When grizzlies and other bear species hibernate, they go months without eating or drinking, living off the fat they accumulated during the summer and fall. They also undergo changes to their metabolism and develop resistance to insulin, a hormone also found in humans that helps regulate blood sugar levels. The development of resistance to insulin can be an early indicator of type 2 diabetes in humans, a potentially chronic condition that left untreated can damage the kidneys and other organs.
Researchers at the Washington State University in Pullman used blood samples and cell cultures taken from grizzlies at the Washington State University Bear Center to identify eight proteins that are responsible for regulating insulin sensitivity in bears. The proteins caused changes in gene expression, leading to insulin resistance during the winter hibernation and insulin sensitivity during the active spring and summer months. Versions of these proteins also exist in humans, revealing a possible molecular roadmap to develop better medications for controlling the insulin resistance that can lead to diabetes. Joining us now is Blair Perry, a post-doctoral researcher in the School of Biology at Washington State University, and a co-author of the study on insulin resistance in bears published this month in the journal iScience.
Note: The following transcript was created by a computer and edited by a volunteer.
Dave Miller: From the Gert Boyle studio at OPB, this is Think Out Loud. I’m Dave Miller. We turn now to some exciting research that came out of Washington State University, Pullman. Scientists there studied grizzly bears to unlock some of the secrets of their metabolism. When grizzlies hibernate, they go months without eating or drinking, living off the fat that they’ve accumulated during the summer and fall, and they develop a resistance to insulin, something that in humans can be an early indicator of type 2 diabetes. But that does not happen in grizzlies. Blair Perry is a post-doctoral researcher in the School of Biology at Washington State University. He’s a co-author of this study on insulin resistance and bears that was published this month in the journal iScience. He joins us to talk about what makes bears unique, plus the enticing possibility of using these findings to treat diabetes in humans. Blair Perry, welcome.
Blair Perry: Thank you so much for having me.
Miller: What is the big question that you and your team started with?
Perry: So, at a very broad level, hibernation and bears is a really extreme and complex adaptation. It’s more than just a long sleep through the winter. There’s a lot of physiological and metabolic changes that are happening in their body throughout this period of time that allow them to survive these long periods without eating or drinking, like you said. So on a very broad level, we’re interested in understanding all aspects of what goes into hibernation, what allows bears to do this when other mammals like humans obviously can’t. This involves measuring and studying metabolism and other aspects of physiology, but more recently, looking at a genetic level to try to understand what genes are involved and how those genes may or may not be acting differently than similar genes would in humans.
Miller: Before we get to that level, that molecular level, can you just remind us about the yearly cycle of bear activity? I mean, what are they doing when?
Perry: Yeah, so we like to divide it up into three different seasons. So, you’ve got the active season, which is typically the warm summer months. This is when bears are kind of doing normal bear stuff. They’re foraging around, they’re eating, they’re looking for mates, things like that. And in the fall, you enter this period called hyperphagia, which means essentially excessive eating. During this period of time, they’re obsessively trying to eat as much as they can to fatten up in preparation for winter. So this is when you see those videos and pictures of them in the waterfalls catching salmon and all this, and during this period they can even put on up to about 9 pounds per day, in some cases, due to the amount that they’re eating. At the end of the fall, as winter really starts to set in, they transition into hibernation, which is something that I think everyone is more or less familiar with the idea of. But like I mentioned earlier, a lot of people think they’re essentially just going to sleep for the winter, but there’s actually a lot going on biologically that allows them to go this really long period of time, burning all that fat that they gained in the fall, without having to eat or take an additional nutrients during that time.
Miller: Can you describe how you set up this experiment?
Perry: Right, so we used a method called cell culture which allows us to take cells from living tissue, from a small tissue sample of a bear, and essentially grow and maintain these cells in a lab so that we can do things with them, study them without actually having to interact with the bear frequently. By using the cell culture system, we stimulated cells that were collected in different seasons. For example, the active season in the summer and the hibernation season in the winter, and we stimulated these cells with blood serum that was collected from these different periods of time as well. And by doing this we were able to see that something in the blood essentially is playing a really important role in changing what genes are active during these different times of year, and how these changes are actually probably underlying some of these really interesting aspects of hibernation, such as the fact that hibernating bears become insulin resistant.
