

00:09:24: What we've seen in in pre-diabetes patients or insulin resistant patients is that this transition from the fat to the fasting state, it's basically absent.

00:09:34: It looks like their body is in a fat state all of time and even when we have those people on the lab under control conditions where they eat at six o'clock still during night we don't see these responses.

00:09:53: Why that is we don't know exactly.

00:09:55: That's still ongoing, but what we think that exercise can do if you do exercise in the evening and late-evening maybe it can induce this fasting effect further because one thing for example In the fasting is your free fatty acids and blood go up then fat oxidation goes off.

00:10:14: And these are also things happen after exercise.

00:10:18: So if this rhythm for whatever reason is disturbed in pre-diabetes insulin resistant people, maybe with having them doing exercise in the evening we can boost that they also get into this faster fat oxidative state.

00:10:33: That's one hypothesis.

00:10:34: I mean there are other hypotheses and it works directly on the molecular biological clock.

00:10:41: so really Do not know exactly.

00:10:50: Yes,

00:10:51: as I said i think a person's chronotype is for every person different.

00:10:58: How should we distinguish?

00:10:59: A person's Chronotype from their preferred exercise time?

00:11:02: like you said Not nothing but the preferred Time and how reliable would chronotype need to be assessed before You can make a clinical decision on it?

00:11:12: Yeah And this is actually a good point.

00:11:14: so As I said, this field really boosted the Nobel Prize.

00:11:21: Before that it was already interesting in Grono biology of course because that's also why the Nobel prize is given to the discovery of the biological clock.

00:11:31: but after that the interest in the metabolism field came.

00:11:38: and what happened?

00:11:41: We had these studies where timing for exercise was considered.

00:11:46: So it's evening exercise better than morning exercises, but in all these studies this one size fits all approach.

00:11:53: so the same for every one.

00:11:56: and now I think more recently we came to the conclusion that actually we need to take the grown-up biology or the grown type into account and that means maybe evening exercise is okay for evening persons.

00:12:14: So far there have not been really studies done on that field.

00:12:18: We are going to do a study, but what has been done and what has shown is morning people versus evening people.

00:12:27: you can really distinguish them.

00:12:29: I mean there's questionnaires that really clearly define them And if you then study them they also really metabolically different.

00:12:37: so it's a real thing, it's not just sometimes people say okay this is just in your head you think you're morning or evening.

00:12:45: No!

00:12:45: This is really biological things.

00:12:47: there are also genes associated with.

00:12:50: that might explain and what we now need to do.

00:12:56: if we give advices for example morning exercise or eating smaller breakfasts or larger breakfasts does that account both grown types?

00:13:07: As I said, that's not so much done yet.

00:13:10: We are going to do a study on this topic where we will investigate whether exercise in the evening versus the morning what has more beneficial effects on insulin sensitivity measured next day and is it different for those two grown-up types?

00:13:27: So in that study we'll do morning people, evening people have them exercise in their morning or evening then do outcome measures if we need to make it specific for the specific grown types.

00:13:42: A question which comes in my mind, what is about people who work at night?

00:13:48: They have another day plan and I think after some years they will change the chronotype or biology of them as well.

00:13:57: that you test somebody like this.

00:14:02: Yes i know but first there's a very good point because Yeah, a lot of people say okay yeah, chaos morning evening it doesn't matter.

00:14:11: exercises is beneficial anyway but and this ronobiology are really important.

00:14:17: Is that now?

00:14:18: But we have to realize that fifteen to twenty percent of the people work in night shift nowadays.

00:14:27: uh... And you can see words getting worse and worse!

00:14:30: Of course there always has been jobs where Nowadays, we also want to order something until ten o'clock in the evening and one who ever delivered it next morning.

00:14:40: So that means more people need to work at night.

00:14:44: What has been shown is quite good evidence for shiftwork.

00:14:51: It's not healthy, increases your risk on type two diabetes.

00:14:57: We have done this study where we had healthy people studied them during the day and three days in the lab, did a lot of measurements.

00:15:08: And then on another day I studied that again but when they shifted day-night.

00:15:14: so it meant that we had to sleep during today and be awake at night.

00:15:17: Then there were similar measurements.

00:15:20: We could see already after few or three days they developed instrument systems.

00:15:26: Of course, that's reversible.

00:15:28: If they stop again then it will be okay again.

00:15:31: but you can imagine if you do work shifts... night shift works for long periods of time That you really increase your risk of developing diabetes.

00:15:39: And You just ask about these grown-up types.

00:15:43: and the same is basically for shift works.

00:15:44: What are good advice to them?

00:15:46: When should we exercise?

00:15:49: First of all when are they available?

00:15:51: because think of all kinds of vices, but I mean if you have to work at night or in the evening.

