β Cell Hypoxia-Inducible Factor-1α Is Required for the Prevention of Type 1 Diabetes

The development of autoimmune disease type 1 diabetes (T1D) is determined by both genetic background and environmental factors. Environmental triggers include RNA viruses, particularly coxsackievirus (CV), but how they induce T1D is not understood. Here, we demonstrate that deletion of the transcription factor hypoxia-inducible factor-1 alpha (HIF-1 alpha) from beta cells increases the susceptibility of non-obese diabetic (NOD) mice to environmentally triggered T1D from coxsackieviruses and the beta cell toxin streptozotocin. Similarly, knockdown of HIF-1 alpha in human islets leads to a poorer response to coxsackievirus infection. Studies in coxsackievirus-infected islets demonstrate that lack of HIF-1 alpha leads to impaired viral clearance, increased viral load, inflammation, pancreatitis, and loss of beta cell mass. These findings show an important role for beta cells and, specifically, lack of beta cell HIF-1 alpha in the development of T1D. These data suggest new strategies for the prevention of T1D.