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“Death Receptor” Identified as Factor in Type 1 Diabetes

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“Death Receptor” Identified as Factor in Type 1 Diabetes

A protein that researchers have called the “death receptor” seems to foster the development of type 1 diabetes, according to a new study published in the journal Nature Communications. The study went on to say that blocking the action of the death receptor has a beneficial effect on insulin production in the pancreas and might point the way to a new and effective way of treating type 1 diabetes.

It’s been known for a long time that the key factor in type 1 diabetes is the destruction of beta cells in the pancreas. Beta cells are the entities that produce insulin, the hormone that regulates the amount of sugar in the blood. Diabetes researchers define type 1 diabetes as an autoimmune disease, which means that, for some reason, the body’s immune system attacks the insulin-producing beta cells. Although several theories have been proposed, the reason this attack happens remains puzzling. Now, the discovery of the death receptor might provide a key to unlocking the secrets of this process.

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The researchers, who were led by Paolo Fiorina, MD, of Boston Children’s Hospital and Francesca D’Addio, MD, of the University of Milan, identified an entity called transmembrane protein 219, or TMEM219 for short, as a crucial actor in beta cell destruction (hence the name “death receptor”). They discovered that a protein called insulin-like growth factor binding protein 3 (IGFPB3) binds to a part of TMEM219, thereby setting off a deadly process in the beta cell. This process is called apoptosis, a fundamental procedure that causes body cells to die. Normally, this is a good thing because it enables to body to get rid of unneeded or abnormal cells, but when healthy beta cells are destroyed it’s just the opposite. According to Dr. Fiorina, “We believe this might be a natural mechanism to keep the beta cell population under control. We think that in disease, IGFPB3 production may be increased, so there is a loss of beta cells.” The researchers found support for their hypothesis when they tested different diabetes patients and found higher levels of IGFPB3 in their blood.

Blocking death receptor preserved beta cells in animal models

To further test their theory, the researchers turned to special lab mice that had been genetically modified to be prone to developing type 1 diabetes. The investigators tried three procedures designed to block the IGFPB3/ TMEM219 pathway — blocking IGFPB3, deleting the TMEM219 gene, and using a recombined protein based on part of TMEM219. They discovered that each technique not only preserved the beta cells, but also raised insulin production and delayed or prevented the onset of diabetes. And the longer they blocked the pathway, the more beta cells were created. The researchers also looked at actual human pancreatic cells, the cells that contain the beta cells. Exposure to IGFPB3 brought a higher rate of beta cell death, while blocking the death receptor allowed the beta cells to continue producing insulin.

“The common thought for Type 1 diabetes is that it is autoimmune,” Fiorina said in a press statement. “But immunotherapy doesn’t completely cure diabetes. We think that dysregulation of beta cell homeostasis also plays a role and that IGFBP3 acts as a ‘betatoxin.’” Accordingly, Dr. Fiorina has created a new biotechnology company based in Milan, Italy, called Enthera. According to the company’s website, it’s “building a pipeline of first-in-class biologics for several underserved autoimmune conditions, with a focus on Type 1 diabetes (T1D) and Inflammatory bowel disease (IBD)…. Our therapeutics are founded on the novel scientific discovery of a pathway, the IGFPB3/ TMEM219 axis, found to be involved in stem cell apoptosis in the gut, as well as pancreatic and other tissues.” The company hopes that the first trials of ways of blocking the IGFPB3/ TMEM219 pathway in human subjects can begin as early as September.

Want to learn more about type 1 diabetes? Read “Type 1 Diabetes Questions and Answers,” “Six Type 1 Diabetes Symptoms You Need to Know” and see our type 1 diabetes videos.

Joseph Gustaitis

Joseph Gustaitis

Joseph Gustaitis on social media

A freelance writer and editor based in the Chicago area, Gustaitis has a degree in journalism from Columbia University. He has decades of experience writing about diabetes and related health conditions and interviewing healthcare experts.

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