Miller: There’s a lot in everything you just said, but let’s start with the last thing. What does it mean for a bear that’s hibernating to be insulin resistant?
Perry: Right, so insulin is a hormone that typically is kind of a key that tells cells that there is blood sugar available that they can take into the cell and use for energy. So when we eat, it’s converted to glucose or blood sugar, essentially. When this blood sugar level increases, insulin also increases, essentially telling cells there’s plenty of sugar here, take it in, use it for energy, use it to do what you need to do as a cell. Insulin resistance is a condition where those cells no longer respond to insulin. Essentially the key no longer works. So even if there’s plenty of blood sugar available to these cells, they’re not able to respond to insulin, take that blood sugar in and use it for energy, which can lead to a bunch of downstream consequences essentially, cells and tissues and organs not working as they should or potentially being damaged.
Miller: What does it mean that a hibernating bear is insulin resistant?
Perry: We’ve shown that in fat tissue – again, they’re relying on all this accumulated fat, burning that to survive hibernation, fat tissue – these fat cells essentially no longer respond to insulin during the hibernation season. This is partially because insulin typically inhibits the ability for fat tissue to mobilize or burn that fat, essentially. By turning off this sensitivity to insulin, that appears to really kind of ramp up their ability to burn fat and survive the winter months. But it’s likely not necessarily the case for all tissues. There are likely other tissues – for example, the brain and other nervous system tissues – that remain sensitive to insulin and are able to take up that blood sugar and use that to stay functional and stay healthy through the winter.
Miller: What were you able to learn? I’m not sure if you were studying this piece in particular, but about the period before hibernation, the massive eating time of berries and salmon, a time when bears effectively and necessarily put on tons and tons of fat. What do you know about that period and how their metabolism works there?
Perry: Yeah, so that wasn’t something that we looked at in too much detail in this particular study, but is something that we’ve been interested in looking at in the past. A recent study that we published in the last year actually identified several changes in gene activity during that season that we think are actually essentially boosting their ability to put on fat by changing how cells are metabolizing and storing fat. We think that there are actually changes going on at a genetic level in terms of how these genes are functioning that is giving them an extra ability to put on fat, in addition to the fact that behaviorally, they’re essentially obsessed with eating and focusing all their time and energy on eating as much as they can and getting as fat as they can.
Miller: What do you see as the most important results from this study?
Perry: Well, in addition to showing that something in the blood, essentially, is controlling how genes are active during hibernation, we were able to compare that blood serum from different seasons and identify changes in the composition or essentially what proteins are present in that blood during hibernation versus during the summer. And we see that this blood serum really can change the activity of thousands of genes in some cases. But when we looked at what is different between the active serum, blood serum, and the hibernation blood serum, we only found a small number of proteins – eight proteins in particular – that were significantly different. So this suggests that these eight proteins, or perhaps even a subset of these, are having these really drastic impacts in change, effects on changing how these genes are active during the different seasons and allowing these bears to achieve these different aspects of hibernation, essentially.
Miller: How closely related or or how different are insulin in bears and humans and these eight proteins in bears and potentially in humans? I guess I’m wondering how similar we are on a molecular level to bears.
Perry: Yeah, absolutely. That’s a really interesting question. And surprisingly, I think to a lot of people, we are much more similar at a genetic level to bears and most other vertebrates than you might think. Bears and humans obviously look and live and act very differently. But most of the genes that are present in a human are also present in some form or another in bears as well. And a lot of these cellular processes, like the metabolism and control of insulin, from what we know, a lot of these seem to be pretty well conserved or shared across all sorts of vertebrates. We think that the basic way that bears are metabolizing nutrients and responding to insulin and things like that are probably very, very similar to humans, but perhaps a few changes in how particular genes or particular proteins are acting might be the key to unlocking these abilities that they have that humans don’t. So in other words, we have a lot more shared at a genetic level with bears than you might expect. And all of these eight proteins that we identified as potentially really important here, these eight proteins are also proteins that are present in humans and some of them, for example, are known to play a role in the regulation and response to insulin in humans.
Miller: What are the next steps for you and your team with this research?
