Season 3

Episode 1 – Diabetes, Obesity, and Metabolic Dysfunction – ft. Prof. Jens Brüning

Episode 1 Episodes list Episode 2

In this episode, Bea talks about diabetes and obesity to Professor Jens Brüning, a Director of the Max Planck Institute for Metabolic Research in Cologne, as well as head of the clinic for Endocrinology, Diabetes and Preventive Medicine at the University Hospital in Cologne. About 10% of the people worldwide have diabetes and it is one of the leading causes of death in the world, with its prevalence steadily increasing over the past few decades.
Bea and Jens talk about the diabetes epidemic and the link between diabetes and obesity. Jens explains the two types of diabetes, the function of insulin, ghrelin, and leptin, and the role genetics and lifestyle play in diabetes and obesity. He also clarifies pre-diabetes and gestational diabetes, and sheds some light onto the connection between diabetes and COVID-19.
Jens emphasises the importance of sports for metabolism, in general, and in diabetes, in particular. The two also discuss how realistic the plans for a miracle pill that could replace sports are and the importance of eating with your circadian rhythm.

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Bea: Hello and welcome back to the Offspring Magazine the Podcast, season 3! It’s Bea and I will be hosting today’s podcast, the first episode of season 3. Today, we will be talking to professor Jens Brüning, who is Director of the Max Planck Institute for Metabolic Research in Cologne, as well as head of the clinic for Endocrinology, Diabetes and Preventive Medicine at the University Hospital in Cologne. In today’s podcast, we will be specifically talking about diabetes, obesity, and metabolic dysfunction. I hope you will enjoy this podcast!

B: Hi, Jens! Thank you so much for joining us today on this podcast! I’m really excited to talk to you so why don’t you just start by introducing yourself and telling us what you do?

Professor Jens Brüning: Okay. I’m Jens Brüning. I’m director of the Max Planck Institute for Metabolic Research in Cologne, at the same time I’m heading the clinic for Endocrinology, Diabetes and Preventive Medicine at the University Hospital. And so doing both, clinical practice in Endocrinology as well as, you know, directing the research program.

B: Okay, so the works are really closely related?

JB: Yeah. And so the concept behind it maybe originates from a history: so I’m a trained endocrinologist, so I went to medical school, and then I started clinical training, and with a focus on diabetes. And I was really, you know, trying to understand what is really the basis of the disease? And this is why I went to the States. I did a postdoc at Joslin Diabetes Center, and started working on insulin action and insulin resistance. And then I, you know, after a couple of years, I came back to Cologne, finished my residency, and then got more and more interested in basic science. And basically moved out of medicine and took on a professorship in Biology here, at the University of Cologne. And then, after some years, I was recruited and, at the same time, a possibility came up that I could also go back to clinic. And so I’m really now combining both sides, which I really like. And so, conceptually, the idea is that we run very basic studies at the MPI but we also have a translational angle, so we have groups who are working on MRI imaging. So we’ll be talking about our science later, right? So we do a lot of work in most models, trying to understand the neurobiology of metabolism regulation. And so then, we have groups who are trying to, you know, translate that to the human situation using, for example, fMRI imaging. And then it’s, of course, great to really have the link to the clinic to also eventually bring in the patients suffering from the relevant diseases to also include them in the studies. And, I think, that’s really the uniqueness about this place: that we can really go all the way from, let’s say, a molecule in a neuron to a neural circuitry in the mouse. You know, generate models that we eventually can test in the human situation.

B: Yeah. Yeah, it’s actually a perfect setup here, I saw that it’s really close.

JB: And it’s really on campus so it’s really… The university hospital is, you know, 100 meters away so it’s really, you know, I walk, you know, in between probably 5-10 times a day. So it’s really really convenient to be on the same campus.

B: Yeah. And you go there to mainly like advise or treat patients?

JB: Well, it’s basically so: I do one day outpatient service myself, so really see patients that day, and the rest is really interacting with the colleagues and also trying to bring them together with the colleagues in the Institute and to nurture collaboration. And so this has been really really very fruitful. And so we have residents in clinical training who, then, maybe spend the time for like two or three years in a more basic science, either in the lab or in the human translational group. And then they go back to the clinic but they, you know, carry on and remain as a link between both entities.

B: Yeah, cool, yeah. So we’re at the Max Planck Institute of Metabolism Research, translated in English. So why don’t we start by talking about metabolism because a lot of people always use the term “metabolism” and a lot of people also claim like, “oh, I have a fast metabolism,” or “oh, I have a slow metabolism”. So let’s just start by defining what is metabolism?

JB: Well, the metabolism, in any principle, is just, you know, converting things in the body, in the broader sense, and, of course, the specific metabolism that we are most interested in is actually glucose metabolism. And this is really where I come from and this is how our understanding is. What usually happens to glucose: so we consume carbohydrates, they get absorbed in the body. and eventually they have to be, you know, deposited in the cell, which needs the energy to be generated from it, with it being, for example, classically, a muscle cell or a fat cell, which is responsible for the uptake of glucose and to further metabolize it. And so if you think about how to maintain a stable glucose concentration in blood, the only hormone that is really in action to do that is insulin. And this is released from the pancreas, and then insulin acts on your muscle and fat cells to promote glucose uptake. And, at the same time, it acts on the liver to suppress the new generation of glucose. So it does everything to lower blood glucose concentrations. And that balance is very tightly regulated – and that, of course, doesn’t work if you develop diabetes. And that’s the disease we’re interested in and it affects currently about 10% of the population. And we know it’s tightly coupled to increased body weight, to obesity. So the more obese you get, the more likely you become insulin resistant, so the hormone doesn’t work anymore. And this is kind of the field we’re operating in, asking, why do you get obese, why does, you know, body weight regulation fail, and why subsequently then glucose metabolism gets out of control?

B: So also, just talking about glucose metabolism, is there something as, “I have a fast glucose metabolism” and “I have a slow glucose metabolism”?

JB: Well, not that we’re aware of it. I mean, there’s no such thing as an intrinsically slow or fast way. The question is, how your body manages, basically, to fuel, you know, glucose into the pathway to be metabolized? In other words, you know, how quickly does it get into a muscle cell and how is it then subsequently metabolized. But there’s no intrinsic differences in that.

B: And so what actually controls then the glucose metabolism?

JB: Well, fundamentally it’s insulin and, you know, on the flip side of the coin, of course, you have a system in place that if you don’t get fuel sources from outside of your body, let’s say, under starvation conditions where no glucose comes in with the food, then your body can convert, you know, fatty acids and amino acids into glucose in the liver, which then maintain stable blood glucose concentrations, although at a lower level, because glucose is critical for your brain to function and to survive. And this is why you, basically, have this fine-tuned balance and, you know, on the other side, there are hormones like glucagon or corticosterone, which are active to maintain gluconeogenesis, a new production of glucose from the liver under conditions of starvation. So it’s always, you know, it’s very, and this is what, I think, is so fascinating, that you have sensors, which kind of sense any deviation to any direction, either going up or down, and that they then try to counter-balance that, this regulation, and to really maintain what people consider homeostasis, you know, stable regulation of a variable.

B: And so when we’re all born as newborns, I’m assuming that everyone has perfect regulation of insulin as well in the body?

JB: In principle, yeah, I mean unless of super rare events. Let’s say, if you’re born with a, you know, genetic mutation of an insulin, yeah.

B: But there’s not so many cases?

JB: I mean, in principle, let’s assume you’re fine.

B: Yeah, and so then, when you lose this insulin regulation, why is that the case? So I’m assuming it’s lifestyle factors if it’s not genetic?

