The neuroscience of metabolism

 

An estimated 130 million adults are living with diabetes or prediabetes in the United States right now. So it might come as a shock that a fundamental concept of diabetes – that the condition is rooted in the role of the pancreas on blood sugar levels – might not be the whole truth.

 

Dr Michael Schwartz of the University of Washington researches the role of the brain in hunger, metabolism and homeostasis. His work opens new questions around obesity and health, and new treatment prospects for all those affected by diabetes.

 

Read the original article: https://doi.org/10.1038/s42255-021-00408-5

 

Image credit: Ahmet Misirligul/Shutterstock

 

 

Transcript:

 

00:00:06 Will Mountford

Hello, I’m Will. Welcome to ResearchPod.

Today, we’re discussing diabetes – A condition that may impact the lives of many of our listeners, or those around you, and one that’s taught about in science classes as early as secondary school.

 

00:00:19 Will Mountford

So, may surprise you as much as it surprised me to learn that – we seem to have it all wrong.

Professor Michael Schwartz from the University of Washington is speaking with me today about his research into the role of signalling hormones in the brain to affect, and maybe even restore, the organ functions thought all-but-lost in diabetes.

 

00:00:42 Will Mountford

Well hello, thanks for joining us today.

 

00:00:45 Michael Schwartz

Thank you very much, happy to be here.

 

00:00:47 Will Mountford

And by way of introduction, could you tell us all a bit about yourself, what’s

 

00:00:51 Will Mountford

Led you to your research on diabetes and, well, a bit about your journey through medicine.

 

00:00:56 Michael Schwartz

Sure, well, when I was in college at the University of Colorado, which began in the 1970s, I developed an interest in sort of the brain behaviour interface. In other words, how does the substrate of the brain result in perceived feelings or motivations? That type of question. And when I went to medical school in Chicago after college I continued to have that kind of an interest. And after medical school I relocated to do my medical training at the University of Washington in Seattle. But throughout that training period, I retained that sort of research interest and I ended up selecting a fellowship in endocrinology and diabetes with a research focus, although it was a clinical fellowship.

 

00:01:47 Michael Schwartz

Because there’s a lot of interaction between the endocrine systems which make hormones and so on and the brain. And so this was an opportunity for me to pursue this sort of brain behaviour question with some really talented scientists that could help me develop my research career.

 

00:02:11 Michael Schwartz

You know, when I started my career, obesity was viewed as mainly a problem of willpower.

 

00:02:18 Michael Schwartz

That people who become obese are eating too much and if they could control themselves better, they wouldn’t have that problem.

 

00:02:27 Michael Schwartz

And that was despite a lot of sort of basic science evidence that suggested that body weight is actually regulated through a biological control system. Now, when you say body weight is regulated, what are we really talking about? We’re talking about body fat stores. And why is this important from a biological perspective?

 

00:02:47 Michael Schwartz

Well body fat mass is your body fuel stores so in a way the amount of stored fuel in body in the form of body fat is related to the amount of circulating fuel in the form of glucose.

 

00:03:01 Michael Schwartz

One is something that you store away for when you need it. The other one is what you’re going to use right now.

 

00:03:07 Michael Schwartz

And so it would make sense that the regulation of these two things would go together. And it also therefore makes sense that if you have a problem with one, you might have a problem with the other, which is what occurs in type 2 diabetes.

 

00:03:19 Will Mountford

Now, diabetes is something that a lot of people listening to this may have first or second hand experience with, and it’s covered in a lot of biology classes around the globe.

 

00:03:27 Will Mountford

So maybe we can kind of set the scene and recap at first what everyone knows about diabetes before we get into what’s new to know about diabetes.

 

00:03:37 Michael Schwartz

Well, diabetes is a condition that is associated with an elevation of the blood sugar level, so blood sugar or glucose in the bloodstream is the main body fuel, and it’s tightly regulated within a very narrow range. In normal individuals, and as people develop diabetes that range becomes impaired and the blood glucose level trend tends to rise.

 

00:04:05 Michael Schwartz

And over time, having an elevated blood sugar level can cause serious damage to the body, so that sort of defines diabetes.

 

00:04:12 Michael Schwartz

But there are different types. The main distinction between the types of diabetes depends on whether you’re able to make the hormone insulin or not. So insulin is made in specialised part of the pancreas called the pancreatic islets.

 

00:04:28 Michael Schwartz

It’s made by a specialised cell called the beta cell and in patients with type 1 diabetes, your own immune system attacks and kills the beta cells, so you can’t make any insulin and the blood sugar level rises. In type 2 diabetes, that’s not what happens at all.

 

00:04:51 Michael Schwartz

In fact, exactly what causes the problem is not really clear, but type 2 diabetes is highly associated with obesity, and obesity is associated with resistance to the action of insulin, so your body tissues that respond to insulin become less responsive.

 

00:05:09 Michael Schwartz

And in normal individuals you compensate for that by making more insulin. But in patients who develop type 2 diabetes, the ability to make more insulin becomes impaired, and so you end up with the combination of insulin resistance and inadequate insulin secretion in the setting of obesity is the classic picture for type 2 diabetes.

 

00:05:31 Michael Schwartz

But while all of those statements are true, it’s also true that we actually don’t know how these things evolve. What is the relationship between obesity, insulin resistance and beta cell failure leading to inadequate insulin secretion in Type 2 diabetes? That’s still an open question, and that was something that became a major focus of interest over the course of my career.

