Type 1 diabetes results from immune-mediated destruction of pancreatic beta cells. Although immune dysregulation plays a vital role in type 1 diabetes pathogenesis, emerging data suggest that beta cells are not passive bystanders but play an active role in their own demise. For example, beta cells synthesize and secrete large amounts of insulin in response to glucose, hence they are highly prone to overloading of the secretory pathway and are very sensitive to perturbations in endoplasmic reticulum (ER) homeostasis. Aberrant unfolded protein response (UPR) and beta-cell ER stress has been linked to type 1 diabetes. However, the molecular mechanisms by which the UPR regulates pancreatic beta-cell death/survival in type 1 diabetes remains largely unknown, due primarily to a lack of in vivo preclinical genetic models. Here, we discuss the first genetic model of the UPR in type 1 diabetes, which targets IRE1α in the beta cells of NOD mice. Deletion of IRE1α in beta cells of NOD mice prior to islet immune cell infiltration triggers transient beta-cell dedifferentiation. Interestingly, these beta cells redifferentiate within about two weeks, recover from stress, and, remarkably, restore their identity and function and are protected from autoimmune destruction. These findings suggest that induction of transient beta-cell dedifferentiation early in disease progression may represent a novel therapeutic approach for type 1 diabetes.
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