Perry: So we’ve got a lot planned and a lot in the works. One immediate next step for this study is trying to dig deeper into these eight proteins that we identified and understand what exactly they are doing. What specific genes and what specific aspects of hibernation they are specifically involved in controlling. So we think that they’re playing a role in insulin resistance, but we need to dig deeper and try to specifically test what genes, for example, are specifically being controlled or impacted by these proteins. So, that’s one level. There’s also a lot of additional things. Biology is complicated and these proteins are likely probably just one part of the story. We are working with collaborators to look at other molecules that might be circulating in the blood and other aspects of biological regulation or control that might be playing additional roles in turning on and turning off different aspects of cellular biology in these bears during hibernation.
Miller: It seems like, because you’re still early on in terms of all the questions you’ve just outlined, that the big switch, going from this basic research to human medicine, it still is pretty far away. But I’m curious if you just sort of imagine possibilities that are out there, how could what you’re learning right now, what does it suggest in terms of a possible mechanism for human medicine to treat diabetes? What’s the way that you can imagine something working?
Perry: Absolutely. So, again, we think that there’s probably essentially … these bears have evolved a slightly different way of regulating or controlling some aspects of their metabolism, differently than what humans are able to do. So, if we can identify what is different about bears, their metabolism, what genes are involved from humans and what proteins or other molecules are responsible for making those things behave differently – essentially what is controlling these differences – we could in theory try to develop medicines or therapeutic approaches that stimulate similar behavior of those cellular processes or genes and humans to essentially develop ways to help humans overcome insulin resistance.
So, again, humans becoming resistant to insulin typically is an early sign of progressing to type 2 diabetes. And in an ideal world, these bears again are becoming insulin resistant during hibernation, but every spring, reversing out of it completely naturally, never developing diabetes and never having any harmful consequences. So, if we can figure out how they’re able to turn off insulin resistance, essentially make things work as they did before they went into hibernation, make that same thing work in human tissues, we might be able to develop new medications that can help humans to overcome insulin resistance, avoid that progression down to type 2 diabetes, and overall improve the possibility that people that are becoming insulin resistant can reverse out of that and continue to have a healthy life moving forward.
Miller: Where do you get the grizzlies to study? And where is this work being done?
Perry: Right. So we have, at Washington State University in Pullman, a literally one of a kind facility – the only facility like this in the world – the Washington State University Bear Center, which has a population of eleven grizzly bears ranging from 7 to 21 years old, currently, that we are able to work with and have really unique and incredible access to these animals that you would not normally be able to do in the wild. So through training and reinforcement with food and things like that, we’ve trained these bears to be able to interact in safe ways with researchers. So we’re never in there with the bears, but for example, they can present a paw through an opening in the fence so that we can take a blood sample or give them exams and things like that. So it allows us to study all aspects of bear biology, from the genetics to their ecology, to diet, in a way that’s safe for the researchers and also safe for the bears, not impacting them negatively in any way and allowing them to live happy bear lives while we’re also gaining incredible knowledge that we wouldn’t be able to get anywhere else.
Miller: Speaking of knowledge you can’t get anywhere else, so this is focused on bears obviously, but your PhD involved snakes, your PhD research. What should we know about snake metabolisms? What should every person know about the snakes you’ve been studying?
Perry: A lot of my PhD research focused on something that obviously sounds very different than than grizzly bears and hibernation but has some parallels, which is that some snake species like Burmese pythons – these really big, heavy- bodied, chunky snakes – in the wild they will often only eat once a year, in some cases, due to just seasonal availability of their prey. So for example, a python might eat in August and go the entire year until it even encounters a prey item to eat again. And they eat these really large meals. And these snakes have evolved the ability to essentially shut down their digestive system during those long periods of fasting so that they’re not wasting energy keeping their digestive tissues and functions essentially turned on. And by shutting that down, they conserve energy, can survive that long period of fasting, and then when they finally find another large prey item like a deer or something like that, maybe a year later, within about a day they’ve regenerated, regrown and turned back on that digestive system so that they can process that prey item, digest it and start the cycle all over again. You know, snakes and bears, obviously very, very different things, but both have these really interesting and extreme metabolic and physiological adaptations to these long periods without eating food, essentially. And that research was interested in trying to stimulate ways to regenerate damaged intestinal tissue and things like that in humans as well. So similar, but similar outcomes in the long run for benefiting human medicine in that case too.
Miller: Blair Perry, thanks very much for joining us.
Perry: Thank you so much for having me.
Miller: Blair Perry is a research associate in the School of Biological Sciences at Washington State Washington State University in Pullman.
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