 

00:05:56 Will Mountford

Now this would be something for me to edit back into what we were talking about earlier in terms of what led you to diabetes research.

 

00:06:01 Will Mountford

That food itself is a particularly emotive topic for a lot of people, and that there’s this tangled web between mood and food and emotional regulation via hormones. Well, it’s perhaps a cyclical arrangement.

 

00:06:16 Will Mountford

So I mean definitely, not just the straight line of A to B to C.

 

00:06:20 Michael Schwartz

But to get back to your question about the relationship between motivation, diet and body weight control, what became clear from basic science work and then now has been pretty clearly shown in human obesity research is that its important to think about the cause of obesity (or ‘obesity pathogenesis’) as having two separate and distinguishable components.

 

00:06:45 Michael Schwartz

First I would emphasise that there is no one cause of obesity. Every individual has probably somewhat different factors, but there are two separable components — on the one hand, you have to enter a state of positive energy balance, where the calories that you’re consuming exceed the calories that you expend and so you gain weight as a result of consuming more calories than you’re expending over time. And that can happen for any number of reasons that can be related to how active you are, what type of foods are eaten, your emotional state, social and environmental factors, and so on. But the thing that makes obesity somewhat perplexing is that, as I mentioned, body weight is regulated in normal individuals.

 

00:07:34 Michael Schwartz

And what I mean is it tends to remain relatively constant over time, and if you try to change it by going on a diet and losing weight or overeating for some period of time, your body will correct for that so that typically and you’ll come back to where you started from. So there are biological processes in each of us that are designed to keep our body weight constant, and individuals who become obese enter a state of positive energy balance where you’re gaining weight. But if you check whether that new weight is being biologically defended, it is — so part of the problem is the defense of elevated body weight. That is, one problem is gaining the weight, the other problem is biologically defending it, and there’s actually been a lot of work done to understand how that biological control system works, and we’re making progress in understanding what goes wrong with it that can lead to obesity.

 

00:08:30 Michael Schwartz

Well, the the unfortunate reality is that conservative treatments for obesity tend not to work very well, which gets back to the brain-behaviour link that we started out with . My interest was, you know, for example, why do you feel hungry sometimes, and then you eat and you don’t feel hungry anymore? How does that work? And if you try to lose weight, or you succeed in losing weight? Why do you feel more hungry than you did if you didn’t try to lose weight?

We’re beginning to understand that the way that that works is that there are systems in the brain that control your appetite and there are signals that are generated by the fat mass that go back to the brain to tell the brain how much body fat you have. One of these is a hormone called leptin, which is secreted by fat cells themselves, and there are other signals that convey this information as well, but the point is that in the normal brain, whether it’s an animal or a human, at an unconscious level is being apprised of what the status of your body fuel stores are. Are they OK or not? And have body fuel stores begun to drop?

 

00:09:45 Michael Schwartz

That will be signalled by changes in blood levels of, say, leptin dropping, and other hormones that the brain is sensing, including insulin, are dropping, and the level of blood sugar is dropping if you haven’t eaten for awhile. All of these signals end up activating neurocircuits in the brain that drive feeding behaviour. And if you have lost weight from your previously regulated level, that system gets turned on even more, and that activation leads you to feel hungry — if you have lost a lot of weight –at times when you wouldn’t otherwise necessarily have been hungry, and that that state will persist until you restore your body fat stores to where they were at baseline.

 

00:10:35 Michael Schwartz

So the problem with concurrent conservative management of obesity is not that you can’t lose weight, it’s that it’s very hard to keep it off because once you lose it, your brain has a memory of what it thought your body fat mass should be, and it will motivate you to eat more and to lower your energy expenditure until you get back up to that starting point.

 

00:10:56 Michael Schwartz

Now, there are medications that are available that have had a significant impact, but you have to keep taking them in order to keep the weight off. There are also forms of bariatric surgery that can be beneficial to sustaining weight loss in some individuals, but there’s a long ways to go for us to say, well, we have a handle on how to manage obesity from a medical standpoint.

 

00:11:30 Will Mountford

Now to kind of recap on some of what you’ve just said and expand on neural circuits and their involvement.

 

00:11:36 Will Mountford

Why look at the brain in the 1st place when it’s something that could and you know, has for a long time been widely considered as just a pancreatic process?

 

00:11:46 Michael Schwartz

Well, when I did by fellowship training and my subsequent early years of training as an academic, my mentor was a fellow named Dan Port and he was a leader in the study of insulin secretion in humans and animals.

 

00:12:03 Michael Schwartz

And in fact, he was really the first one to show that insulin secretion is governed in part by endocrine and neural inputs to the pancreas. So it’s not simply that the beta cells in the pancreas are responding to the blood sugar. They’re responding to the blood sugar in a way that can be dialled up or down depending on other inputs, including from the brain. But I was perfectly happy with the idea that most of what controls blood sugar is how much insulin is coming out.

 

00:12:34 Michael Schwartz

And how much insulin is coming out is determined mainly by what happens to the blood sugar, and that there’s some problem with that in diabetes. And that was the dogma. And so to provide a context for how my thinking about this topic changed, we’ll go back 10 or 15 years to the work that we were doing in animal models of diabetes, and these are models where there’s a drug that you can use to cause diabetes by basically damaging the pancreatic beta cells.