JB: First of all, it is genetic. So we know that relatives of patients with diabetes have a higher risk to develop diabetes so there is a genetic predisposition, which is polygenic in nature. So it’s not like, you know, monogenic disease… I mean they’re rare, as I said, super rare cases but, let’s say, for the garden variety of subjects affected, it is really, you know, different alleles coming together, each of them having only minor effects. But then, if you accumulate a critical, let’s say, number of variants in different, let’s say, components of insulin signaling, for example, that then, you know, you reach a certain threshold of impairment of insulin signaling, and then it turns against you. But, unfortunately, it’s really not even clear. I mean although the genetic evidence is clear and we start seeing, you know, identifying more and more contributing variants, it’s just very difficult because, you know, it’s a combination of so many alleles, which has to come together.

B: Yeah.

JB: And so that is one side and then the other side as you mentioned is clearly our lifestyle right and so then what we know is the more obese you get the more, you know, fat you accumulate that massively drives the risk of diabetes and insulin resistance. and there’s a lot of research has been going on, of course, trying to understand, what is the link between being overweight and becoming insulin resistant in diabetes or pre-diabetes?

B: Yeah.

JB: It really flips over. And one, I think, very attractive hypothesis is a concept, which is called lipotoxicity. And so what’s behind that is that the best way to store fat is in highly specialized fat cells. So fat cells in our body, they’re perfectly primed to safely store lipid. It’s basically, they have a huge lipid droplet, and then, on the muscle base, you take up calories, it gets stored away in fat. And this is pretty much inert, it’s not hurting, it’s just sitting there and waiting to be used under conditions of starvation, for example. Then, you know, the fat is released, travels to deliver, and so on. The problem probably begins if you exceed the storage capacity of that highly specialized cell. So that’s, a friend of mine always terms it, like, that a fat cell in obesity is your friend and not your enemy. If you would have an unlimited expandability of your fat tissue, very likely you wouldn’t even get sick. Because you kind of put away your fat in a safe place and nothing really happens at worst to your body. But for reasons, which we haven’t fully understood, you know, the expandability of fat cells in their lipid storage becomes limited, and then you get kind of spillover of lipids into tissues, such as liver and muscle. And this is what we then call ectopic lipid deposition or, let’s say, an unphysiological flow over of lipid into tissues, which do not have that specialized storing capacity. And then, in those tissues, the lipids can exert, you know, can inhibit insulin signaling, and then, that leads to the development of insulin resistance and ultimately diabetes. And so that’s kind of, at least, an important contribution. And, of course, we’re trying to understand, exactly which specific lipid species out of the thousands of lipids is really the driver of insulin resistance. And this is also where we have a research program and we’re pretty active and really excited about. 

B: I really like that hypothesis, actually. I’ve never heard of it so it was really interesting. It makes sense as well.

JB: It actually, generally, you know, it started being recognized from a rare disease. There’s a monogenic disease, which is called lipodystrophy, and those are patients who cannot form fat cells, right. Because of developmental defects, so they lack certain factors, which allow them to make fat cells. And under that condition, you can easily imagine you consume fat, you cannot put it into adipose tissue, because you don’t have fat cells, and then, you know, the fat immediately goes to liver. And those patients, basically, they have no fat. They have massive enlargement of the liver, which is basically full of fat, they’re massively insulin-resistant. And so they’re kind of the extreme model, which led to recognize, you know, that this partitioning of fat across different organs is really critical to maintenance of normal. And then, they develop massive insulin resistance, completely uncontrolled diabetes.

B: But then, based on this hypothesis, it seems like diabetes… This hypothesis would only fit really if you are diabetic because of your lifestyle, so maybe?

JB: But it’s a combination of both, right. I mean, so if you assume it’s a genetic disease, you start out with a certain risk to get it, and then, you’re basically on a curve that… Maybe your genes make you resist even ectopic factor, that you’re not very vulnerable to develop that insulin resistance. But there may be others who had, you know, at the very low end, already are predisposed to, you know, to flip over. And then, of course, the second component of that is, I mean, one is insulin action.

B: Yeah.

JB: But the other one is that insulin has to be produced and released from the pancreas, from the pancreatic beta cells. And so these are cells, which produce insulin. And they have glucose sensors so they kind of measure on a minute-to-minute basis how much glucose is there. And the moment the glucose rises, the insulin is released from those cells. And, of course, at some point or, until a certain point, you can have insulin resistance, but the beta cell kind of can compensate by, you know, making more and more, putting out more and more into circulation to kind of overcome that resistance. But then, eventually, if the beta cell had to work against that mountain of resistance, eventually, it collapses, fails. And then you get a reduction in insulin secretion. And then the whole thing totally turns against you. And then your glucose control gets out of control.

B: Yeah. So, I mean, it’s been already a lot of information, so if we just break down, also for the audience that doesn’t know so much, what exactly is diabetes? Or, if anything, also metabolic dysfunction? I guess we’re only talking about diabetes here but maybe we can also talk in general terms?

JB: I think, in general terms, it is ultimately: if a homeostatically regulated variable gets out of control. So if the body does not manage to maintain a certain variable, in that case, glucose, within the pretty well-defined physiological range. And, of course, all components that contribute to the physiological regulation: it being insulin, you know, signaling in the periphery, and some release. So all the parameters, which feed into that regulation, can be, you know, subject to alteration and basically flip you into this regulated metabolism, in the broader sense.

B: Yeah. And so yeah, so I guess you said, I mean, it can be genetic, it can be lifestyle but we’re really in an epidemic or in our pandemic of obesity. Yeah, so… And I was also interested in, kind of, what controls this “energy in, energy out” process, you know, because I guess that’s also related to metabolic dysfunction? So what, kind of, are the main players that determine how much energy we keep in and how much energy we…?

JB: So there’s, again, as it’s exactly the same principle and, I think, this is what fascinates me about Endocrinology, is really the feedback regulatory mechanisms, which are put in place to maintain homeostasis. So you could, I’ve described or we’ve discussed, insulin feedback system to control glucose concentration. And there is a similar system in place, which you can view as a central regulator of, let’s say, fat homeostasis. And that hormonal system was only identified in the early 90s. And that has completely opened a way into understanding how body weight is regulated. So this was really a black box. I mean. compared to other regulatory systems. such as insulin, you know, which has been around for 100+ years. The question was really, I mean, how is body weight regulated? And so there was a nice hypothesis, put forth in the 50s by Kennedy. And he said, well, he proposed a homeostatic regulatory system for body weight. And he basically proposed that there should be a sensor, in the broader sense, which detects how much energy is in the body. So what that would predict is that there is a signal, which is released in proportion to how much energy you have in your body. And he said, “well, the brain is ultimately what decides am I going to eat or not”, so he predicted that there would be soluble factors coming from the periphery, kind of as measures of energy state, in the broader sense. And he predicted that then there should be a receptor for that signal in the brain, which then initiates a response to, you know, stop eating. So in, you know, homeostatic model, you would say, you have enough fat: something x is released from fat, it acts on the brain, and suppresses appetite. And if then, if your energy stores drop, that factor drops: you disinhibit appetite, you start eating. And that was a nice model, and it was around for 40 years, and nobody knew really what the molecular correlate for it was. And then a colleague at Rockefeller, Jeff Friedman, identified exactly that factor. And he, basically, found a monogenetic, he defined the genetic defect of a monogenic mouse model, which was massively obese, weighing three times. So I have an unstoppable eating desire, let’s put it like this. And so he found, basically, that this mouse model was lacking a hormone, which is released from adipose tissue. The more fat you store, the more of that factor you release. And he termed this leptin for, is coming from Greece, Greek ‘leptos’, lean. So he said, that’s a lean factor. So it’s, basically, released from, if you have a lot of fat, you release a lot of leptin and then, subsequently, they identified the leptin receptor, which was exactly in the brain centers, which control eating. And if you now take that factor, let’s say, inject it into the brain of a mouse, then the mouse will stop eating because the receptor is in the brain. And so then, so that really pushed the door open for first molecular correlate system of body weight regulation. And then, basically, the research unfolded around that. So then a colleague at Cambridge, Steve O’Reilly, he identified the first human who had monogenic obesity. And they were, I mean not the first ones which had monogenic obesity, but he identified the first patient who was basically the equivalent of that mouse who was lacking leptin. And it was entirely recapitulating the phenotype. So just telling us that this was really an evolutionary conserved pathway of body weight regulation. So if you take a kid which lacks leptin, put them in front of a buffet, they will literally not stop eating. And so, and they get massively obese, they develop all complications very early on, at a young age. And that, of course, offers a chance for these kids, that you can replace leptin, the hormone, which is lacking, and to completely normalize their body weight. The problem is that, you know, the garden variety of obese patients, they have high leptin levels, indicative of leptin resistance. So the hormone is there but it just doesn’t execute its normal regulatory function, meaning you eat, despite having a high signal coming from fat, where there is enough fat, stop eating. But somehow the brain doesn’t, you know, listen to that signal. And this is, like, basically, it’s a complete analogy to diabetes that I was discussing. You have, you know, high glucose levels, you have high insulin, but then, at some point, muscle, liver, and fat do not respond and we term that “insulin resistance” and similarly, in obesity, you know, it seems to be the case that you develop leptin resistance. So the signal is there, it, you know, runs to the brain, but the brain doesn’t, you know, initiate the appropriate response to reduce eating in proportion to the energy store that you have.