00:15:59: You cannot do exercise at the same time.

00:16:01: But we have to develop programs that fit them and especially for this group it might help them suffer less from negative health effects on shiftwork

00:16:15: After three days, that's really surprising.

00:16:17: I would never have thought it.

00:16:18: as you already see effects on after three days is crazy

00:16:24: how fast this goes?

00:16:27: It basically the same... This we could say was a shift work or jet lag study and if you had a jetlag You also don't feel comfortable in your home at strange moments of times But then you still eat in new rhythm.

00:16:45: If you would do that, then measure it.

00:16:47: It also has negative consequences.

00:16:50: I have to say if we did this... Of course when i fly to the United States and stay there ...I adapt completely again.

00:17:00: The fact is after three days doesn't mean we still see it.

00:17:03: after seven days Your body might adapt.

00:17:06: but often what's with shift work?

00:17:08: people don't always work in the same shift, but they they shift to shifts.

00:17:12: They

00:17:12: change

00:17:13: exactly and that makes it even worse.

00:17:15: probably

00:17:18: you already said there is a new study at the DD set realign study.

00:17:23: um You are leading this uh study?

00:17:25: And can you just elaborate on the central hypothesis from this study?

00:17:31: yeah so The central hypothesis The timing of exercise matters based on your grown-up type.

00:17:40: So what we would like to do is include people with the morning and evening grown types, so that they always wake up early our late evening people.

00:17:57: First, we want to study them just in the normal condition so at baseline and see what are the metabolic differences?

00:18:03: As I said there has been a study that already showed metabolic difference but we wanna do it little bit more into details with the methods that we have here at the German Diabetes Centre.

00:18:14: And then we want those people who do an acute bout of exercise.

00:18:18: So one hour of exercise either in the morning or in the evening, I mean they will do both but of course with separated time between and then next day we'll study effect on their insulin sensitivity.

00:18:35: And so now our hypothesis is that morning exercise might work better for them.

00:18:47: You might think, yeah okay that makes sense.

00:18:49: That's quite logical.

00:18:50: uh well we first need to show.

00:18:52: but it's also important because if you follow the literature a little bit... The tendency for the recommendations are now is that evening exercise is better and we should do an evening exercise.

00:19:06: be careful with that recommendation and really see if it works for everyone, or maybe this extreme morning group might have worse effects.

00:19:22: We need to test before we can give recommendations.

00:19:25: so the question is also should we adjust our recommendations?

00:19:30: Why does the real line focus on people with pre-diabetes and pronounced morning and evening chronotypes?

00:19:38: So why was that a starting point.

00:19:42: Yeah, so to start for the letter we take the extremes morning an evening because I mean those people are metabolically most different.

00:19:55: Most people are somewhere in between, they're neither really morning or evening but still it's around twenty percent on both sides that really is morning and evening.

00:20:03: so its a large population actually.

00:20:05: So we want to compare these extremes because especially for this recommendations can be important.

00:20:15: Also maybe I wanted stress about exodus recommendation.

00:20:21: I'm from the Netherlands, um i don't know how it's in Germany but in that Netherlands there are also discussions on politics for example what we should do with school children and should restart earlier later because children tend to have another grown-up type uh behavior.

00:20:39: so its not only this exercise is a general question.

00:20:43: thats really relevant.

00:20:45: Does it matter the grown type?

00:20:46: And should we adjust and make it more

00:20:48: personal?".

00:20:50: Then your question was why pre-diabetes patients.

00:20:53: Well, that's not a particular reason but I mean of course exercise is quite strong in prevention of diabetes.

00:21:03: so that's why if you do first study then we do the prediabetes because there the chance to preventions are highest.

00:21:13: If this works out we should also do a study in diabetes patients or even people without pre-diabetes, but yeah.

00:21:22: We know that this group responds quite good to exercise with response insulin sensitivity.

00:21:28: so it's a good starting point and an important group of course.

00:21:32: Yeah, that's of course because prevention is something we really have to go forward too especially in Germany.

00:21:37: Absolutely yeah.

00:21:39: but I think also exercise it a strong competitor and the treatment of people with type two diabetes.

00:21:47: so i think its off of course something to go into future also to differentiate their chronotypes.

00:21:57: for

00:22:00: Absolutely, yes.

00:22:04: How is the comparison of exercise timings designed and how will a study distinguish

00:22:22: both exercise in the morning but also evening, so of course that's a misaligned and this is also research question.

00:22:30: Is evening excise bad or does it have very little effect for morning people?

00:22:37: And vice versa.

00:22:39: So there one answer.

00:22:43: we choose to have fixed clock time.