 

00:13:07 Michael Schwartz

So you damage the pancreatic beta cells and within a day or two, the blood sugar goes up very high as you would expect, and at the same time, the insulin levels drop off to very low values very quickly. That’s the whole thing you expect to happen.

 

00:13:12 Michael Schwartz

But the other thing that happens that we realised is that the leptin levels in plasma also drop off very rapidly when you kill the pancreatic beta cells, and that’s because the fat cells are relying on an insulin signal in order to make leptin. And if that insulin signal goes away, the leptin goes away. So what we realised is well, now you have high blood sugar, and you think it’s due to low insulin, but how do you know that low leptin wasn’t also playing a role? So we wanted to answer that question.

 

00:13:55 Michael Schwartz

Now here’s getting back to the food intake story. Its well known that in people who have especially type 1 diabetes would know — that when your blood sugar is out of control, you tend to be hungrier than normal, and this is called ‘diabetic hyperphagia’ or increased food intake in uncontrolled diabetes. And it’s very easy to demonstrate in animal models, so we wanted to know, what is the role of leptin deficiency in these aspects of what happens when you have diabetes. So we arranged to give leptin back as a subcutaneous infusion over time in rats and mice that had diabetes, and we only gave the leptin back to replace what would normally be there, and what we found was when we did that, their food intake never went up. So the reason that diabetic animals have increased food intake is because of low leptin, not because they had diabetes per say.

 

00:14:53 Michael Schwartz

So that was kind of interesting, but then we wanted to show — we assumed that this effect of leptin was occurring in the brain, because that’s where most of the action of leptin occurs.

 

00:15:04 Michael Schwartz

But it hadn’t really been demonstrated, so we wanted to repeat the study, but give leptin directly into the brain as an infusion into brain ventricles.

 

00:15:15 Michael Schwartz

And to do that, we infused leptin at a much lower dose than you would need when you gave it into the circulation. And when we did that infusion, we did find that the food intake became normal as you would predict.

 

00:15:30 Michael Schwartz

But we also saw something else that we didn’t really expect, which was after about four or five days, the blood sugar went from being quite elevated to gradually dropping, dropping, dropping, and then by about a week it had become completely normal. So here you took animals that make no insulin, put leptin in the brain and their blood sugar becomes completely normal after about a week, and that that wasn’t thought to be possible. How can you reverse the elevation of blood sugar induced by insulin deficiency by targeting the brain? But that’s what the data showed. And when we stopped infusing the leptin into the brain, the blood sugar came back up again to where it was before.

 

00:16:14 Michael Schwartz

So this was the first evidence that the brain can be targeted to normalise the blood sugar of a diabetic animal, and for me that was kind of a game-changer because this whole idea that it’s all a relationship between insulin secretion and glucose handling and peripheral tissues like liver and muscle and adipose tissue, and it was like,

 

00:16:38 Michael Schwartz

“Wait a minute. What is leptin in the brain doing? The first thing we thought of course is well, maybe leptin in the brain is reversing the problem with insulin, and now you’re actually making insulin, whereas you weren’t before, but we looked very carefully at that, and you’re not. You don’t make any more insulin when you get leptin in the brain than if you got a control vehicle infusion into the brain so it wasn’t that we were replacing insulin, it was that we were normalising the blood sugar through a mechanism that was completely insulin independent.

 

00:17:12 Michael Schwartz

In other words, the brain has the inherent ability to normalise the blood sugar of diabetic animals without the need for insulin. That was kind of a game changer for us.

 

00:17:22 Michael Schwartz

Now of course, we haven’t shown that that’s true in humans, although we are planning a study to do that over the next year or so, to basically recapitulate what we had shown in the animal models in a collaboration with a colleague of mine named Zaman Mirzadeh who is a neurosurgeon down at the Barrow Neurological Institute in Phoenix.

 

00:17:51 Will Mountford

Now maybe I’m just being overly suspicious, but did you ever face any internal challenge or opposition in terms of conducting your research that you know either this would be a dead end of research or that there’s you know someone is making very good money producing insulin over here and don’t go rocking the boat.

 

00:16:08 Michael Schwartz

Well, I wouldn’t say that, but I would say that the bar for overcoming scepticism is higher when you’re pursuing an idea that is new and is not widely accepted or has not widely been demonstrated by lots of other people, especially if it kind of causes a paradigm shift. The way we think about blood sugar control and high blood sugar levels and diabetes, in my view, needs to be modified in view of these types of findings, at least based on the animal literature.

 

00:18:41 Michael Schwartz

So we decided to continue pursuing it, but we decided to move over to type 2 diabetes from type 1 diabetes because 1) type 2 diabetes is much more common. So about 90% of diabetes is type 2 diabetes and, 2) because it’s associated with obesity and we were already doing work on brain systems that are involved in body weight control and that become abnormal in obese individuals.

 

00:19:15 Michael Schwartz

So it might help just to take a moment to go back to what I mentioned earlier about the defense of elevated body weight or body fat mass. In a way, you can make the argument reasonably that as an individual goes from being normal body weight to having increased body fat mass to the point of becoming obese, it’s not that there’s a failure to regulate body fat mass, it’s that the defended level of body fat mass is increasing over time. You can make the same argument about blood sugar levels in patients who go from having normal blood sugar to type 2 diabetes.

