Do Brown Bears Hold the Secret to Curing Diabetes?

Scientists uncovered eight key proteins that may explain how bears regulate insulin sensitivity when transitioning between hibernating and active states

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When you think of brown bears, like the subspecies grizzly bear, certain terms may come to mind – powerful, apex predator, and ferocious. Some may also think warm, cute, and fuzzy. What probably does not come to mind is their ability to avoid disorders related to sedentary lifestyles. Yet this is a remarkable feature of brown bears that is being studied to possibly identify cures for diseases in humans like diabetes.

Brown bears are well adapted to sedentary lifestyles because they evolved to hibernate, or enter a state of ‘dormancy’, five to eight months a year. During hibernation bears are incredibly inactive, yet they completely preserve organ function and avoid blood clots, heart failure, and loss of bone density or muscle mass; bears also tolerate drastic shifts in weight without major health consequences as they store large amounts of fat in preparation for hibernation and burn through that fat during hibernation.

These are all feats a human could only dream of with a sedentary lifestyle, because unlike bears, humans develop many disorders when they are inactive. This is because humans are adapted to a highly mobile lifestyle and evolved to be continuously active as hunter-gatherers. However, in recent societal times, humans have become quite sedentary which has led to a rise in disorders related to inactivity. One very prominent disorder in humans is diabetes [>37 million Americans or about 1 in 10 have diabetes], where the body struggles to regulate and maintain appropriate blood sugar levels.

In a healthy state, blood sugar is regulated by hormones released from the pancreas called glucagon and insulin. Glucagon helps raise blood sugar when it is too low, and insulin helps lower blood sugar when it is too high. Insulin works by triggering cells to uptake sugar from the blood and either use it as energy or store it for later use. A sedentary lifestyle, obesity, and poor diet can drastically decrease the sensitivity of cells to insulin, which is referred to as insulin resistance. Insulin resistance can progressively get worse without lifestyle changes and eventually leads to diabetes. Diabetes causes higher levels of sugar in the blood than should be, which can be damaging to the body and lead to diseases like heart disease, vision loss, and kidney disease.

Miraculously, bears do not get diabetes and actually show the capability of switching between insulin resistant and insulin sensitive states as they switch between hibernating and active states, respectively. This suggests the brown bear genome (or collection of all the genes in brown bear DNA) may contain the secret to reversing insulin resistance. That is one of the reasons why scientists have been interested in understanding the physiology of hibernation – in hopes that a deeper understanding may lead to new treatments and cures for disorders related to inactivity like diabetes.

In the last several years, scientists have made advances on determining how bears can reverse insulin resistance. In a study from 2017, researchers collected fat cells (or adipocytes) from hibernating bears and mixed them with blood serum (the watery, clear portion of blood) that came from either hibernating or active bears. When cells were incubated with serum from hibernating bears, the cells showed insulin resistance; whereas, when cells were incubated with serum from active bears, they showed insulin sensitivity. The researchers also heat treated serum from active bears (to deactivate any proteins present) and showed this mostly prevents the increase in insulin sensitivity. This means scientists figured out that proteins in blood serum may represent a key aspect of how bears switch between insulin resistance and sensitivity. In other studies, like one from 2019, researchers have done large genetic experiments and have identified many of the genes that show changes in gene expression (or turning ‘on’ or ‘off’ of a gene) in brown bear tissue between hibernating and active states. Many genes that have been identified are involved in insulin regulation and may help scientists understand how insulin sensitivity is being regulated.

In a study from 2021 scientists found a third state in addition to active and hibernating states to add to future studies. This third state occurred when scientists disrupted hibernation by feeding the bears sugar for ten days (i.e. fed state). The feeding triggered an increased metabolism and partial return to insulin sensitivity making the fed state one that is somewhat between the active and hibernating states. So, the next step was to directly compare all three states and that is just what a group of researchers did in a recent study published in 2022 in the journal iScience. The goal of this study was to identify the specific serum proteins that cause the switch between active and hibernation states (and therefore the switch between insulin resistance and sensitivity), which could bring us one step closer to the development of a therapeutic for diabetes. 

To address this goal, the scientists worked with captive bears that are housed at the Washington State University Bear Research, Education, and Conservation Center. Using captive bears for research can have several benefits over wild bears because captive bears can be weighed regularly, can have blood samples drawn easily, and their diets can be regulated. Even though these bears are in captivity, they still hibernate yearly after eating to build up fat reserves from August to early-November. The bears hibernate in pairs where the lighting and temperature of their housing is maintained throughout the year to represent the natural environment. For the study, blood serum and tissue samples were collected from bears in January to represent the hibernation state; in January after sugar feedings to represent the fed state; and during late-May to early-June to represent the active state. The bears were anesthetized during the sample collections to maintain comfort for the bears and safety for the scientists (seeing as poking a woke bear may not go over well).

The scientists used the collected samples to generate six different combinations of tissue cultures by mixing fat tissue collected during the hibernation and active seasons with the three different types of blood serums [hibernating, active, fed]. Using these cultures, the scientists measured gene expression differences between the six combinations to understand what genes are turned ‘on’ and ‘off’ differently in hibernating versus fed and active states. The scientists also measured the abundance and composition of proteins present in serums from bears that were in either the hibernating, active, or fed state. 

By comparing and contrasting their data, the scientists discovered eight proteins that were differentially present in hibernation serum compared to both the active or fed serums. This could represent an important breakthrough, as these eight proteins may be key to reversing insulin resistance. Intriguingly, these eight proteins are not bear specific and similar proteins are evolutionarily conserved and found in humans. This means their function may directly translate into human physiology. Additionally, because hibernating tissue mixed with hibernating serum showed unique features (like gene expression differences) compared to the other combinations tested, it suggested that hibernating cells may have unique cellular characteristics that also play role in regulating insulin sensitivity in addition to proteins circulating in the blood.

…eight [newly identified] proteins may be the key to reversing insulin resistance…[and] hibernating cells may have unique cellular characteristics that also play role in regulating insulin sensitivity…

Overall, this most recent study revealed eight candidate proteins that may play a significant role in regulating a reversal from insulin resistance to insulin sensitivity. Future studies will have to characterize these proteins to understand their exact function in this process. Additionally, the scientists showed that proteins in serum are not the only contributors, and the intrinsic cell characteristics of hibernating cells also play a role in reversing insulin resistance. Future investigations will have to try and understand what these important cell characteristics are. The scientists have also stated a caveat to their study, in that it is possible that metabolites or other additional serum proteins not detected in the study could be playing a role and should be kept in mind for future studies.

Excitingly, there is more good news for future studies, because scientists also recently sequenced and published the highest resolution brown bear genome to date. This has added to several already existing genome assemblies for the brown bear and has improved gene identification accuracy. With these recent advances, persistence, and continued collaborative work among scientists, we may one day be able to unlock the secrets within the brown bear genome and find cures for several human diseases.