00:22:46: The morning excise will be around nine evening excite around five o'clock, that is just more for practical reasons.

00:22:56: I mean you could determine exactly the an individual's droner type when it goes to sleep and then adjusts it to this.

00:23:04: but we thought we also need one to have a study.

00:23:07: that's practically so.

00:23:09: if you find something that we can give practical advice like okay these time points Yeah, that's basically the question.

00:23:21: So it is of course an experiment where we want to test hypolysis and if the hypothesis works I mean... If you are correct that it matters?

00:23:31: The growing time matters yeah then We will need to do further refinement Of these timings.

00:23:39: How large would an effect have?

00:23:42: To be clinical meaningful And not just merely a statistical effect?

00:23:48: Yeah, that's always a difficult question of course and it I mean to be honest.

00:23:53: It is difficult to answer because We we tend to say okay?

00:23:56: We should have an effect on insulin sensitivity of ten fifteen percent or whatsoever.

00:24:02: But if you're honest, we don't know what the long-term consequences Of all ways having small effects.

00:24:09: so of course We now little bit water.

00:24:15: our rhythm in insulin sensitivity is, and mitochondrial function is.

00:24:19: And these markers we will also measure.

00:24:21: so for example for mitochondrial functions we know that it fluctuates over the day by twenty five percent.

00:24:34: If we can boost, if the right timing of exercise would boost your mitochondrial function with ten to fifteen percent that would already be quite a lot because it's basically halfway.

00:24:43: The difference is best as you can completely restore.

00:24:49: but all studies and typical in fields are always short studies.

00:24:55: It really difficult funding for really, very long-term studies.

00:25:00: And then you have to start looking more into epidemiological data and also... I think it's a strength as well for these effects.

00:25:11: The chronotypes of exercise has been studied in large epidemiological cohort studies so real life studies that they clearly see this effect if there's cohorts where activity has been measured for several days, and then they divide how much activity people do in the morning or evening.

00:25:36: And also see that there is a higher or lower risk of developing disease when you exercise at the right time.

00:25:48: So back from the studies to the evidence and systematic review.

00:25:52: From twenty, twenty six you co offered a morning exercise was associated with slightly higher fasting glucose than afternoon or evening exercises in longer term interventions.

00:26:03: how robust is this finding?

00:26:05: And what are the main limitations of that current evidence?

00:26:09: yeah so I think for some of these parameters, the data is relatively good and robust.

00:26:20: But it really still depends on... And that comes then immediately to the limitations under selection of population.

00:26:27: so i think for diabetes patients It's quite robust.

00:26:33: For large group pre-diabetes I think the overall tendency is that it points into this direction.

00:26:43: But what we limit, like i said long-term studies.

00:26:46: That's a really important one and as We just discussed None of these studies I Think One maybe did to little bit extent Is take this prototype Into account for example.

00:27:00: So we need those Studies that are larger And also take These kind of Factors in Account.

00:27:07: also sex difference male or female have been not really being studied to the detail.

00:27:14: they should have been studied.

00:27:17: For diabetes it's really interesting because now, there start to come out papers that suggest in type one diabetes might actually be different than in type two diabetes.

00:27:26: so yes It is very important to define what you study and make a recommendation for for this group, including for the grown-up type.

00:27:40: Maybe even from males and females different as we still don't know.

00:27:44: so that are the main limitations.

00:27:48: We need more randomized clinical trials to really say okay how large is these effects?

00:27:55: And preferably also longer trials.

00:27:59: It's a big discussion this year, I think about the populations in the study especially concerning women and their hormonal status because that is so different from men doing the lifetime.

00:28:11: So it has to be changed for the future.

00:28:15: you have more distinct populations of studies?

00:28:20: Absolutely!

00:28:20: Yeah i'm starting get older already so little bit longer than when we started.

00:28:28: almost no attention for sex differences.

00:28:32: It was just thought, okay it's all the same and I mean the metabolic responses.

00:28:38: luckily now we realize this is absolutely not a case and i think that there's quite clear consensus that we should do way more studies.

00:28:49: female male differences but also within females indeed during the month are really important, of course.

00:29:00: And they also impact the metabolism a lot.

00:29:02: so that's another kind of cycle uh...that also needs to be taken into account and we need to do way more studies to really understand this!

00:29:12: This is extremely important.

00:29:13: yeah absolutely

00:29:15: Of course, especially when we look also.

00:29:18: I had something to read about the menopause.

00:29:22: There's next no study at all who includes women over the age of forty or fifty and so you can't take into account what manopause do with diabetes in the metabolism And it is a very hormonal strict line for woman.

00:29:39: So No one has looked into that.

00:29:45: Absolutely, that's extremely important.

00:29:51: I think the field realized a long time ago already... ...that this menstrual cycle has an impact on metabolism.