B: It seems like lectin and insulin are very much related. So do we also see that when leptin goes up, insulin goes up as well?

JB: So they’re not completely related. So, basically, they’re not completely related but you can, in a way, conceptually, you can view them as slightly different entities. So leptin is really released from the fat cell in response to how much fat is stored. So you can really look at it as a fat sensor. And insulin is released in proportion to circulating blood glucose concentration. So it’s more like the glucose sensor. So, in principle, they’re both sensing energy and, therefore, under many circumstances. they’re regulated in parallel. But they sense different, let’s say, qualities of energy. And this is basically how we came into this. So we really, then, hypothesize, “well, could insulin also act as a communicating signal to the brain?” And then, we generated mice, which lack the insulin receptors, so the signaling molecule in the brain, and they also get mildly obese. So it’s really not that insulin is such a strong regulator of body weight as is leptin, but what was really interesting, and that is what my lab has been working on for the last 20 years, is like… I mean, what I’ve been describing is kind of the textbook knowledge, so your insulin acts on the liver to suppress glucose production, and on muscle and fat to remove glucose. So you would predict in that picture: insulin signaling in the brain has no role, right?

B: Yeah.

JB: And so, when we then looked at mice, which had no insulin receptor in the brain, despite the fact that they had the signaling machinery in the liver, in the muscle, and in the fat cell, they still were not able to maintain normal glucose concentration. So indicating that there was an additional signal coming from the brain, which also contributes to glucose regulation. And this is basically what my lab has been working on for the last 20 years: trying to understand, where exactly in the brain, which neurons are involved, which other cells do they talk to, what kind of the neuronal network, which controls peripheral glucose metabolism. And so the way we are really viewing the system is that we, you know, many other colleagues and us, have identified specific cell types in the brain, which respond to leptin and to insulin. And so they have all the machinery to send, so many different aspects of energy. So they can, you know, they integrate the signal of leptin, they integrate insulin, they also respond to another hormone, which is called ghrelin (this is released from the stomach when you’re hungry so it’s more the driver of eating). And they, all those signals converge on the same neurons. And the concept that we’re most interested in is, basically, so you have those highly specialized neurons, which get constantly instructed how much energy is in your body, you know, from all the different qualities of sensing. And then, on one hand, they will control how much you eat but, on the other hand, they also regulate how energy sources within your body are partitioned and distributed. And so that is, conceptually, what we’re interested in. So it’s really like adapting whole-body physiology. So it’s not only, “am I going to eat, am I not going to eat? Will glucose be taken up here or there?” It’s really, what fascinates me personally the most is that, I think, we’re looking at a system, a regulatory system, which kind of integrates all different aspects of physiology.

B: Yeah.

JB: In accordance with the energy state of the world.

B: I mean it seems so complex.

JB: It’s totally complex.

B: Like it’s just, it’s so complex. So this is why I also wanted to ask you, so there’s this whole, like, “calorie in, calorie out”, like the calories that I take in… That’s how much, that’s what’s going to determine weight loss and weight gain?

JB: Yes, in the end.

B: Is that true? But that would only apply to people that are metabolically healthy? Because if you’re metabolically unhealthy and your signals are all out of balance then that doesn’t count anymore?

JB: Of course, and, of course, as you say, there are two different components of that. I mean one is “calories in, calories out” but, of course, there is still a different rate, at which different people metabolize the same amount of calories, and that truly exists. But, at the end of the day, it, you know, it is really the sheer simple balance between your personal actual energy expenditure on a given day, at a given age (which also declines over age, importantly) and the calories that you consume. And, I mean, you can always make a very easy, you know, basically, you can calculate the individual’s energy expenditure. And if you eat beyond that, your weight goes into one direction, if you drop it…  And this is what, I think, is so fascinating about the system: how accurate it actually has to balance this. Because you can make very simple calculations. If your that system is only off by a percent each day, that will give you an extra 20 kilos over a period of a few years, right. I mean, so it’s really that your system has to be so accurate in exactly determining, you know, “how much do I burn right now?”, and really balance how much will they take up. And that’s, of course, the problem, I mean, that system doesn’t work.

B: So, going back to, also, leptin and insulin. Because, when we define diabetes, it’s usually insulin resistance, but it seems like leptin plays a huge role in it as well?

JB: Absolutely, yes. I mean, again, it always comes from, I mean, what is a driver in an individual patient, right? So if what drives you towards your insulin resistance is really this massive weight gain, then, probably, the defect is more, or that the starting defect is more, on the body weight regulation side. But then, as I said, there are others who are more insulin-resistant and don’t have to gain so much weight, if at all, to get diabetes. So it’s, for each and every patient, you know, it may be different that it’s more on the body weight regulation side or more on the insulin action signaling side…

B: Yeah.

JB: …where the individual problem lies. But it’s, I mean, overall, if you look at overall population, clearly, the problem for us, as a population, is increasing numbers of obesity. And then, diabetes, basically, runs in parallel with that. So we have now approximately 30% of, you know, really obese patients in the population. And you can look at the map where you, you know, if you have epidemiological data, if you plot it, the increase in obesity and in diabetes over the last 30 years, it runs totally.

B: So is there also a link between… So obesity, would it be more genetic? Or is that also more lifestyle factor? So we’ve talked about diabetes, but obesity, is there still a difference?

