In a classic chicken-and-egg scenario, researchers have long known that something causes the pancreatic beta cells of people with type 1 diabetes (T1D) to die, but they don’t know what causes it or when in the disease the beta cells began to fail. Are healthy beta cells being targeted by a misguided autoimmune reaction, resulting in beta cell death, or are the beta cells being targeted by the immune system because there is something going wrong in the beta cell that triggers the autoimmune reaction? While much of the focus to date has been on the first option, a new study by JDRF-funded scientists suggests that the second alternative may also be occurring and the beta cell may be as much a victim as a perpetrator in its own demise in T1D.
The study now provides evidence that the beta cells start to experience stress reactions early in the disease process that may then provoke an autoimmune response.
The research, led by Sarah Tersley, Ph.D., and Raghavendra Mirmira, M.D., Ph.D., at the Indiana University School of Medicine, was published in the April 2012 issue of Diabetes and is the first to show that beta cells in a mouse model of T1D are not functioning normally during the early stages of disease before symptoms emerge, providing new insight into how T1D starts and suggesting a potential target for treatment. “We don’t know a lot about what happens at the early stage of the disease, or what initiates progression,” says Andrew Rakeman, Ph.D., senior scientist in cure therapies and regeneration at JDRF. “But this study shows that stress in the beta cells is happening at the earliest stages, so targeting that stress early might allow us to prevent or slow down disease.”
Inside every human cell is a small, multilayered structure called the endoplasmic reticulum (ER), which functions as a protein-producing factory. In pancreatic beta cells, which are specialized to produce and secrete the protein-based insulin hormone, the ER is especially active and can undergo a stress response if overworked. Drs. Tersley and Mirmira found that when beta cells are unable to alleviate ER stress, they appear to initiate a suicidal signaling cascade, and it may be the altered or dying beta cells that trigger the autoimmune reaction that is characteristic of T1D. If researchers could find a way to alleviate ER stress, or a way to help beta cells cope with that stress, it might be possible to prevent loss of beta cells.
“It really starts to shift the way we think about the role of beta cells in the progression of type 1 diabetes,” says Dr. Rakeman. “The more we understand about how the disease is working and what events trigger it, the more we can understand about ways to stop progression, and treat the disease at an earlier stage.”
With insight gained from this research, future studies can look more closely at how to rescue beta cells and prevent the disease.