00:29:59: so especially in the metabolism fields it always been studied only one phase of the cycle or people have been included after the menopause to circumvent the effect.

00:30:13: And that has biased a little bit, the populations have been studies and as you say there's not so much data really on good metabolism in diabetes or obesity or other diseases That I've really compared all these factors and luckily we are quite aware now A lot of study is being initiated on this topic.

00:30:41: What evidence would be needed before exercise timing could really incorporate it into diabetes prevention or treatment pathways in the future?

00:30:54: Again, I repeat that exercise is always better than no exercise.

00:30:59: That's a very important thing Of course, if you can optimize the benefits of the exercise.

00:31:07: that's really important because most people have very little time to do exercise and so we want to do it as optimal as possible.

00:31:15: We discussed about this.

00:31:16: I think... ...we need more long-term randomized clinical trials that really take all these factors that we now know.

00:31:25: and because we learn i mean.. ..we learned on that this chronotype might be important know now better what are the good times.

00:31:36: So, what do we compare?

00:31:38: We also start to learn whether how the interaction with meals might be important and so you need to do it after dinner before a dinner.

00:31:48: All these factors needs to be taken into account then optimized in randomized clinical trials And then I think we need also more pragmatic trials where it's brought into practice and see how does that affect in the end.

00:32:08: blood glucose regulation because often our outcome measurements in experimental studies are influence sensitivity and we need longer studies to really also look at blood glucose, regulation fasting glucose.

00:32:20: And these kind of effects.

00:32:22: for that you need longer trials and also trials that are more practical.

00:32:27: In all the studies which should take as if we discuss populations into account so make it specific for grown new type We need to learn about the male-female difference.

00:32:40: Yeah, I mean we discussed these things and So we will still needs some some Some time at things too.

00:32:47: really make this recommendations.

00:32:50: on The other end i think we should not ignore it.

00:32:53: It is this rhodobiology Is extremely important?

00:32:56: And we cannot ignore the effect that we live in a twenty four hour culture.

00:33:04: one of the reasons why we have so many metabolic diseases, it's not only overeating or being less physical active.

00:33:13: The timing is also really important and how we behave in a twenty-four hour rhythm.

00:33:19: that is important.

00:33:20: then We discussed now on exercise.

00:33:23: I think there are food we mentioned quite clearly.

00:33:27: if you eat late at night just before going to sleep and you do that for a long period of time, then this is really bad effect.

00:33:36: And it boosts little bit.

00:33:38: the same It has to with... The night should be where your body can use all the fat stores, the glycogen stores.

00:33:47: Then in next morning on meal you can refill them again.

00:33:51: If you eat too late You don't replenish your stores In next meals just store it but adds up And this rhythmicity, so fuels should go down and up.

00:34:04: That's basically an older process in our body.

00:34:08: So I'm a hundred percent confident that growing biology is really important factor in the diabetes field.

00:34:15: Actually i am also convinced of other diseases but maybe thats different topic for another time.

00:34:21: What do you think, what is the importance of real life data?

00:34:25: Because I always think it's something different if you have like this experimental study where you have persons in a lab and can give them exactly the same food on insect time.

00:34:36: And then people will have treatments or recommendations for doing that at home... ...I think there are huge differences!

00:34:47: No, I agree completely and actually i have been leading last five years a large international consortium also with Canadian partners.

00:34:57: It was timed.

00:35:00: The nice thing about this consortium was that it's covered from cell to animal, through these experimental studies.

00:35:07: To large cohort studies but also two patient perspectives so also research on.

00:35:13: okay how do patients perceive this now?

00:35:16: How do they perceive these recommendations and can they accommodate them in their real life?

00:35:22: because of course we come up with all kind of recommendation.

00:35:26: They are not interested, or they think it's impossible for me to incorporate.

00:35:31: What is the deal?

00:35:32: But also as I said larger cohort studies... ...are important to use because that's real-life data.

00:35:40: there you can see.

00:35:42: okay how does this work in daily practice?

00:35:48: but what we do here and the studies that i have been talking about most are somewhere between animal studies and is real life.

00:35:57: And I think that's an important step in the translational pipeline, because there's way more animal data.

00:36:03: In animals' data it's all clear... There are evidence!

00:36:06: The evidence is there but then it might work different than humans?

00:36:11: Then we do a small experiment of studies.

00:36:14: We also need these cohorts so if you bring them together they can find out whether this is really an important issue or not.

00:36:25: I think so.

00:36:26: Thank you very much for this very interesting talk and specific insights in all the studies, what's to be done about chronobiology?

00:36:35: I really hope that if we talk five years or there will be some results already maybe incorporated into recommendations.