By Randolph Fillmore
Diabetes is classified into two types – Type 1 or Type 2. Previously called “juvenile diabetes,” Type 1 diabetes (T1D) is usually diagnosed in children, teens and young adults, but it can develop at any age. T1D is caused by an autoimmune reaction — a case of the body attacking itself and during T1D, the autoimmune reaction destroys specific cells in the pancreas, called beta cells, that make insulin.
Over time, diabetes can cause serious health problems, such as heart or kidney disease or vision loss. People with diabetes need to take insulin to counter the effects of high blood sugar. In 2021, Johns Hopkins All Children’s Hospital treated 1,122 patients with Type 1 diabetes.
While there is no cure for T1D, and its causes are not well understood, researchers at Johns Hopkins All Children’s in St. Petersburg, Florida, have made great strides in gaining a better understanding of the condition. Their findings were recently published online for an upcoming issue of JCI Insight.
Their study, entitled “Evidence of islet CADM1-mediated immune cell interactions during human type 1 diabetes,” investigated molecular “targets” that may be useful in understanding and ultimately preventing T1D.
CADM1 is “On the Radar”
Islet cells — pancreatic cells that produce insulin and other hormones — are normally secreted into the bloodstream to help control blood sugar levels. But a destructive immune response can destroy these cells. With the goal of understanding the autoimmune response that causes islet cell destruction, and with hopes of preventing T1D, Johns Hopkins All Children’s researchers investigated CADM1 — an “adhesion molecule” expressed in pancreatic endocrine cells.
“CADM1 is known to be expressed in pancreatic alpha and beta cells,” explains study co-author Matthew Poy, Ph.D., associate professor, Johns Hopkins University School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism. “As a membrane protein involved in intercellular contact we sought to address whether CADM1 mediated interactions between immune cells and the endocrine cells of the pancreas. By establishing that CADM1 is highly expressed in macrophage cells and dendritic cells in proximity to alpha and beta cells during T1D, this may suggest that CADM1 plays a role in ‘recruiting’ immune cells that ultimately lead to destruction of beta-cells.”
“It was critical to emphasize identifying islet proteins involved in immune cell infiltration that could be targeted to preserve pancreatic beta-cell function to possibly develop strategies that prevent the immune response that initiates T1D,” says Poy, a researcher in the Institute for Fundamental Biomedical Research at Johns Hopkins All Children’s.
The researchers also found that the destructive immune system cells, known as CD8 T+ cells are adjacent to CADM1-expressing islet cells, and suggests CADM1 mediates a network of interactions leading to the infiltration of “cytotoxic” white blood cells.
“The destructive role of immune cellsis central to understanding T1D,” explains Poy. “Finding out why and how these CD8+ T-cells are called up, and why they attack healthy cells, is the ‘holy grail’ for understanding how to prevent T1D.”
“We did show in our study that the numbers of CADM+ macrophages are increased in T1D along with increase in the number of interactions between CADM1 and the CD8+ T cells in the pancreas,” Poy says.
CD8+ cells are believed to mediate destruction of beta cells in the pancreas, causing T1D. But, Poy explains, CD8+ cells do not occupy the pancreas — they have to be “recruited,” and CADM1 may play a role in recruiting these cells. That knowledge may make CADM1 a strategic target for preventing or curing T1D if the interaction between CADM1 and CD8+ cells can be stopped.
“Further investigation will be needed to find out if these CADM1-mediated interactions in the pancreas come before the infiltration of the islet cells and ultimately the destruction beta cells,” wrote the researchers. “The precise function of CADM1 during the development of type 1 diabetes has not been studied before, and its identification in our study as a mediator of immune cell interaction is new and important.”
While the team concludes that their observations support the idea that CADM1 in immune-islet cell contact contributes to the autoimmune destruction of the pancreas, there may be several ways to use this knowledge to prevent T1D. Several pharmacological approaches may be developed by designing inhibitors or other blocking mechanisms to go between the CADM1 “antenna” and cell receptors to keep immune cells out of the pancreas; however these methods take several years to develop and are ongoing.