 

00:19:48 Michael Schwartz

It’s not that the blood sugar control system has failed, it’s that that in a typical human, this evolution from normal blood sugar to diabetic range blood sugar occurs over 5 to 10 years or more.

 

00:20:02 Michael Schwartz

And it’s a gradual process where the blood sugar is still being regulated. It’s just being regulated at a higher level. So in some ways the underlying disease process is similar — you have a variable that is subject to homeostatic control, and that homeostatic control continues, but the level that’s being defended is gradually rising.

 

00:20:28 Michael Schwartz

You could say the same thing about high blood pressure. Normal people maintain their blood pressure in a normal range, and in people with high blood pressure, it’s not that they don’t regulate their blood pressure, it’s that the level that they’re regulating gradually increases to the point where it’s abnormal. And from that standpoint, it’s kind of interesting that high blood pressure, obesity, and type 2 diabetes all tend to occur together in humans as part of what’s known as the Metabolic Syndrome, so we think there may be some causal link between them and that the brain may be involved.

 

00:21:02 Michael Schwartz

Now why do I say that? Well, if you look at the brain area called the hypothalamus, which is important for energy homeostasis neurocircuitry. We and others have shown that if you look at animal models like rats or mice, within a very short time — a few days or a week or two — of switching them onto a diet that will cause them to become obese, for example, a diet high in fat and sugar (as compared to their normal chow , which doesn’t have really much of any fat or sugar in it) as the animals start eating, they love this diet and they start eating a lot.

 

00:21:44 Michael Schwartz

They love it, and within a short period of time you can see injury occurring in this particular hypothalamic area where these neurocircuits are involved.

 

00:21:54 Michael Schwartz

And markers of that injury are activation of non-neural cell types, so called glial cells. There are multiple different glial cells which are basically support cells or inflammatory cells in the brain and they get activated in this specific brain area and that occurs not only in animals that are obese, but if you look using imaging methods in humans, obese humans also have this evidence of what we’ll call gliosis in this part of the hypothalamus.

 

00:22:28 Michael Schwartz

So these things go together. The human work has been done primarily by Ellen. Sure, who’s a colleague of mine here at the University of Washington who does brain imaging research in humans.

 

00:22:40 Michael Schwartz

And she found that just as in the animal models, humans also develop gliosis in this part of the brain in the setting of obesity. Not only that, she more recently published a paper showing that this gliosis response is even more strongly linked to type 2 diabetes than obesity, and that the degree of gliosis is directly proportional to the impairment of blood sugar control along a spectrum of human subjects with and without diabetes. So this raises the possibility that maybe the same problem that is occurring in the hypothalamus in association with obesity is also somehow contributing to the defence of elevated blood sugar levels in patients with type 2 diabetes.

 

00:23:32 Michael Schwartz

And in some ways it makes sense because body fat stores are the stored fuel and blood sugar is the circulating fuel, so the idea that they are regulated through an overlapping shared set of brain controls makes a certain amount of sense, and it’s a way to at least tie together the observations that we had been aware of.

 

00:23:57 Michael Schwartz

So to move this in a more therapeutic direction, we began studies in animal models of type 2 diabetes, again in rats and mice, and we focused on a family of peptides known as fibroblast growth factor peptides, and there are many of these different peptides, and they are known to have many different functions in the body.

 

00:24:14 Michael Schwartz

But work out of a couple of pharmaceutical companies had shown that if you just administer them at pharmacological doses in these models of type 2, the blood sugar gets better and it came as a little bit of a surprise. We suspected that that was probably because they’re acting in the brain.

 

00:24:34 Michael Schwartz

There’s a lot of fibroblast growth factor or FGF receptor in the brain and the types of effects we were seeing looked to me as if they were involving the brain. So we set out to to study whether these different fibroblast growth factor peptides had anti diabetic effects that were mediated in the brain and we have focused in recent years on the peptide known as fibroblast growth factor one or FGF1 and we found kind of to our amazement that in a particular mouse model of type 2 diabetes that if you give FGF1 directly into brain ventricles as a single dose just one time, the blood sugar will drop initially, and it continues to drop over about 24 hours or so until it reaches normal. So it goes from being quite elevated, maybe three or four times normal, down to normal.

 

00:25:33 Michael Schwartz

So that was exciting that it seemed to be working in the brain, and this was a relatively low dose of FGF1.

 

00:25:39 Michael Schwartz

But what was even more amazing was that the blood sugar just stayed normal well after the FGF1 would have disappeared, so it came as a surprise, but we ended up just monitoring the blood sugar of these mice.

 

00:25:52 Michael Schwartz

And it turns out that even if you go out four or five months, the blood sugar is still normal after a single injection.

 

00:26:00 Michael Schwartz

So that again was a sort of unprecedented finding that the brain can be targeted in ways that with a single dose will reset the blood sugar level from being diabetes-range to normal, and will maintain it there over time.

 

00:26:20 Michael Schwartz

So that’s quite different from insulin treatment of diabetes — insulin will lower the blood sugar, but it doesn’t reset it at normal, it just lowers it.

