The immune system mistakenly identifying insulin-secreting beta cells as a potential danger and, in turn, destroying them has long been considered the root cause of type 1 diabetes. Now, an international team of researchers led by City of Hope’s Bart Roep, Ph.D., the Chan Soon-Shiong Shapiro Distinguished Chair in Diabetes and professor/founding chair of the Department of Diabetes Immunology, has been able to justify a new theory about the cause of type 1 diabetes through experimental work. The study results were published online yesterday in the journal Nature Medicine.
Type 1 diabetes affects an estimated 1.5 million Americans and is the result of the loss of insulin-producing beta cells in the pancreas.
Now Roep, along with researchers from the Leiden University Medical Center in the Netherlands, have found a mechanism in which stressed beta cells are actually causing the immune response that leads to type 1 diabetes.
“Our findings show that type 1 diabetes results from a mistake of the beta cell, not a mistake of the immune system,” said Roep, who is director of The Wanek Family Project for Type 1 Diabetes, which was recently created with gifts from the Wanek family and anonymous donors to support the institution’s goal of curing type 1 diabetes in six years. “The immune system does what it is supposed to do, which is respond to distressed or ‘unhappy’ tissue, as it would in infection or cancer.”
In order to gain a better understanding of why the immune system attacks the body’s own source of insulin — the pancreatic beta cells in the islets of Langerhans — the team took some clues from cancer molecules that are targeted by the immune system after successful treatment of the cancer with immunotherapy.
One of these cancer targets is a so-called nonsense protein, resulting from a misreading of a DNA sequence that makes a nonfunctional protein. It turns out that the same type of protein error is also produced by the beta cells in type 1 diabetes. Therefore, Roep and the other researchers believe it is a ‘wrong read’ of the insulin gene itself that proves to be a major target of the immune system. This error product of the insulin gene is made when beta cells are stressed, Roep said.
“Our study links anti-tumor immunity to islet autoimmunity, and may explain why some cancer patients develop type 1 diabetes after successful immunotherapy,” he added. “This is an incredible step forward in our commitment to cure this disease.”
According to the paper titled, “Autoimmunity against a defective ribosomal insulin gene product in type 1 diabetes,” the findings “further support the emerging concept that beta cells are destroyed in type 1 diabetes by a mechanism comparable to classical antitumor responses where the immune system has been trained to survey dysfunctional cells in which errors have accumulated.”
The results of the study give Roep new insight, he said, for his work in developing new vaccines to desensitize the immune system so that it will tolerate islets again, as well as for research into combining immunotherapy with more traditional diabetes treatments to reinvigorate islets.
“Our goal is to keep beta cells happy,” Roep said. “So we will work on new forms of therapy to correct the autoimmune response against islets and hopefully also prevent development of type 1 diabetes during anti-cancer therapy.”
Roep’s program at City of Hope plans to change the entire way we view a “cure,” shifting from a one-size-fits-all method of research and goals to a system of precision medicine; a way to offer individualized and personalized therapies for people with diabetes much in the same way cancer treatment does today.
The program will draw heavily from a biorepository, something Dr. Roep says will save millions of dollars and many years in helping them embrace the concept of diabetes being unique in almost every individual. Armed with that knowledge they will dig back into human clinical studies that may not have succeeded on a mass scale and look to see if they can help patients on a smaller scale.
For instance, if a study failed for 70 percent of the participants, it may have held answers for other 30 percent.
The focus at City of Hope will be threefold: to stop the progression of the disease (something Roep calls the “low hanging fruit” of the effort), get people off injections for good (something he admits is “much more of a challenge but not impossible,”), and preventing, stopping, and reversing complications.
The work described in the Nature Medicine paper was supported by the Dutch Diabetes Research Foundation, the DON Foundation and JDRF.
Source: City of Hope press release.