JB: I mean, clearly, it’s the same thing as diabetes, at the end, there is clear genetic, you know, determination of that, of body weight regulation. And we also, you know, start understanding polygenic defects that contribute to obesity. But if you look at the dynamics of that, your epidemic, as you termed it, right, it’s, I mean, our genes didn’t change over the last 30 years. So it’s really that, you know, I think if you look for it from an evolutionary perspective, I think, our organism has been optimized, evolutionary speaking, you know, to make sure that, what I mean, basically, our organism has been optimized under conditions of limited fuel sources, right? So if you want to evolutionary develop that organism according to that environment, you know, the system is more tailored to making sure, when energy shows up in front of your body, that you readily absorb it, store it away as fat. And in our daily life today, you know, basically, over a short period of time, has put that optimized organism in a completely different environment where suddenly food becomes available, you know, 24/7. And, I think, this is what we’re witnessing. It’s really not that our genes have changed but that our lifestyle has changed so dramatically. And that, you know, our body isn’t really prepared for that.

B: Yeah. So the majority of obesity is still due to lifestyle changes, yeah?

JB: But not of an individual, right? It’s not to blame, and obesity…

B: Yeah, yeah.

JB: I think, that’s really, really important to state is that it’s not about just…

B: It’s the environment, yeah?

JB: That really the environment we are living in. So it’s more, you know, it’s not an individual’s fault. And, I think that’s really important because it, otherwise, really leads to stigmatization of patients. And we really start understanding, there’s a real molecular basis why the system, you know, doesn’t sensitively operate under the conditions we’re living in. So it’s not just, you know, lack of willpower or something. I mean, we really start understanding the molecular correlate of why the system doesn’t operate under the, you know, the conditions we’re living in. And, I think that’s really, really important to highlight again and again.

B: Yeah. Yeah, and so what about diabetes in children or, I guess, obesity and diabetes? I think, we can talk about them kind of as linked, but what about obesity or diabetes in children versus adults? What’s the difference between them also on a biological level?

JB: Increasingly less. So the problem is, what we’ve been talking about is, all what’s called type 2 diabetes, which is called the typical, let’s say, age-related diabetes, which are characterized by insulin resistance.

B: Yeah. I guess maybe we should define that, yeah? Just to define one thing, real quick, type 2 diabetes is what we’re talking about, which is what you can develop later in life. And type 1 diabetes is usually what you’re born with.

JB: Not really born with, but you develop it very early. So, let’s say, in a traditional view, if you look back textbook 30 years ago, before all of what’s happening right now, you have type 2 diabetes of the elderly, which is 90% of the cases. And, you know, it develops closely associated with obesity and some resistance – everything we’ve talked about. But then, there’s 10% of patients, which are affected by type 1 diabetes. And it’s a completely different pathophysiology. So you get an autoimmune attack against the cells, the beta cells in the pancreas, which produce insulin. They get destroyed and your body does not produce any insulin. So usually these patients are lean, they’re young. It’s an autoimmune disease and, basically, your body kills its own insulin production. And then the only way to treat it is, of course, to exogenously provide the insulin to replace it. Completely different as physiology.

B: Yeah.

JB: But what we’re seeing now, due to the obesity epidemic, we’re seeing more and more obese kids. Yeah, and now we start seeing something in pediatrics, which you have, not never but rarely seen 30 years ago, is very obese children, which now very early on develop insulin resistance. And so, basically, the classical type 2 diabetes. It’s very frequent but, you know, it increases and that is, of course, in a way, dangerous because diabetes, in the long run, leads to complications. So, and they affect the eye, so you can get eye complications, you can get nerve complications. And it’s typically that the finest vessels in your body get damaged by the high glucose. And so this affects the micro-vessels, which serve the nerves. So then, patients start losing, you know, sensitivity, touch sensitivity. They develop pain due to the nerve degeneration, so that’s called diabetic neuropathy. Then it damages the fine vessels in the kidney, which is called diabetic nephropathy. And so diabetes is, together with hypertension, the most frequent cause for the people to have, ultimately, kidney failure and have to go on to dialysis. And because of the damaging the smallest vessels in the eye in the retina, you know, patients develop diabetic retinopathy. And that’s the leading cause for blindness in western population. So it’s really, in the long run, of that glucose dysregulation, which then leads to all of those complications. And you can imagine, you know, if you have, you know, 20 more years time with diabetes as you develop it, let’s say, in early adulthood, something that you otherwise only would have developed 50+, that gives you another 30 extra years to develop the complications. You start seeing the complications earlier. And this is a real dilemma.

B: Yeah. So we keep on talking about diabetes but what about pre-diabetes? What, kind of, defines the difference between when you’re pre-diabetic and when you’re actually diabetic?

JB: So the formal, you know, definition of diabetes is that your blood glucose exceeds a certain limit, which it usually shouldn’t exceed, and so then it’s blunt diabetes, glucose is high. But there is a pre-diabetes, where you, basically, if you look sensitively enough, you can find that the person is insulin-resistant and that, on occasion, the glucose excursions will be higher upon a challenge.

B: Yeah.

JB: But then they still return to some normal level. So if you take a day-to-day blood test, it’s still within the formal range. But if you look careful enough, you can see, let’s see, and there is a test, which is called an Oral Glucose Tolerance test, so you bring in a patient, didn’t eat overnight, and you give a defined dose of glucose (75 grams), and then you, basically, look two hours later, what happened to the blood glucose concentration. And so, if it’s your normal insulin-sensitive subject, it should be below 140 milligram per deciliter: that is normal insulin sensitivity. So the glucose comes in, it gets clear. If you’re diabetic, either you start out already with a high level (then you have a diagnosis of diabetes) or your body does not manage to bring it after the two hours below 200. That is an alternative way to really put the formal diagnosis of diabetes. And if you’re in the range in between, let’s say, between the 140 and 200, 2 hours after that glucose load, and this is what we call impaired glucose tolerance. And it’s, you know, very likely that, in the long run, you will develop diabetes. And that is, kind of, pre-diabetes. So it really tells you that if you, you know, if you challenge the system, it doesn’t have the full flexibility to respond, and it’s usually indicative that later in life it may go down to develop…

B: What about continuous glucose monitors? Like, could those be used more to see, or detect, if someone is pre-diabetic? In the hope to then maybe prevent diabetes?

JB: I think, it’s a pretty pretty high effort to do that, right. I mean, so, basically, what you’re referring to is that there’s now continuous blood glucose monitoring – but you, basically, implant a sensor and you can, you know, just continuously see. I think, that is very good, it has been really good to improve treatment, because you just get a much finer, you know, time-scale resolution of glucose concentrations than always having to, you know, basically, take a little drop of blood from the finger, which eventually is pretty cumbersome. But it’s not a good screening test, you know, it’s a pretty high effort. So, basically, what it says, the easiest test is that glucose tolerance test.

B: Yeah.

JB: And it also predicts, I mean, if you have a perfectly fine glucose today, you know, it would be enough to look later and, I think, it’s just a one-day measure – pretty straightforward. And that is much easier. But there are clearly circumstances where the, you know, continuous glucose monitoring has key advantages. For example, we know it’s a different aspect than just, you know…

B: Yeah, that’s fine…

JB: Okay, let’s talk about everything, yeah. But what is also, you know, really important is gestational diabetes.

B: I’m not sure… I don’t know what that is, maybe you could define it?

JB: Okaym so it’s, basically, diabetes occurring during pregnancy.

B: Okay, what’s it called again?

JB: Gestational. Gestational diabetes.

B: Okay.