 

00:26:29 Michael Schwartz

You have to titrate the insulin dose to figure out how much to give and then you have to keep giving it ’cause if you stop giving it, the glucose level goes back up to where it was.

 

00:26:37 Michael Schwartz

What we’re talking about here is a single dose of a peptide given into the brain that causes the blood sugar to come down to normal and then just stay there for weeks or even months without having to do anything else.

 

00:26:51 Michael Schwartz

And to make this point even more clearly, it’s not simply that you’re lowering the blood sugar, it’s that you’re resetting the defended level of blood sugar — because the blood sugar will stay at this normal level over long periods of time, and if you try to change it, for example, if you give a bolus of glucose into the circulation, the glucose goes up as you’d expect, but then it comes back down to where it was. And if you give a bolus of insulin to lower the blood sugar, it’ll go down as you expect. Then it’ll come back up to where it was.

 

00:27:26 Michael Schwartz

So you haven’t just lowered the blood sugar, you’ve reset the defended level of blood sugar at normal.

 

00:27:32 Michael Schwartz

What this means again is that the brain has the inherent capacity in diabetic animals to reset the blood sugar to normal, and that would be of great therapeutic benefit to patients with diabetes to simply reset the blood sugar at a normal level rather than having to everyday check your blood sugar and give a dose of this drug or that drug. Do it again the next day – that is how diabetes is treated.

 

00:28:01 Michael Schwartz

So we do feel that this is an important project, ultimately with potential to change not only how diabetes is understood, but how it’s treated.

 

00:28:17 Will Mountford

And now I’m kind of waiting for the other shoe to drop, you know, give me a reason to not get my hopes up too high to not get too excited about this because it can’t be this easy to just completely shake the foundations of biology, right?

 

00:28:30 Michael Schwartz

Well within the last year we advanced our studies to inject FGF1 into the brain of diabetic monkeys and that was done in collaboration with Peter Peter Havel at the University of California, Davis, at their primate centre. But unfortunately the doses that seem to be effective in lowering the blood sugar also seemed to make the animals feel sick. I mean they basically stopped eating and drinking for a couple of days and so we decided we’re going to put that on hold until we either figure out how to prevent that effect of FGF1 or we figure out how to do what FGF1 is doing without causing the sickness, using some other intervention. So this doesn’t have to be all about FGF1. It should be about understanding what it was doing and then seeing if there are other ways of accomplishing the same thing.

 

00:29:24 Michael Schwartz

So let me let me tell you a little bit more of a story about that work.

 

00:29:28 Michael Schwartz

Because I think we’re making progress there.

 

00:29:30 Michael Schwartz

What we found is that there is a set of neurons that are important not only in food intake control, but in blood sugar control, and they’re called AgRP neurons, and I won’t get into the details of why they’re called that. But when they’re activated, they drive feeding behaviour and they can also raise the blood sugar level.

 

00:29:54 Michael Schwartz

And if you inactivate them in diabetic animals, the blood sugar level will come down at least somewhat, and so we became interested in them as potential targets for the effect of FGF1 with the idea being to find a way to inhibit these neurons that would happen in a sustained manner that could help to explain the sustained reversal of diabetes. So we began a series of experiments, and we found that lo and behold, the area of the hypothalamus that is mediating the effect of FGF1 to lower the blood sugar is the same brain area where these neurons are located.

 

00:30:36 Michael Schwartz

Number 2, we have shown that in an acute setting administering FGF1 either to a brain slice or to a living mouse will inhibit the activity of AgRP neurons.

 

00:30:50 Michael Schwartz

Number 3, if you put FGF1 into the brain of a mouse model of type 2 diabetes at a dose that normalises the blood sugar level, and then you wait two weeks and then go and look at the activity of the neurons, they’re still inhibited 2 weeks later.

 

00:31:12 Michael Schwartz

So there was no precedent, you know, that you could do something to these neurons that would last for two weeks, but the fact that that seems to be happening suggests that perhaps the effect of FGF1 to normalise the blood sugar in type 2 diabetes animal models is mediated by long term inhibition of these neurons. Now, that’s important for a couple of reasons, and I wouldn’t say that’s the only thing. It’s probably multiple neural circuits that are changing, but it’s important for a couple of reasons. One is that it simply raises the possibility that if you could find some other way to inhibit neurons in humans, you might have beneficial effects.

 

00:31:58 Michael Schwartz

And I do think that that’s a therapeutic direction that’s worth pursuing, but it also suggests that the only way you could get an effect that lasts for two weeks – I think – is to do some sort of structural reorganisation of the circuit.

 

00:32:15 Michael Schwartz

In other words, this can’t just be happening to the neurons themselves, it has to be happening to the environment in which the neurons live, and so that gets back to the glial cells that I talked about, and we published a paper in Nature Communications about two years ago with Tune Pers at the University of Copenhagen, showing that when you give FGF1 into the brain of these type 2 diabetes mice, you do have effects on neurons, but by far and away, glial cell types are much more responsive to FGF1 than the neurons are, especially a cell type called the astrocyte, which is a major glial cell that regulates neuron function in a whole variety of different ways, so we think probably the sustained inhibition of the neurons has to do with effects on astrocytes, but that remains to be proven. We’re getting funding to examine that question.

