beta Cell Hypoxia-Inducible Factor-1alpha 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-1alpha (HIF-1alpha) 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-1alpha in human islets leads to a poorer response to coxsackievirus infection. Studies in coxsackievirus-infected islets demonstrate that lack of HIF-1alpha 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-1alpha in the development of T1D. These data suggest new strategies for the prevention of T1D.
|Authors||Lalwani, A.; Warren, J.; Liuwantara, D.; Hawthorne, W. J.; O'Connell, P. J.; Gonzalez, F. J.; Stokes, R. A.; Chen, J.; Laybutt, D. R.; Craig, M. E.; Swarbrick, M. M.; King, C.; Gunton, J. E.|
|Responsible Garvan Author|
|Publisher Name||Cell Reports|
|Published Pages||2370-2384 e6|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/31116982|