JB: So it develops during during pregnancy. And that is really important to be diagnosed because f the mother’s glucose has high excursions, as it does in diabetes because it cannot control it, the glucose can be passed on to the fetus, and that, at later developmental stages, has its own pancreas, which then senses the high glucose being reached over from the mother and starts releasing high levels of insulin. And then those kids basically are, you know, growing and developing under unphysiologically high insulin concentrations. And this leads to, eventually, insulin is a growth factor, so there’s a closely related growth factor, which is called insuling-like growth factor one, IGF-1, and they act on closely related receptors. And then, if you have very high insulin concentrations, that can also act on IGF-1 receptors and you get fetal overgrowth. It’s called macrosomia. So you have big kids being born and it’s also an interesting, I mean, interesting, what we know from epidemiology, that offspring that is born to mothers who are suffering from diabetes during pregnancy, gestational diabetes, they are born with a lifelong predisposition to develop metabolic disorders and hypertension later in life. So it’s really important to control blood glucose concentrations and to diagnose diabetes in pregnancy in order to prevent the next generation even being affected. And so that’s also something that we’re scientifically interested in: is really asking the question, you know, “how does this high insulin eventually also act on neural circuits? Which controls body weight, in the long term, in the offspring?” And so we’ve done a mouse study, where we, basically, can show that certain neurons, which are in place to suppress feeding in response to leptin, the high insulin in the fetus suppresses their projection formation. And that is developmentally timed in mice, right, but, basically, if we mimic this in the mouse model, that then, basically, the pup is born with the brain, which is soft-wired for bodyweight regulation. And that itself is enough to set it off with a higher, you know, propel predisposition to develop obesity later on. And so this is exactly what we’re working on. But, coming back to the continuous glucose monitoring, that is, of course, very effective and it’s probably the best tool to really monitor mothers with gestational diabetes, once it’s diagnosed, to really optimally treat them, to reduce the negative impact on the developing fetus. 

B: Could you reverse the diabetes?

JB: You can give the insulin, basically, to the mother.

B: Yeah.

JB: Then you reduce the glucose concentrations. The insulin is not being passed on through the placenta, and then, if you manage to reduce the glucose concentration in the mother, then the fetus will be developing fine there.

B: But, I guess, there, we’re just talking about insulin resistance, but what about leptin? Is that not something to worry about?

JB: Well, it’s not. I mean, first of all, leptin very likely, I mean, it doesn’t cross the placenta either.

B: Okay.

JB: So if you manage to, basically, control the metabolites, such as glucose, which would be passed on…

B: Yeah.

JB: Then, I think, you can kind of shield the fetus from the adverse things going on in the mother. And so, it’s really well defined for, you know, gestational diabetes. And so, if you control that in a very tight range, and, therefore, it’s really important that all pregnancies are really screened for. And this is why it’s part of the real routine screening program, to look at certain points of pregnancy, to do exactly that glucose tolerance test, to really sensitively detect women who have gestational diabetes. You want to treat it optimally to reduce the adverse effects.

B: But this gestational diabetes, does that mainly come to women that are pre-diabetic or can that come to anyone?

JB: It’s perfect, I mean, that’s exactly the right question, but probably happens. In many instances, we know that if a woman developed gestational diabetes, which can revert after pregnancy, that she has a very high likelihood to develop it later on. So it’s, basically, just the, you know, the environment of the pregnancy is probably unmasking a predisposition that individuals carry on. She would develop diabetes, let’s say, 20 years later anyways, but now, under the conditions of the pregnancy, that is pushed and it manifests earlier. And it may even revert after the pregnancy. But then, you really have to closely follow these women because, you know, there is a very high likelihood they will develop, you know, diabetes later again, even if it reversed after pregnancy. So it’s, basically, the pregnancy is unmasking a predisposition which has been around.

B: Yeah. So with, I guess, with those kind of women, it doesn’t really make sense to wear a continuous glucose monitor beforehand because…

JB: You don’t know who they are, right. But you have to screen the pregnancy to identify the ones, which have tipped over.

B: But what about in other patients? I still feel like, or to me it seems like, continuous glucose monitors could be a really good tool to try to detect early levels of pre-diabetes?

JB: Well, but, I, mean what would you want to do? I mean, the question is: do you really want to, you know, put a continuous blood glucose monitor on anybody? Because this is what it comes down to, right? I mean, the proportions of diabetes will be 10%. I mean, they are 10 right now. And they if, you know, everything continues on the same dynamics, they will be even higher. And so then the question will be: when do you put it on for how long do you put it on? So, I think, as a screening, it’s not really, I think, the standardized tests operate pretty well, okay, in order. But it would be already a great help, you know, to implement those, which are really straightforward, as I’d say, simple screening strategy. Because one of the problems is, if, you know, if I may go into the direction, is, I mean, a high glucose doesn’t hurt. And, you know, and usually there is a lag time between it, with type 1 diabetes, it’s really clear. I mean, the bitter cells are destroyed, then you suddenly get a glucose of 500 and the kid almost…

B: Yeah.

JB: If worse comes to worse, in coma, in an emergency room… And then diagnosis is done. So there’s no real lag time between the real happening and the diagnosis. But with type 2 diabetes, you know, you can develop elevated glucose concentrations for a period of time and don’t really recognize it. It doesn’t hurt and it, you know, doesn’t, you know, so usually the signs of the first manifestations is that, if the glucose goes beyond a certain threshold. So usually glucose is filtered out into the urine and it’s reabsorbed. But the reabsorption capacity is limited, so beyond a certain threshold you then start losing glucose in the urine. And that acts as an osmotic force. And you will, you know, develop something that’s called polyurea. You will, basically, just get up at night because, basically, the glucose in the urine starts draining more water into the urine. But this, of course, takes time and it’s a gradual process. So you can be running around before you hit that kidney border really without recognizing what is happening for a year, two years. three years. But then, during that period of time, the elevated glucose can already operate, you know, on the vessels in your eyes, on the vessels in your kidney, in your nerves. And what it really means is, that you have that lag period of, let’s say, two-three years, on average, until it’s really diagnosed. And then, at the first point of diagnosis, already more than 20% of the newly diagnosed diabetic patients have already the complications developed. So it’s really more important, you know, coming back to your glucose monitoring, then, yeah, just rolling out the broad program. Everybody running around, for the continuous, it would be just much more feasible to really give everybody at some point a test and you really pick them out as early as possible.

B: Could it maybe be beneficial just to see what kind of foods a pre-diabetic person should be eating? And which ones they should be avoiding? I’m asking this based on the perspective that pre-diabetes is reversible, maybe. So that’s also a question?

JB: To some extent, sure. I mean, but what’s really good, I mean, what we know is, let’s assume that even in pre-diabetes your insulin-mediated glucose transport doesn’t work as well, right, so then, the question could be also: is there an alternative way to deposit glucose, independent of insulin? And there is actually a way. And a way for muscle cells to take up glucose in an insulin-independent way is exercise. So during exercise, your muscle basically takes up, even if it’s insulin-resistant, it can still take up glucose. So, really, exercising is a way to normalize, to reduce blood glucose concentrations, independent of insulin. And this is why exercise really is an important component, in addition to, you know, losing weight.

B: Yeah.

JB: And then, of course, there are certain recommendations, I mean, that you shouldn’t go for your carbohydrates, which are, you know, rapidly absorbed, give you peak glucose concentrations. But that you rather go for more complex carbohydrates, which gets slowly absorbed, and that you don’t get profiles where the glucose shoots up very high. So it’s really the combination of both what you eat, it’s reducing body weight, on one hand, to increase insulin sensitivity, the quality of what you eat to really avoid the peaking glucose concentrations, and then, of course, maybe capitalizing on exercise, you know, to help support the system, independent of the impact insulin has.

B: I definitely want to talk about exercise, as well. Because, I think, that’s fascinating. Yeah, so maybe you want to tell us more about exercising? Also, like, the role that exercise can plain in, maybe, reversing pre-diabetes or diabetes?