 

00:33:15 Michael Schwartz

So the point is that all cells in the body are in what’s called extracellular fluid and the extracellular fluid is not really a fluid, it’s more like a gel or a matrix, and the extracellular matrix contains all kinds of biologically active molecules that are regulating cell function from the outside, and there’s a particular type of extracellular matrix in the brain that is called a perineuronal net, where elements of the extracellular matrix actually form a physical condensation – like a mesh – around neurons.

 

00:33:46 Michael Schwartz

Not all neurons, only some neurons, and this has been studied mostly in other brain areas like the hippocampus or the cerebral cortex.

 

00:33:55 Michael Schwartz

But with Zaman Mirzadeh, we reported in Nature Metabolism in 2019 that most AgRP neurons are actually enmeshed by perineuronal nets, so that suggested there might be a way to regulate the activity of the neurons by effects on perineuronal nets.

 

00:34:15 Michael Schwartz

And then Kim Alonge, who trained with me as a postdoc and is now a junior faculty member of our programme here at the University of Washington, showed that in a rat model of type 2 diabetes, the abundance of perineuronal nets around the AgRP neurons is reduced.

 

00:34:33 Michael Schwartz

And when you give FGF1 to fix their diabetes — because FGF1 works very well in those rats to normalise their blood sugar — you also restore their perineuronal nets to normal around the neurons.

 

00:34:48 Michael Schwartz

And we even she even showed that if you use an enzyme digestion method to get rid of the perineuronal nets in the hypothalamus at the time that FGF1 is given, the ability of FGF1 to sustain the normalisation of blood sugar is blocked.

 

00:35:10 Michael Schwartz

So in other words, the ability of FGF1 to have a sustained antidiabetic effect seems to require its effect to rebuild the extracellular matrix around these neurons. The extracellular matrix is being determined partly by the glial cells, so there’s a connection between FGF1, the glial cells, the extracellular matrix, and sustained changes in neuron activity that result in remission of diabetes.

 

00:35:40 Will Mountford

At this point, it sounds like there’s more happening in the brain than there is in the pancreas or, well, anywhere else.

 

00:35:45 Michael Schwartz

It’s complicated, yeah.

 

00:35:47 Michael Schwartz

But it’s worth pursuing because it ultimately helps us to understand not only how normal blood sugar is controlled, but what causes diabetes to occur.

 

00:35:58 Michael Schwartz

What is driving the elevation of blood sugar in patients with diabetes and can we target that process to provide relief to patients with diabetes?

 

00:36:08 Michael Schwartz

In ways that would be less invasive and less demanding than current diabetes treatments.

 

00:36:22 Will Mountford

So you know what changes with this new knowledge and is there anything that is going to be coming out? Any more projects about it that we can be looking forward to?

 

00:36:32 Michael Schwartz

Right, so you know.

 

00:36:34 Michael Schwartz

I am a physician.

 

00:36:35 Michael Schwartz

And my goal, an important goal of my research, in addition to sort of improving our understanding of, you know, how body systems work is that we can use this information to improve treatment options for patients with obesity or diabetes. And so that work progresses.

 

00:36:56 Michael Schwartz

I think there’s a long ways to go because we’re just really beginning to peel back the layers of our understanding of what the brain is doing with regard to the control of blood sugar, but there have been some translational developments. I guess you could say one of them is that in collaboration with my former trainee Zaman Mirzadeh, who is a neurosurgeon working at the Barrow Neurological Institute in Phoenix, along with irl Hirsch, who’s a colleague of mine and an expert diabetologist at the University of Washington, we are developing a study plan to test hypothesis that I mentioned earlier that came out of basic science studies. And so the idea is that we know in rats and mice that if you have uncontrolled diabetes due to destruction of insulin-secreting beta cells, if you simply infuse the hormone leptin directly into the brain of those rats or mice, the blood sugar after a couple of days will come down to normal even without any need for insulin, and so you know that was important, not only in identifying the brain’s ability to control the blood sugar, but it was also the first sort of evidence that uncontrolled type 1 diabetes, or diabetes where the problem is you don’t make any insulin, can be treated effectively without using insulin. There is really no precedent for that, certainly not in the the clinical literature.

00:38:45 Michael Schwartz

So as a proof of concept experiment, we have developed a collaboration and have a proposal that is under review at the FDA in the United States — you have to have approval from the FDA to do this kind of study where we’re going to be bringing well-controlled patients with type 1 diabetes into an intensive care unit type of clinical environment, and actually inserting a catheter directly up into the base of the brain of these individuals on a temporary basis to infuse leptin directly into the brain of humans and then gradually withdraw their insulin, with the goal being to determine whether type 1 diabetes patients can maintain normal blood sugar without insulin by providing insulin by providing leptin directly into the brain. The timetable for that really depends on when it gets approved by the FDA and I don’t know when that will be but I would imagine we’ll begin on that sometime in the next year, so that’s one example of a clinical translational dimension of our work.

 

00:39:47 Michael Schwartz

I’ll give you another one that also involves my colleague Irl Hirsch, and this has to do with the standard of treatment for hospitalised patients whose blood sugar is elevated, especially in the intensive care unit, so this is a very common problem.

 

00:40:04 Michael Schwartz

Patients who are really sick often have high blood sugar levels, and for about 20 years now the standard of practise for all comers who come into the ICU and have elevated blood sugar, whether they have diabetes or not, is to infuse insulin, usually intravenously to the patient to get the blood sugar down closer to a normal level, with the idea being that normal blood sugar is better than high blood sugar.

