Swapping alpha cells for beta cells to deal with diabetes


IMAGE: On the left is a healthy island with many insulin-producing cells (green) and a few glucagon-producing cells (red). On the right this situation changes on a diabetic islet with a strong overweight … view More

Photo credit: UT Southwestern Medical Center

Blocking cell receptors for glucagon, the counterhormone to insulin, cured mouse models of diabetes by converting glucagon-producing cells into insulin producers instead, a team led by UT Southwestern reports in a new study. The results, published online in PNAS, could offer a new way to treat both type 1 and type 2 diabetes in people.

More than 34 million Americans have diabetes, a disease characterized by the loss of beta cells in the pancreas. Beta cells produce insulin, a hormone that cells need to take up and use glucose, a type of sugar that circulates in the blood and serves as cell fuel.

In type 2 diabetes, the tissues of the body develop insulin resistance, which causes beta cells to die of exhaustion when they secrete excess insulin so the cells can absorb glucose. In type 1 diabetes, which affects around 10 percent of diabetics, beta cells die from an autoimmune attack. Both types of diabetes lead to severely elevated blood sugar levels that eventually lead to a number of possible complications, including loss of limbs and vision, kidney damage, diabetic coma, and death.

Most treatments for diabetes focus on insulin, but its counterpart – the hormone glucagon, which is produced by alpha cells in the pancreas – has received comparatively little attention, says study leader May-Yun Wang, Ph.D., assistant professor of internals Medicine at UTSW. Glucagon binds to receptors on cells in the liver, causing this organ to secrete glucose. Some recent studies have shown that depleting the glucagon or blocking its receptor can help animals or people with diabetes better control their glucose levels. However, how this phenomenon occurs is unknown.

To answer that question, Wang and her colleagues, including William L. Holland, Ph.D., a former assistant professor of internal medicine at UTSW who is now at the University of Utah, and Philipp E. Scherer, Ph. D. The professor of internal medicine and cell biology at UTSW and director of the UTSW’s Touchstone Center for Diabetes Research used monoclonal antibodies – artificial proteins that act like human antibodies and help the immune system identify and neutralize anything they bind to – against the Glucagon receptor in mouse models of diabetes.

In a model called PANIC-ATTAC (beta cell apoptosis of the pancreatic islets through targeted activation of caspase 8), a genetic mutation causes beta cells to selectively die when these mice receive chemical treatment. As soon as the beta cells in these animals were depleted, the researchers administered monoclonal antibodies against the glucagon receptor. The weekly treatment with the antibodies lowered the rodents’ blood sugar significantly, which continued weeks after the end of the treatments.

Further research showed that the number of cells in the pancreas in these animals, including beta cells, increased significantly. In search of the source of this effect, the researchers used a technique called lineage tracing to mark their alpha cells. As they followed these alpha cells through rounds of cell division, they found that treatment with monoclonal antibodies pushed a portion of the glucagon-producing alpha-cell population to convert to insulin-producing beta cells.

Although the PANIC-ATTAC model exhibits the same beta cell loss that occurs in both type 1 and type 2 diabetes, it lacks the autoimmune attack that causes type 1 diabetes. To see if beta cells can rebound through alpha cell conversion under these circumstances, the researchers worked with another mouse model called NOD mice (Nonobese Diabetic), in which their beta cells are depleted through an autoimmune reaction. When these animals were given monoclonal antibodies, beta cells returned despite active immune cells.

In a third animal model that more closely mimics a human system, the researchers injected human alpha and beta cells into immunodeficient NOD mice – just enough cells to produce enough insulin to push the animals to the limit of diabetes. When these mice were given monoclonal antibodies to the glucagon receptor, their human beta cells increased in number, protecting them from diabetes, suggesting that this treatment could do the same for humans.

Holland notes that getting alpha cells to switch to beta cells could be particularly promising for type 1 diabetics. “Even after decades of autoimmune attack on their beta cells, type 1 diabetics will still have plenty of alpha cells. They aren’t the cells in the pancreas that die,” he says. “If we can take these alpha cells and convert them to beta cells, it could be a viable treatment for anyone with type 1 diabetes.”

Native insulin production, Wang adds, could have significant advantages over the insulin injections and pumps used by both type 1 and type 2 diabetics. Finally, similar monoclonal antibodies could be tested in clinical trials in diabetics.

“While type 1 and type 2 diabetics do their best to keep glucose under control, it fluctuates quite a lot throughout the day, even with the best state-of-the-art pump,” says Wang. “If they give back their own beta cells, it can help restore natural regulation and greatly improve glucose regulation and quality of life.”

Scherer holds the Gifford O. Touchstone Jr. and Randolph G. Touchstone Distinguished Chairs in Diabetes Research and the Touchstone / West Distinguished Chair in Diabetes Research.


Other UTSW researchers who contributed to this study include Ezekiel Quittner-Strom, Zhuzhen Zhang, Shangang Zhao, Na Li, Risheng Ye, Young Lee, Yiyi Zhang, Shiuhwei Chen, Xinxin Yu, Derek C. Leonard, and Roger H. Unger. Unger, a pioneer in diabetes research and founding director of the Touchstone Diabetes Center at UT Southwestern, died in August 2020.

This research was supported by grants from the Juvenile Diabetes Research Foundation (SRA-2016-149-QR), the National Institutes of Health (R01DK112866, K01DK117969, DK106755, DK20593, DK117147), the National Institute of Diabetes and Digestive and Kidney Diseases the Human Islet Research Network (RRID: SCR_014393; https://hirnetwork.org; UC4 DK104211 and DK112232) and the Department of Veterans Affairs (BX000666). The research team collaborated with several researchers from Eli Lilly and Company on the study.

Via UT Southwestern Medical Center

UT Southwestern, one of the leading academic medical centers in the country, combines pioneering biomedical research with exceptional clinical care and training. The institution’s faculty has won six Nobel Prizes and includes 23 members from the National Academy of Sciences, 17 members from the National Academy of Medicine, and 13 investigators from the Howard Hughes Medical Institute. The full-time faculty, with more than 2,500 employees, is responsible for breakthrough medical advances and is committed to translating science-based research into new clinical treatments quickly. UT Southwestern doctors care for more than 105,000 hospital patients, nearly 370,000 emergencies, in approximately 80 specialties, and monitor approximately 3 million outpatient visits annually.