Blocking cell receptors for glucagon, the anti-hormone to insulin, models of diabetes treated mice by converting glucagon-producing cells to insulin agents instead, a team is led with UT Southwestern reporting in new study. The findings, published online in PNAS, they could offer a new way to treat both Type 1 and Type 2 diabetes in humans.
More than 34 million Americans have diabetes, a disease characterized by the loss of beta cells in the pancreas. Beta cells make insulin, a hormone that is essential for cells to absorb and use glucose, a type of sugar that circulates in the blood and serves as cell fuel.
In Type 2 diabetes, the body’s turf develops insulin resistance, causing beta cells to die from emptying too much insulin to allow cells to absorb glucose . In Type 1 diabetes, which affects about 10 percent of the diabetic population, beta cells die from autoimmune attack. Both types of diabetes lead to highly elevated blood sugar levels which can lead to a number of potential complications, including organ and vision loss, kidney damage, diabetic coma, and death.
Most treatments for diabetes focus on insulin, but its comparison – the hormone glucagon secreted by alpha cells in the pancreas – has very little effect. get attention, says study director May-Yun Wang, Ph.D., assistant professor of internal medicine at UTSW. Glucagon binds to receptors on cells in the liver, stimulating this organ to replenish glucose. Some recent studies have suggested that lowering glucagon or blocking its receptor may help test animals or people with diabetes to regulate their glucose levels. better. But it is not known how this phenomenon occurs.
To answer this question, Wang and her colleagues, including William L. Holland, Ph.D., a former associate professor of internal medicine at UTSW who is now at the University of Utah, , and Philipp E. Scherer, Ph.D., professor of internal medicine and cell biology at UTSW and director of the UTSW Touchstone Center for Diabetes Research, used monoclonal antibodies – human proteins that acts as human antibodies and helps the immune system to identify and neutralize anything they bind to – against the glucagon receptor in mouse models. diabetes.
In one model, called PANIC-ATTAC (pancreatic islet beta-cell apoptosis through targeted activation of caspase 8), genetic mutation causes beta cells to selectively die when these mice receive chemical treatment. Once the beta cells of these animals were depleted, the researchers administered monoclonal antibodies against the glucagon receptor. Weekly treatment with the antibodies significantly reduced the blood sugar of the rodents, an effect that continued even weeks after the treatments were stopped.
Further studies showed that the number of cells in the pancreas of these animals increased significantly, including beta cells. Finding the source of this effect, the researchers used a method called line tracking to record their alpha cells. When they followed these alpha cells through cycles of cell divisions, they found that treatment with monoclonal antibodies pushed some of the alpha population of glucagon – producing cells into insulin – producing beta cells.
Although the PANIC-ATTAC model shares the same beta cell loss that occurs in both Type 1 and Type 2 diabetes, it lacks the disease-inducing autoimmune attack. Type 1 diabetes. To see if beta cells could be converted through alpha cell conversion under these conditions, the researchers worked with a different mouse model called nonobese diabetic mice (NOD) in which their beta cells grow through autoimmune reaction. When these animals were administered monoclonal antibodies, beta cells returned, despite active immune cells.
In a third animal model that resembles a more dense human system, the researchers injected human alpha and beta cells into immune NOD mice – just enough cells to make enough insulin to make the animals near diabetic. When these mice received monoclonal antibodies against the glucagon receptor, their human beta cells increased in number, protecting them against diabetes, suggesting that this treatment could do the same for humans.
Holland notes that pushing alpha cells to move to beta cells could be particularly promising for Type 1 diabetics. alpha cells are still in Type 1 diabetics. It is not the cells in the pancreas that are dying, ”he says. “If we can take advantage of these alpha cells and convert them to beta cells, that could be a viable treatment for anyone with Type 1 diabetes.”
Being able to produce native insulin, Wang adds, could have major benefits over the insulin injections and pumps used by both Type 1 and Type 2 diabetics. Finally, she says, similar monoclonal antibodies could be tested in diabetics in clinical trials.
Even though Type 1 and Type 2 diabetics try their best to control glucose, it fluctuates dramatically throughout the day even with the best pump available. Restoring their own beta cells could restore much better natural regulation, greatly improving glucose regulation and quality of life. “
May-Yun Wang, Ph.D., Associate Professor of Internal Medicine, UTSW
Source:
UT Southwestern Medical Center
Magazine Reference:
Wang, MY., et al. (2021) Glucagon inhibition restores active β-cell mass in type 1 diabetic mice and enhances human islet function. PNAS. doi.org/10.1073/pnas.2022142118.