JB: Yeah. It’s probably, to me, it is one of the best measures. And so there are really great studies showing, I mean, you know, colleagues in Denmark are very focused on this there. And they have put, you know, patients, even, let’s say, diabetic patient who runs on two or three medications in a real, let’s say, strenuous exercise program: you’re going in five days a week, a supervised combination of cardio and strength training. And they can show that, I mean, a large proportion can even drop their diabetic medications. And, I think, that’s really impressive, right. So the number of medications drops, there is even, I think, up to 20% as a complete reversal, even of, you know, manifest diabetes. And, I think, that just highlights the potential and the power of that, right? So it’s really looking at exercise as a kind of, yeah, basically, medicine, right?

B: Yeah. Is there any particular exercise that works better? So cardio or…

JB: It’s a combination of both. So, basically, what they really recommend: this is a balanced program between both. And yeah, I mean, that’s the way. But I want to and, of course, what’s also interesting is, research-wise you can also imagine, I mean, I’m not advocating it in a sense, but if you would understand what is the molecular mechanism of exercise…

B: I was just thinking that!

JB: I mean, so, basically, what you could if you really do science, and people do it, right, I mean, basically, if they understand… Because, eventually, also the, you know, the physical exercise has molecularly to be linked to glucose uptake. And if you define, could define those mechanisms, I know it would be a fantasy to basically develop the exercise mimicking pill. Yeah, which, you know, triggers the exact same mechanisms. And you’re sitting on the couch and your body, you know, is performing exercise.

B: I mean it’s exactly what I was thinking! Like, if we can understand why the role that exercise plays…

JB: Exactly!

B: …you can develop something in the lab. The only question that I ask is: exercise is free, basically, for everyone. It’s the easiest thing to do or, well, it depends on your personality, as well, and stuff. And I know some people would prefer just a pill but…

JB: No, I told you, advertising. Don’t get me wrong but yeah, I know, to me, I also have the same problem, let’s say. I usually run in the morning with our dog and it’s easy in the summer but, you know, sometimes you have this, or you have a cold, then you drop out of it for three weeks, and then it’s so difficult. I mean, there is something, you know, then it’s dark, raining. Yeah, in order to really make that hurdle, maybe I’m just not the right, perfect exercise addict but, you know, it’s really an effort to really do it continuously over long term.

B: Yeah, no, it definitely is an effort. And then, with busy schedules and stuff. In the end, if you have an alternative to just exercise, that’s still the best thing because if that can help reverse diabetes, then.

JB: I totally agree. I totally advertise. I mean, so it’s really, like, exercising, and this is also, I mean, that’s really the most effective that we can offer our patients right now. So we also run an obesity clinic, right. And right now there is limited, you know, pharmaceutical potential to really treat obesity, to reduce body weight. And so the best thing that we can offer at this point is really very intense programs, where we do dietary counseling, together with an exercise program, you know, psychological support, you know, people meeting in a group. And really have a very structured program running over a year. And that really works. I mean, people lose, let’s say, on average, 20 kilograms in such a program. And even if then they go back to the wild, they are able to maintain that reduced body weight. But if you really try to do all of that on your own, without the right counseling, and, I mean, so many people want to lose weight, but it’s just so hard to do it, right? And so, therefore, it really needs the whole framework to support that initial drive.

B: I think, also one of the main problems is that there’s just, for example, with healthy eating, there’s just so many different opinions out there. So who do you listen to if you don’t have medical advice, right?

JB: I mean, basically, you should see professional advice. And this is why we’re offering exactly those programs. But what is also, I mean, at the end, you find, I mean, you can read about it in press, you know, no carbohydrates, only fat diet, this diet, that diet, right? At the end of the day, there’s no convincing data to suggest that any specific diet type is superior to another one as long as… you should use calorie intake, right, I mean, so…

B: Yeah.

JB: And you shouldn’t go to extreme diet. So, I think, in in my view, it is really the recommendation to go for calorie-reduced balanced diet. I mean this is what it comes down to: eat healthy food, less of it, yeah, and that’s the safest way. And there’s no magic to only eating this or only eating that, that will give you weight loss despite eating. And so it’s really…

B: Yeah. What about intermittent fasting? Because that’s a really hot topic these days.

JB: That’s really a hot topic these days. This is also really, really interesting from a scientific point of view because it also, again, offers room for scientific discovery. Understanding molecular mechanisms of intermittent fasting. And so it’s really, I mean, I think, the glucose-metabolism-improving actions are well-documented, at least in animal models. I think, the human data aren’t even that, despite many people talking about it. I think, it’s really, the strongest is pre-clinical data at this point, and it really remains to be seen what is really the mechanism but clearly it’s… but also one has to say that, even in intermittent fasting, it comes usually if you do it in a clinical setting. It just reduces overall, you know, food intake.

B: Yeah.

JB: It’s usually not that people, if they don’t eat for 16 hours, that they really fully catch up during those eight hours that they are eating. And so it is clearly, it’s a component that you probably drive energy expenditure that, you know, if you don’t eat for a certain period, that you increase burning calories. That is clearly a component. But, at the end of the day, many people doing intermittent fasting, at the end, eat clearly much less than what they would have eaten on a continuous basis.

B: So the fasting period that you get with intermittent fasting you don’t think has such a .. or it’s unknown?

JB: Well, I think, it’s not fully resolved in humans but it’s, like, that in rodent models, it seems to have an effect, a clear effect. But, again, I mean the mechanisms for it are not really well-understood.

B: Yeah. And so in order also to, maybe, prevent diabetes or, if you’re diabetic, is there certain foods that you should eat at certain times of the day?

JB: Well, in general, it’s independent of diabetes or, what is known again from pre-clinical studies, is that, what we’re learning more and more, is that in many metabolic pathways, there’s a natural circadian rhythmicity.

B: Good. I was going to ask if you should eat with your circadian rhythm?

JB: And you should definitely do that.

B: Okay.

JB: …and because there’s, I think, it’s an interesting mass experiment. And there’s also clinical human data to support that if you, let’s say, have a normal mouse, which is lean, and so they’re active during the night: they’re eating during the night, they’re sleeping during the day. I mean they have it reversed.

B: Yeah.

JB: And so. And they eat 90% of what they eat during the night. If you have a healthy mouse, if you measure what they’re eating, and if you, basically, feed them the same, exact same amount of food, same number of calories, that they would have eaten during the natural night cycle, basically, only feed it to them during the day cycle, they will get obese. Just meaning that it’s really important: the timing of your meal. And then, of course, you can extrapolate that to our living. That, you know, we would be normally operating in, you know, days, light cycle. And that also our clocks in our organs, including liver, muscle, everything, are adjusted to that time scale and optimized in terms of metabolic capacity during that time. Then it turns against you, you know, eating the calories at, you know, midnight, when you walk out of a bar or something like that, right. So then, that would just be the total analogy of this. So, I think, it’s really indicating that you should eat, you know, during a natural day cycle and not in the middle of the night. Which, of course, you know, also may explain why, potentially, obesity may be occurring, let’s say, in shift workers more readily than in people who work during the day.

B: Yeah. So what actually happens inside the body on a metabolic level if you eat outside of the most active time of the day?

JB: Well, so, in the most general terms is that the enzymes, which are made in the liver to metabolize, just example, glucose, fat, whatever, they are oscillating on a daily basis. And so that your liver is prepared to deal best with the calories when the enzymes are there to metabolize it. And if you, you know, dump the food on them, on the organ, when any enzyme that is required to take care of it, you know, is at its lowest state, then you can easily imagine that, then, the whole thing gets out of balance and doesn’t work as efficiently as it should be when food intake matches the optimal responsiveness of the organ.

B: Yeah. So, I guess, it’s really important to just eat in the most active time of the day?

