Might reworking alpha cells into beta cells deal with diabetes?


Share on PinterestNew research in mice suggests a new way to treat both forms of diabetes. 1130945222 Tom Werner / Getty Images

  • Scientists have used synthetic antibodies to block cell receptors in the liver that normally bind to glucagon, a hormone that is involved in increasing the amount of glucose in the blood.
  • The antibodies restored normal blood sugar levels in three different mouse models of diabetes.
  • The treatment worked in part by converting alpha cells in the pancreas into insulin-producing beta cells.
  • The researchers believe that the same approach could treat type 1 and type 2 diabetes in humans.

Diabetes prevents the body from regulating the level of glucose in the blood. In the long run, this can lead to a variety of life-changing complications, including loss of vision, kidney damage, stroke, and heart disease.

It is estimated that around 34.2 million people in the United States have been diagnosed or undiagnosed with diabetes. Type 2 diabetes accounts for 90–95% of these cases.

In healthy individuals, the blood glucose concentration is kept at an optimal level by the opposing effects of two hormones, insulin and glucagon.

Beta cells in the pancreas produce insulin, which stimulates cells in the body to extract glucose from the bloodstream.

Other cells in the pancreas called alpha cells make glucagon, which increases the amount of glucose the liver releases into the bloodstream.

In type 1 diabetes, the immune system targets beta cells and reduces insulin production.

In contrast, in type 2 diabetes, the cells in the body become resistant to the effects of insulin. Beta cells respond by making more and more hormones and eventually die.

Previous research in mice suggested that a synthetic or “monoclonal” antibody that blocks glucagon receptors in the membranes of liver cells could restore normal blood sugar levels. However, it wasn’t entirely clear how this worked.

Now, a team led by researchers at the University of Texas’ Southwestern Medical Center at Dallas has found that blocking glucagon receptors has the indirect effect of converting alpha cells in the pancreas into beta cells.

The newly created beta cells produce insulin, which lowers the levels of glucose that circulate in the blood.

Currently, some people with diabetes use insulin injectors or pumps to regulate their glucose levels, but these treatments are not perfect.

Although people with type 1 or type 2 diabetes “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,” explains study director Dr. May-Yun Wang, assistant professor of internal medicine at the medical center.

“If they give back their own beta cells, it can help restore natural regulation and greatly improve glucose regulation and quality of life,” she continues.

Converting alpha cells to beta cells could be a particularly promising treatment for type 1 diabetes, says Dr. William L. Holland, the lead study author who is now Assistant Professor of Nutrition and Integrative Physiology at the University of Utah at Salt Lake City.

“Even after decades of autoimmune attack on their beta cells, type 1 diabetics will still have plenty of alpha cells. They are not the cells in the pancreas that die, ”he explains.

“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.”

The research was published in the Proceedings of the National Academy of Sciences.

To find out what happens when antibodies block glucagon receptors, the researchers developed experiments on three different mouse models of diabetes.

In the first model, a genetic mutation induced apoptosis or “cell suicide” in beta cells in response to a specific chemical treatment.

As in people with type 1 or type 2 diabetes, the loss of beta cells decreased the animals’ ability to produce insulin and thus regulate their glucose levels.

When the researchers gave the animals weekly injections of the glucagon receptor antibodies, the treatment significantly lowered the animals’ blood sugar levels.

Notably, the improvement lasted weeks after the injections stopped. In mice with these treatments, the antibodies indirectly increased the number of beta cells in the pancreas by almost seven-fold.

To find out where all of the extra beta cells came from, the researchers used a technique called lineage tracing to mark alpha cells in the pancreas and track them through several rounds of division. They discovered that the treatment turned some of the cells into insulin-producing beta cells.

However, the researchers couldn’t be sure whether the treatment would work on beta cells during a sustained attack by the immune system, which is the case with type 1 diabetes.

To mimic this effect, they used a different model with non-obese diabetic mice, in which the animals’ immune systems depleted their beta cells.

When the researchers treated these mice with the monoclonal antibodies, the animals’ beta cell counts recovered despite ongoing immune attacks.

Finally, the researchers tested whether the treatment would work in human pancreatic cells.

They did this by transplanting pancreatic tissue with alpha and beta cells into non-obese diabetic mice, the numbers of which were low enough to ensure that the animals remained slightly diabetic.

When the team treated these mice with antibodies against the glucagon receptor, the human beta cells multiplied and helped restore blood sugar regulation in the animals.

“These studies give hope that injecting a human antibody to the glucagon receptor once a week can improve function [beta cell numbers]”The researchers write in their work.

“Change small residual amounts [beta] Cells can bring about an enormous improvement in the quality of life for millions of patients with type 1 diabetes, ”the researchers hope.

They find that one limitation of their work was that it was difficult to determine exactly whether the number of human beta cells had changed in response to treatment.

However, they conclude: “These studies give hope that injecting a human antibody to the glucagon receptor once a week can improve function [beta cell] Dimensions.”