 

00:40:32 Michael Schwartz

If you’re sick and that makes sense, of course, and there is evidence that that is true among patients who did not have diabetes beforehand.

 

00:40:41 Michael Schwartz

But what’s becoming clearer now from a lot of studies in hospitalised ICU patients is that if you came in being diabetic already and your blood sugar was already elevated to begin with, and the first thing you do is to normalise the blood sugar – in other words, bring it all the way down to normal levels. Well, if if your body and your brain were used to having a blood sugar that’s elevated and you suddenly lower it, the outcome can actually be worse. In fact, it’s quite the opposite. So in patients who do not have diabetes, if you look at mortality outcomes when you normalise the blood sugar, the mortality is reduced. But if you look at patients who had pre-existing diabetes and had elevated blood sugars at home before they came in with an acute illness, the effect of normalising the blood sugar was to increase mortality.

 

00:41:44 Michael Schwartz

And that’s an important finding, because it suggests that the extent to which you control the blood sugar in hospitalised patients in the ICU should be determined in part by whether they had elevated blood sugar to begin with or not, and that raises the question then, well, why?

 

00:42:04 Michael Schwartz

Why would a patient who is used to having a blood sugar that is elevated have a worse outcome if you suddenly normalise the blood sugar? The work that we have done suggests that part of the reason that patients with type 2 diabetes maintain a high blood sugar is because the brain thinks that that’s the normal blood sugar — the brain is sensing the blood sugar and it is maintaining or contributing to the maintenance of an elevated blood sugar.  At least that’s a hypothesis that we’re continuing to explore, but the point is that if that were true, and you suddenly drop the blood sugar into the normal range, that’s going to be perceived by the brain as being too low. And when the brain thinks the blood sugar is too low, it activates responses such as activating the adrenal medulla and causing epinephrine levels to increase. And if you’re in an acute illness, having an increase of these types of stress hormones may be maladaptive and could contribute to increased mortality.

 

00:43:07 Michael Schwartz

So we’re actually in the process of submitting a commentary to The Lancet that addresses this concern and calls for a re-evaluation of how do you identify the glycemic target in a hospitalised patient, and should the pre-existing diagnosis of diabetes influence that decision. So we don’t know the extent to which that application is a reflection of the role of the brain in control of blood sugar and in the development of diabetes. But my suspicion is that that will be found to be the case.

 

00:43:49 Will Mountford

Think about everything that this does to challenge the previously understood function of sugar processing in the body. Putting some pretty big challenges at the door for what people have spent years and careers thinking that they understood professionally, is it time to rewrite the textbooks?

 

00:44:05 Michael Schwartz

Well, I think the history of science is that the truth eventually wins out and you know, I’m not really interested in viewing my work as being somehow in conflict with mainstream thought or having to fight a battle to win acceptance of our ideas.

 

00:44:24 Michael Schwartz

I think — you know, there is still some scepticism in the community about the extent to which the brain is really important, and the onus is on us to make the case not only in animal models, but in the clinical world as well, so as we begin to make progress in that area, eventually people will have to accept that, you know, you have to accommodate the role of the brain in our understanding of blood sugar control and diabetes.

 

00:44:49 Michael Schwartz

And that’s a process that will take time and you know, I’m committed to continuing to work on that. I do think it’s important for the diabetes community and the rest of the world to be aware of these ideas and their implications.

 

00:45:04 Michael Schwartz

And just to address your specific question about rewriting the textbooks, I actually have been asked to submit a chapter on brain controlled blood sugar to the Textbook of Diabetes, and we submitted that, and that’s basically in press as we speak.

 

00:45:21 Will Mountford

There’s anything that any patient listening to this could take away to, maybe participate in upcoming trials if they are near a centre, that’s recruiting, or if there’s anything that practitioners should know. You’ve mentioned, the hospital admission sugar level stuff that’s coming out in any commentary.

 

00:45:36 Will Mountford

Is there anything that they can take into practise immediately or any upcoming publications that is going to lay things out for them to catch up on?

 

00:45:44 Michael Schwartz

I think it’s safe to say that the neuroscience of metabolism, if you want to call it that, Is a highly integrative multidisciplinary field that is really just emerging. And it’s a bit problematic in that in the sense that most experts in diabetes and metabolism are not experts in neuroscience and most experts in neuroscience are not experts in diabetes and metabolism.

 

00:46:12 Michael Schwartz

But those fields are going to converge. They have to because that’s the only way we’re going to understand these problems. And it’s an exciting field, and it’s a great opportunity for young scientists because it’s both extremely important. But it’s also wide open in terms of opportunities and I would just add on that if there are members of the audience listening to this now who are interested in possible training in our programme in Seattle, we’d love to hear from you.

 

00:46:46 Michael Schwartz

So what about the treatment of these disorders, diabetes in particular. How does all of this inform our thinking? And they’ve sort of touched on this earlier, but I’ll just reiterate that most drugs that are taken today for the treatment of type 2 diabetes are designed to lower the blood sugar for the period of time during which that drug is in the body and then as that drug wears off the blood sugar goes back up, again,

00:47:15 Michael Schwartz

Certainly insulin is the textbook example of this. You take insulin at a dose that will lower the blood sugar. You may bring it down into the normal range and then that effect wears off as the insulin is cleared from the body.