JB: Yes.

B: And are there also certain food, like, food groups that maybe you should be eating in the morning or avoiding in the evening?

JB: I mean, I think it’s really, it’s more the balanced diet, you know, at any time during the day. I mean during the natural eating time.

B: Yeah, okay. What about sleep? Does sleep also play a really important role?

JB: Yes.

B: Like, so, I mean, obviously, sleep is very important. It’s, I think, everyone could say, sleep will play an important role in everything, but do you also have actual data to show that sleep is important?

JB: Well, yeah. You have to inverse data. And we also just have research program on that: so what we know is that, in obesity, the sleeping patterns get disturbed, in the most general term. And so what you seem to get is more fragmented sleep, which, then, of course, in turn, contributes also to an offset of your activities from that natural circle. Just giving one example, right. And then, of course, you don’t feel as well. But it seems that, if you have sleep deprivation, that there might be bidirectional interaction, that then, also your energy homeostasis regulatory system doesn’t operate as sensitively as it usually does. So it really, it goes both ways. So if you don’t sleep appropriately, it may predispose your obesity and, in turn, once you get obese, it further fragments your sleep.

B: Yeah, okay. So we’ve defined sleep, exercise, lifestyle factors: that’s all great. So what kind of medical treatments are there? So, I think, you’ve already mentioned that there’s not really that many medical treatments to treat diabetes?

JB: Well, for diabetes, there were a couple, for obesity, it’s very limited. And so, I mean, of course, it was the hype when, you know, when leptin was identified, everybody’s, like, “okay, obesity is down – we just get leptin”, but then, you know, people start realizing there’s leptin resistance. There is basically one drug right now on the market which, I think, is very promising, which was developed from a diabetes perspective. It was made as a diabetes medication. And it is acting like a hormone, which is naturally produced in our gut. And that’s called “glucagon-like peptide one”, GLP-1. And GLP-1 was first identified, if you eat glucose, that this is released from the gut and it acts on the pancreas to enhance the sensitivity of the beta cells to the glucose to release insulin. And then it was developed. The problem is that natural GLP-1 has a super short half-life. So if you now take that hormone you cannot, basically, well, I should say that, but it’s a peptide hormone, which is usually degraded in the stomach. So you can take it as a pill primarily. But if you inject it, it’s so rapidly degraded, that this didn’t go any further. So then, what was developed is kind of artificial analogues of the GLP-1 receptor, these are called GLP-1 analogs: they act like the natural hormone and they were first developed for diabetes. But then, it was recognized that the GLP-1 receptor is also present in the brain and exactly in those neurons, which respond to insulin, leptin. And that, in addition to controlling glucose, they also reduce the appetite. And this eventually led… and so this put them on the market. So they were first marketed as a diabetes drug – it’s very effective. But through the appetite suppressing effect, it now also has an indication for people. And this is pretty much it at this point of time – what we have to offer for, you know, for our obese patients.

B: Yeah.

JB: On the pharmacological side, but there are new developments. I mean, of course, we’re really trying to understand: can we develop something like leptin sensitizers, you know, something that reads in states normal leptin sensitivity? So there’s, you know, pre-clinical developments in that direction. And there’s a whole more in that area. But nothing really has entered clinical practice beyond, you know, the GLP-1 analog step.

B: Yeah. Actually, you mentioned leptin, and now I do have another question, so I’m gonna go back, and then I’m gonna go back to the treatment. But so, what actually determines how, in healthy human beings right now, what determines how much lectin and ghrelin we have? Because different people can, like, eat different amounts of food so clearly they have…

JB: No, it’s your body, fat it’s a fat content. So, really, the leptin levels in circulation run perfectly in correlation with your fat content.

B: Wow, okay.

JB: And the ghrelin really increases in starvation. So it’s a signal of release. So if you don’t eat for a period of time, then ghrelin levels go up. But this is not a lot of individual variation. So it’s really more this flexible regulation. And it’s really not that, so people also thought, “well, let’s let’s develop ghrelin antagonist block”.

B: Yeah?

JB: And those didn’t work to suppress, inject. And the problem is also that, I think, that the system is so redundant in the brain, as I said, we’re evolutionary optimized to maintain feeding, so if you, you know, go in on one side to suppress feeding, very likely there is a compensatory pathway being activated. And that, of course, makes it super, super difficult. And, therefore, already the GLP-1 is an interesting drug because we know now that it exits so many brain sites. And it’s almost serendipitous how nice it works. And really understanding the full basis, why it works to suppress feeding, isn’t even clear.

B: Yeah. So there’s not so many treatments available. Do you think that in the next few years that’s gonna change? Or a lot more research needs to be done?

JB: But it’s a lot more research going on. And it is also, I mean, they’re clearly promising candidates. So what people have started doing is, so great, you know, is one example. And it works and it can give you, let’s say, a 15% weight reduction, 10%, something like that. So if you have 130 kilograms, on average, better responders, some don’t respond, let’s say, you lose 13 kilograms. I mean that doesn’t solve for your problem, right, and so what people have been trying is to take other gut peptides and fuse them into one molecule. So that you’re not only targeting the GLP-1 receptor but also, you know, tickling receptors for other gut peptides. And there is clearly very promising data from pre-clinical studies and first clinical studies, that they may be superior to the effect of GLP-1 alone. And so those are basically on the verge of entering clinical practice and they, maybe, in the, you know, in the pre-clinical model, they give you 20-25% weight loss. But not, I mean, that hasn’t been fully validated in humans, but there is clearly developments, which look promising. And then, also alternative approaches. The better we understand the system, I think, the more…

B: So what if you combine exercise, sleep, healthy eating with maybe one of these drugs that hasn’t shown amazing results on its own? I’m assuming it’s always been tested on its own?

JB: No, it always comes, I mean, usually it comes, I mean, there’s nothing that you can just normalize sleep…

B: Yeah.

JB: But, I think, usually it should always be, and this is why we’re offering, this is one thing, so this is what we’re offering is these, you know, really controlled interventions, lifestyle interventions. I mean, they are active by themselves. And then, if you add that with something like a GLP-1 analog, of course, it gives you additional effects. And then you can really get into a pretty substantial weight loss. And then, the next problem is to maintain that, right. And then, of course, you have to have your lifestyle adjusted. The problem is when, that our system tries to fight fight back weight loss.

B: Yeah.

JB: So what usually happens, is pretty well-documented, that if you diet, let’s say, your energy expenditure was, whatever, make up a number, 2,000 calories a day. You want to lose weight, you diet, you eat 500 calories, 900 calories, your net balance goes down, you lose weight. The problem is: your body somehow senses that you’re in an energy deficit and what it does is fights it by reducing energy expenditure, which is fine. Let’s say, now it goes down from 2000 to 1700. You’re still eating 900 so you still lose weight. The problem is: your body will remember that perception of energy deficit. When you go back to your 2000 calories, which would have been equivalent to what you spend before you went into the diet, now your body will maintain, for extended period of time, up to two years, the 1700 energy expenditure. So if you only go back to your originally neutral food intake, it will give you the, you know, additional weight gain again. And this kind of, you know, the problem with this yo-yo effect, that you diet and then you overshoot and, at the end, it all goes into one direction. And this is why you really need those structured programs to maintain…

B: Yeah.

JB: Eventually the combination of exercise, reduce feeding, and it’s really it’s a long-term enterprise, but it works. I mean, so it’s not that it wouldn’t work, but you just have to be aware of it, that your body really wants to fight body weight.

