Signaling the End of a Long-Held Assumption About Diabetes with Dr. Raghu Mirmira

Nearly one hundred years ago, the lives of people with type I diabetes were forever changed, for the better: insulin was discovered. Since then, people with type I diabetes have been treated with insulin, and the disease itself has been regarded as a manifestation of an autoimmune response. But is the immune system the only thing that triggers type I diabetes, or is there something else which signals the immune response? Press play to learn:

• Why it might be that some people develop type I diabetes during the first few months of their life, and others don't develop it until they are in their teens, or even several decades later
• How the pancreas is actually two organs in one, and why this complicates our ability to study it, and to cure diabetes
• Which diseases commonly co-occur in people who have type I diabetes (and how this relates to the standard testing protocol for any child who is diagnosed with type I diabetes)

Dr. Raghu Mirmira is Professor of Medicine in the Section of Endocrinology, Diabetes & Metabolism at the University of Chicago, where his research revolves primarily around the signals that cause the immune response which leads to type I diabetes. Contrary to the predominant belief for over 90 years, Dr. Mirmira and his colleagues are learning that pancreatic beta cells send a signal which activates the immune system to respond in a way that ultimately causes the manifestation of type I diabetes. This understanding shifts the focus from being solely on the immune system, to being in large part on these beta cells.

According to Dr. Mirmira, preventing this disease is about figuring out how beta cells turn on these signals, and how to prevent them from doing so. A complicating factor in this type of research is the inability to harvest human beta cells. Instead, two methods of studying the cell are being utilized: one that harvests these cells from mice and fish, and one that involves induced human pluripotent stem cell-derived beta cells.

From research with mice and fish beta cells, Dr. Mirmira and his team have learned that there is a stress cascade in the beta cell. Essentially, this cascade is triggered when something in the environment sends a negative signal to the beta cell, causing the beta cell to produce emergency proteins in the cell. So many proteins are produced that they become disorganized and misfolded, and have nowhere to go; as a result, some leave the beta cell and end up on its surface, exposed to the body's immune system. Recognizing these misfolded proteins as foreign, the immune system attacks them, killing the beta cells to which they are attached. When enough beta cells have been destroyed, the symptoms of type I diabetes manifest.

Dr. Mirmira discusses the ins and outs of all this and more, including the pathophysiology of diabetes type I in general, the role and function of islet cells in diabetes, an ongoing national birth cohort study on type I diabetes, how the microbiome may (or may not) be connected to type I diabetes, what it means to say there are endotypes of people who have diabetes, antigen spreading, misfolded insulin and what this triggers in the body, and where Dr. Mirmira hopes his research will lead.

For access to Dr. Mirmira's original research, search his name on PubMed or Google Scholar. Stay up to date on the latest by visiting https://voices.uchicago.edu/mirmiralab/. Available on Apple Podcasts: apple.co/2Os0myK