Deleting Old Cells

Aging beta cells' link to diabetes may point to new therapeutics  

Human beta cells and insulin granules

Human beta cells and insulin granules. Image: iStock/wikimaji

New research from Harvard Medical School researchers at Joslin Diabetes Center has shown that insulin resistance in mice increases the proportion of dysfunctional aged beta cells. Such an increase in aged beta cells could lead to type 2 diabetes.

The researchers then confirmed a similarly increased proportion of aged beta cells in islets recovered from humans with type 2 diabetes.

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The study also showed that beta cell function can be recovered by removing these aged populations, either via genetic modification or oral medication.

“Our hypothesis was that there was an important component in the development of diabetes, which consisted of accelerated aging of beta cells and that this population could be targeted therapeutically,” said Cristina Aguayo-Mazzucato, an HMS instructor in medicine at HMS and assistant investigator in the section on islet cell and regenerative biology at Joslin. She is also the first author on the paper, published in Cell Metabolism.

The research falls into a broader field of the study of senescence, the slow decline of proliferation and function of a specific cell population. These cells accumulate as organisms grow older, but certain circumstances can cause some cells in an organism to age faster than the whole.

The research team, led by Aguayo-Mazzucato, generated animal models of insulin resistance and tracked the proportion of senescent beta cells.

“What we found is that indeed, insulin resistance was increasing the amount of senescent or old beta cells,” she said.

Next, they deleted the aged cells through either genetic manipulation or medications known to remove senescent cells.

“We were able to recover beta cell function, we were able to restore glucose tolerance,” said Aguayo-Mazzucato.

Restoring function

The ability to restore beta cell function with minimal intervention could be a game-changer in the treatment of type 2 diabetes. For many people with the disease, beta cell function declines to the point where they need injectable insulin. Should the results of this research be borne out in clinical trials, the implications for treatment could be significant.

“When you look at the absolute percentage or quantity of the senescent beta cells, they rarely exceed 20 percent of the whole beta cell population, and yet targeting this relatively minor population had a huge effect on function and glucose metabolism and cellular identity,” Aguayo-Mazzucato said.

Senolytics, medications to delete senescent cells, are still under investigation. This research team hopes to bring a potential treatment closer to the clinic by partnering with companies already working on senolytics and testing their medications in people with diabetes.

“This opens a new target to treat diabetes, which is basically to target populations of old or senescent cells that are really contributing to the local dysfunction,” she said.

Senolysis, or the removal of aged or dysfunctional cells, is a growing field in the treatment of age-related diseases. This new research fits into the larger picture of how senolytics could help combat many different diseases of aging, leading to better quality of life.

While the work was completed in models of type 2 diabetes, the findings could also be relevant in type 1 diabetes.

“What we're seeing is that senescence is, in reality, a response to stress. In the case of type 2 diabetes, this stress is insulin resistance. In the case of type 1 diabetes, it is the immune attack on beta cells,” she said. “But in both models, beta cells are responding to these stresses by becoming senescent. So, we think that the potential of this new vision of preventing diabetes will be valid for both type 1 and type 2.”

This study was supported by grants from the National Institutes of Health, the Diabetes Research and Wellness Foundation and a group of private donors.

Adapted from a Joslin news release.