B: Yeah, it really seems like, actually, to treat obesity, you have to also maintain it. For example, did you change your lifestyle completely? Yeah, and so also these the drugs, or the preventative, or the treatments, actually, against obesity, would they be thought to, then, that you have to keep on taking them your whole life?

JB: Yes. I mean the whole perspective, as of now, is it would be a chronic treatment. As treating, you know, hypertension, where you have to take drugs. And that, of course, is also a problem from a drug development perspective. Because they have to be very safe, right? I mean, what you have to develop is something that somebody potentially has to take for, whatever, 40 years. And that puts a very high burden on the drug development process. And that is also something, which has really made Big Pharma companies, despite having all the potential to develop those drugs, walk out of that indication. Because, you know, it’s much easier, I’ll just say that, but, let’s assume you’re treating cancer, you have a patient who has a very limited life expectancy sadly, let’s say, a year. If you develop a new drug, which helps to survive the patient an extra year, half a year, I mean, almost any side effect will be tolerated, right, if you compare it to conventional chemotherapy. And that, of course, from a marketing perspective of a pharma company is a much easier target than developing a pill, which somebody has to safely take over 40 years, to eventually improve life quality and extend life. And that puts the burden really high on that drug development. And it makes it also very likely to fail in very long-term as side effects. So, for example, there was a drug out, which was a cannabi-receptor-modifying drug, which worked beautifully for weight reduction, very nice. Like, it was only, like, what, 15 years ago. And, you know, huge development cost, it was enrolled into the market and, you can imagine, until a drug really makes it into the market if, you know, the company has spent, whatever, hundreds of millions into that. And then, suddenly, because it was modulating in the brain eating behavior, then, you know, you know, patients treated with it, a few in number, but still, you know, committed suicide in relation to that. Because it was interfering with, bringing circuits, which eventually involved mood. And it was taken off the market. And that, of course, was a clear message, also highlighting the risk of going into that direction. Because, I mean, from a company perspective, it’s a huge loss. And that balancing out, where you put your strategic developments, rather from an economical perspective, it’s much safer to go in certain indications than going into a direction, which really requires, you know, high level of safety for a very long time.

B: Yeah, What about a medication in children? Are we talking about the same ones? Like, you could administer them in children?

JB: But it’s even worse. I mean that they even don’t have the admission. I mean there are basically no clinical trials on medications in children, unless there are certain, again, rare mutations, because the mutations already manifest in children. And there is new drugs coming up, if you have certain mutations in a receptor, which is involved in, you know, downstream neurons of the leptin pathway, that you can, you know, really treat those, which are genetically predisposed with that. But other than, I mean, it’s the same conventional strategy that you would follow in adult.

B: Yeah. Yes, it seems like there’s still some challenging times ahead.

JB: True. But it’s a lot to be discovered. And what I really like about it, is really the fundamental aspect, and this is ultimately what Max Planck stands for, is trying to understand the system, right. I think, it’s really fascinating system and, I think, treating your patients is one thing but, I mean, I think, that you, first of all, you have to understand how the system works. And it’s so complex. And this is, I think, that is really the science that fascinates us, is trying to, you know, first, understand what is the neurocircuitry, where are the neurons, which sends the energy, to which neurons do they talk, you know, how ultimately all the different inputs come together, which are balanced to, ultimately, come to the decision: will I eat, will I not eat? And, I think, this is just fascinating neurobiology. And also, how to integrate, how to send out the signals to your peripheral organs, you know, in complete. Basically, we view those centers: it’s almost like you are a conductor in an orchestra, right. I mean, you have somebody saying, they’re getting all the input from outside, and then you’re orchestrating, you know, something to, you know, take a bite or not, to your liver to, you know, produce glucose or not. And, I think, that’s just what really fascinates me about it, the science behind it.

B: Yeah. I mean, I’m fascinated by how complex our system is but, I think, that’s also what makes developing the drugs so hard.

JB: Yeah, exactly.

B: It’s just, I think, we’re still lacking so much information, so… But, you know, that’s up to you so I will…

JB: Come back in a few years.

B: …come back in a few years, then we can talk about it. So the final thing that I wanted to talk about was COVID, the COVID pandemic, because it seems like a lot of COVID deaths in kids are also due to kids that have comorbidities? And it seems like there is a link between obesity and an increased risk of developing COVID?

JB: But it’s, I mean, basically, the risk that is best documented, I think, at this point. It’s not only true for kids, it’s logic true for adults as well. Yeah, there’s a clear risk factor to develop severe complications of COVID as a consequence of obesity and diabetes. So those are the two and it just highlights, also, the importance in today’s epidemic to really, you know, fight that back. The idea, why that is, is not really 100% clear if you want to get to that.

B: Yeah, I was just interested.

JB: No, I think, it’s multifaceted. We also, for example, we know that one way to become insulin-resistant in obesity is that you also get this regulated inflammation. So what we usually talk about is, if you expand your fat mass as an obese subject or animal model, it’s not only that the fat gets bigger and the fat cells get bigger, and so it’s not only a quantitative change of adipose tissue, but you start seeing that cells, which are usually only present in low number in adipose tissue, start to increase. And those are cells of the immune system like macrophages, lymphocytes, and they somehow get activated in this environment, and they release what usually they would release when you’re fighting an infection. So then, cytokines are released and cytokines have also been shown to cause enzyme resistance. So there is going to be, it’s called, the term is meta inflammation, so that, the obesity, it’s not like, you know, having a fever and a full-blown inflammatory state as, you know, fighting bacteria, but that you have a chronic low-grade inflammation. And so maybe it’s the offset of the inflammatory response which, is driven by obesity, which then you also compromise your ability to fully, you know, fight viruses. And that’s one of the aspects how it’s used, right. That you have a chronic set off in your immune homeostasis due to the metabolic environment.

B: But what about the flu? Do we see the same correlation between obesity and developing…

JB: I would guess, yes. Honestly, I really don’t know the numbers behind that, so it would be a guess. But it’s clear, the data are out there, but I would predict that it’s exactly, that the complication will be more but don’t quote me.

B: Yeah, of course. Yeah, because that’s what would really fascinate me, if it’s just something to do with…

JB: No, it’s not, no, it’s not only… I mean, what’s really clear is that your risk, let’s say, on, let’s say, on an equivalent bacterial infection to go into sepsis, like the full-blown, yeah, it’s much higher if you’re diabetic. So it’s it’s really, this is nothing limited to COVID, I think, it’s just a massive spread which has, you know, brought it to the attention of everybody. But there’s clear predisposition for much more severe cause of many infectious diseases bacterial infections in diabetes, just beyond COVID, definitely. 

B: So it really seems like we need to treat or reverse diabetes and then, automatically, you will also reduce…

JB: Or improve other areas.

B: Exactly, yeah.

B: So this has been a really good conversation. I’ve learned a lot. I hope the audience has as well. I hope you enjoyed it as well.

JB: Totally. And thanks so much for the conversation!

B: Thank you so much!

B: That’s it, thank you all so much for listening! If you would like to learn more about professor Jens Brüning’s work, please, visit the Max Planck Institute for Metabolism Research website. And if you like our podcasts, make sure to follow us on Twitter, LinkedIn, and our Instagram page – this is the best way to stay up-to-date with what episodes we will be releasing in season 3. And trust me, we have a lot of good episodes planned. Thank you again for listening! Bye!

B: Offspring Magazine the Podcast is brought to you by the Max Planck PhDnet Science Communication Group, known as the Offspring Magazine. The intro-outro music is composed by Srintath Ramkumar, and the pre-intro jingle is composed by Gustavo Carrizo. If you have any feedback, comments, or suggestions, please feel free to write us at Until next week! Stay safe stay healthy! Bye!

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