Growing evidence that immune system may not be source of type 1 diabetes 31 August 2022 It has long been accepted that type 1 diabetes results from the loss of immune tolerance to beta cell proteins and that susceptibility to the condition is largely due to the immune system getting out of control. Researchers at the University of Chicago have now identified a potentially critical gene tied to the progression of type 1 diabetes. The removal of this gene curbs stress signalling by the beta cells to the immune system. The study suggests that instead of the immune system being the cause of type 1 diabetes, beta cells themselves may be triggering the process. Other studies have also found that inflammatory signalling within beta cells could be a modifier of the immune response in type 1 diabetes. The University of Chicago study started on the premise that inflammatory signalling within beta cells promotes progression of autoimmunity within the islet microenvironment. To test this hypothesis, researchers identified and then deleted the proinflammatory gene encoding 12/15-lipoxygenase (Alox15) in beta cells of non-obese diabetic mice at a pre-diabetic time point when islet inflammation became evident. (Alox15 is predisposed in people with type 1 diabetes, and 12/15-Lipoxygenase is associated with inflammation in beta cells). To delete the gene, researchers treated the mice with beta cell inflammation with Nolvadex, an oestrogen receptor modulator approved to treat breast cancer. Nolvadex reduced Alox15 expression by roughly 80 per cent. Researchers subsequently identified reduced inflammation in the pockets of beta cells called islets. “When we got rid of this gene, the beta cells no longer signalled to the immune system and the immune onslaught was completely suppressed, even though we didn’t touch the immune system,” said senior author of the study, Professor Raghavendra Mirmira, a professor of medicine at the University of Chicago and director of the university’s Diabetes Translational Research Center. “That tells us that there is a complex dialogue between beta cells and immune cells, and if you intervene in that dialogue, you can prevent diabetes.” Specifically, eliminating the gene helped preserve beta cells, which produce insulin in the pancreas, and reduced the amount of infiltrating cytotoxic T cells (killer cells). That process ultimately prevented type 1 diabetes from developing. The findings are a critical piece of additional evidence to what’s been an ongoing re-evaluation of how type 1 diabetes begins.