The ability of hibernating bears to regulate insulin was limited to eight proteins

Feeding honey to hibernating bears helped researchers at Washington State University find the potential genetic keys to bears’ insulin control, an advance that could ultimately lead to a treatment for diabetes in humans.

Each year, bears gain enormous weight and then hardly move for months, behavior that would lead to diabetes in humans, but not for bears, whose bodies can turn insulin resistance on and off almost like a switch. In their search for the bears’ secret, WSU scientists observed thousands of changes in gene expression during hibernation, but now a research team has narrowed them down to eight proteins.

“There appear to be eight proteins that work either independently or in concert to modulate the insulin sensitivity and resistance observed in hibernating bears,” said Joanna Kelley, a WSU evolutionary geneticist and corresponding author of the published in study iscience. “All of these eight proteins have human homologues. They are not unique to bears. The same genes are present in humans, so maybe there is a direct way to translate.”

The research team analyzed changes in bear cell cultures exposed to blood serum collected from grizzly bears housed at the WSU Bear Center. Both the cells and blood serum were collected from the bears during the active season and hibernation, as well as from an interrupted hibernation phase when the researchers fed the bears honey water.

In the lab, the researchers combined different cell cultures and sera, such as a cell culture from a hibernating season with serum from the active season, to analyze the genetic changes that occurred.

For all combinations, it was the serum from the mid-winter feeding period that helped most in identifying the key proteins.

“By feeding the bears for just two weeks during hibernation, we were able to control other things like day length and temperature, as well as food availability,” Kelley said.

Bears usually get up and move around a bit during hibernation, but they don’t typically eat, urinate, or defecate. The researchers used those waking moments to offer the bears honey water, one of their favorite treats, as part of another study that found the extra sugar disrupted their hibernation behavior. Kelley and her colleagues then used the samples from that study period to conduct their genetic analysis.

When the researchers applied the interrupted hibernation serum to a cell culture of regularly hibernating bears, they found that these cells began to exhibit changes in gene activity that resembled those of active-season cells.

Next, the team plans to study how these proteins work specifically to reverse insulin resistance, research that could ultimately lead to the development of ways to prevent or treat diabetes in humans.

“This is a step towards better understanding what happens at the genetic level and identifying specific molecules that control insulin resistance in bears,” said Blair Perry, co-first author of the study and a postdoctoral researcher at WSU.

The tools for understanding genetics are becoming more sophisticated, and recently Kelley, Perry and their colleagues published an updated genome layout for brown bears, of which grizzly bears are a subspecies. This more complete, contiguous genome could help provide even better insights into bear genetics, including how they manage hibernation.

“There is inherent value in studying the diversity of life around us and all these unique and strange adaptations that have arisen,” said Perry, who has also studied the genetic make-up of snake venom. “By understanding the genomic basis of these adaptations, we gain a better understanding of what we share with other species and what makes us unique as humans.”

Other researchers on this study include co-first author Michael Saxton along with co-authors Brandon Evans Hutzenbiler, Shawn Trojahn, Alexia Gee, Anthony Brown, Omar Cornejo, Charles Robbins, and Heiko Jansen of WSU, and Michael MacCoss, Gennifer Merrihew, and Jea University of Washington Park.