New Study Swaps Alpha Cells for Beta Cells to Treat Diabetes

A new study indicates that blocking cell receptors for glucagon, the counter-hormone to insulin, can effectively treat type 1 diabetes (T1D) and type 2 diabetes (T2D) by converting glucagon-producing cells into insulin producers instead, according to findings published online in PNAS.

The body’s tissues develop insulin resistance, prompting beta cells to die of exhaustion from secreting excess insulin to allow cells to take in glucose in T2D, whereas beta cells dying from an autoimmune attack occur in T1D. Both diabetes types lead to severely elevated blood sugar levels that eventually cause a host of possible complications, including loss of limbs and eyesight, kidney damage, diabetic coma, and death, according to the study.

Most treatments for diabetes focus on insulin, but hormone glucagon that is produced by alpha cells in the pancreas has not received as much attention as other options. Glucagon binds to receptors on cells in the liver, prompting this organ to secrete glucose. Further, some recent studies have suggested that depleting glucagon or blocking its receptor can help patients with diabetes better manage their glucose levels.

May-Yun Wang, PhD, and her colleagues William L. Holland, PhD, a former assistant professor of internal medicine at UTSW who is now at the University of Utah, and Philipp E. Scherer, PhD, professor of internal medicine and cell biology at UTSW and director of UTSW’s Touchstone Center for Diabetes Research, used monoclonal antibodies—manmade proteins that act like human antibodies and help the immune system identify and neutralize whatever they bind to—against the glucagon receptor in mouse models of diabetes.

The PANIC-ATTAC (pancreatic islet beta-cell apoptosis through targeted activation of caspase 8) model analyzed a genetic mutation that causes beta cells to selectively die off when these mice receive a chemical treatment. Once these animals’ beta cells were depleted, the researchers administered monoclonal antibodies against the glucagon receptor. Weekly treatment with the antibodies substantially lowered the rodents’ blood sugar, an effect that continued even weeks after the treatments stopped, according to the study authors.

Further investigation showed that the number of cells in the pancreas of these animals significantly increased, including beta cells. The research team used a technique called lineage tracing to label their alpha cells. When they followed these alpha cells through rounds of cell divisions, they found that treatment with monoclonal antibodies pushed some of the glucagon-producing alpha cell population to convert into insulin-producing beta cells.

To see whether beta cells could rebound through alpha cell conversion under these circumstances, the research team worked with a different mouse model called nonobese diabetic (NOD) mice, in which their beta cells become depleted through an autoimmune reaction. When these animals were dosed with monoclonal antibodies, the beta cells returned despite active immune cells, according to the study authors.

In a third animal model, the researchers injected human alpha and beta cells into immunodeficient NOD mice, which were enough cells to produce sufficient insulin to make the animals borderline diabetic. When the mice received monoclonal antibodies against the glucagon receptor, their human beta cells increased in number and protected them against diabetes, suggesting this treatment could do the same for humans, according to the study.

Holland notes that being able to push alpha cells to shift to beta cells could be especially promising for type 1 diabetics. “Even after decades of an autoimmune attack on their beta cells, type 1 diabetics will still have plentiful amounts of alpha cells. They aren’t the cells in the pancreas that die,” Holland said in a press release. “If we can harness those alpha cells and convert them into beta cells, it could be a viable treatment for anyone with type 1 diabetes.”

Being able to produce native insulin could hold significant advantages over the insulin injections and pumps used by both T1D and T2D diabetics. Wang hopes that similar monoclonal antibodies will eventually be tested in diabetics in clinical trials.

“Even though type 1 and type 2 diabetics try their very best to keep glucose under control, it fluctuates quite massively throughout the day even with the best state-of-the-art pump,” Wang said in a press release. “Giving them back their own beta cells could help restore much better natural regulation, greatly improving glucose regulation and quality of life.”

REFERENCE

Swapping alpha cells for beta cells to treat diabetes. UT Southwestern Medical Center. https://www.utsouthwestern.edu/newsroom/articles/year-2021/beta-cells-diabetes.html. Published March 1, 2021. Accessed March 3, 2021.