 

00:47:34 Michael Schwartz

In other words, these treatments are not reestablishing normal blood sugar control. They’re simply dropping blood sugar potentially into the normal range for a while, and then you have to administer the drug again.

 

00:47:49 Michael Schwartz

The new version that we see unfolding that involves the brain is the potential not just to lower the blood sugar, but to reset the blood sugar at a normal level and have it be maintained in normal or near normal range for long periods of time, potentially indefinitely.

 

00:48:14 Michael Schwartz

You know interventions that don’t necessarily need to be given every few hours or every few days or maybe even every few weeks in order to get there, we need to identify the neural targets that are responsible for establishing or the brain? What the defended level of blood sugar is going to be, and we know using interventions like putting leptin in the brain that we talked about, or FGF1 in the brain we talked about.

 

00:48:39 Michael Schwartz

You know as we work through basic science to understand what the targets are that those agents are acting on. We can then begin to identify targets that might be attractive for diabetes treatment. In other words, once we know what the neuro circuits are, we may be able to target them selectively using medications.

 

00:49:04 Michael Schwartz

That will correct the abnormality in their function that is promoting elevated blood sugar levels and allow the blood sugar to come back closer to normal in a more naturalistic way that can be sustained over time. But the cautionary note here is that going from someone who is used to having a high blood sugar to all of a sudden, having a normal blood sugar as an abrupt transition.

 

00:49:32 Michael Schwartz

Maybe we should be thinking twice about that objective, especially in individuals who have underlying illness like cardiovascular disease or being at risk of a heart attack which many patients with diabetes are.

 

00:49:45 Michael Schwartz

So that would be one point, especially in this in the setting of a hospitalised patient or a patient in the intensive care unit.

 

00:49:52Michael Schwartz

I think some caution is warranted in terms of deciding what you think the target blood sugar level should be, and if the person had been accustomed to having a high blood sugar level before they came in.

 

00:50:03 Michael Schwartz

I think the idea that they’re going to benefit from suddenly normalising the blood sugar may be mistaken, the longer term goal I guess would be to be open to the possibility that the brain might ultimately be more effectively targeted in the treatment.

 

00:50:20 Michael Schwartz

Of diabetes than it currently is, and I think we’re already headed in that direction because the one of the most widely and effective used medications for type 2 diabetes now are the family of drugs that act at the receptor for a peptide known as GLP 1.

 

00:50:43 Michael Schwartz

These are the so called GLP 1 agonists and there’s a whole series of these GLP one receptor agonists that are being generated and that have long durations of action and or can be mixed with other molecules to have kind of a super potency.

 

00:51:02 Michael Schwartz

And some of the effectiveness of the GLP one agonists are mediated through peripheral actions like directly on the insulin secreting beta cell to make more insulin, but others of the effects are mediated in the brain. So even though people may not think about the brain as being an important target for these GLP one analogues. They are in fact having significant effects on the brain that promote both weight reduction and improvement of blood sugar control.

 

00:51:31 Michael Schwartz

The upshot of the work that we and others have done have led us to an understanding that we already knew that stored fuel in the form of fat and circulating fuel in the form of glucose are subject to tight biological control. But what we’re now learning is that the brain is playing an integral role to control both of them.

 

00:51:55 Michael Schwartz

And that’s not surprising because, You know, the stored fuel and the circulating fuel are sort of two sides of one coin as far as the body is concerned, and as far as the brain’s own needs for fuel are concerned. Moreover, we know.

 

00:52:11 Michael Schwartz

That the neuro circuits that are involved in controlling energy balance and body fat stores are overlapping with those that are involved in the control of blood sugars, suggesting that they’re really part of one large integrated brain control system. This doesn’t mean that the pancreas and peripheral tissues are not important, they are. They’re all sort of part of 1 integrated system.

 

00:52:38 Michael Schwartz

We’re also learning it. It appears highly likely that brain’s ability to sense relevant signals related to both stored fuel, like the hormone leptin and circulating fuel, like the blood glucose level is critical to the proper functioning of this integrative system. So why does this matter? Well, because it’s easy then to understand that.

 

00:53:04 Michael Schwartz

If there was a disorder in the brain system controlling body fuel stores, it wouldn’t be that surprising that that same disorder could leak into the neural circuits that are involved in blood sugar control, and you’d end up with a problem.

 

00:53:24 Michael Schwartz

Of having both excessive body fat mass and elevated blood sugar levels even though both are still being regulated. They’re being regulated at an abnormal level. And that’s actually a pretty accurate description of Type 2 diabetes, 90% or so of patients with type 2 diabetes are also obese, so you have a situation where the fat mass is elevated.

 

00:53:47 Michael Schwartz

The blood glucose levels are elevated and we have growing evidence that the ability of the brain to sense and respond to the signals that control body fat mass and that control the blood sugar are compromised in individuals with type 2 diabetes. Certainly in the animal models that we study, this appears to be true.

 

00:54:12 Michael Schwartz

I think we can be optimistic that the future is bright for patients with diabetes, that as progress is made in understanding how these systems work, new medications can be identified that improve outcomes and make the disease easier to manage for affected individuals.

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