β Cell Hypoxia-Inducible Factor-1α Is Required for the Prevention of Type 1 Diabetes
Amit Lalwani,
Joanna Warren,
David Liuwantara,
Wayne J. Hawthorne,
Philip J. O’Connell,
Frank J. Gonzalez,
Rebecca A. Stokes,
Jennifer Chen,
D. Ross Laybutt,
Maria E. Craig,
Michael M. Swarbrick,
Cecile King,
Jenny E. Gunton
Affiliations
Amit Lalwani
Center for Diabetes, Obesity, and Endocrinology (CDOE), The Westmead Institute for Medical Research (WIMR), The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
Joanna Warren
Mucosal Autoimmunity, Garvan Institute of Medical Research, Sydney, NSW, Australia
David Liuwantara
National Pancreas Transplant Unit (NPTU), Westmead Hospital, Sydney, NSW, Australia
Wayne J. Hawthorne
Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; National Pancreas Transplant Unit (NPTU), Westmead Hospital, Sydney, NSW, Australia
Philip J. O’Connell
National Pancreas Transplant Unit (NPTU), Westmead Hospital, Sydney, NSW, Australia
Frank J. Gonzalez
Laboratory of Metabolism, National Cancer Institute, Bethesda, MD, USA
Rebecca A. Stokes
Center for Diabetes, Obesity, and Endocrinology (CDOE), The Westmead Institute for Medical Research (WIMR), The University of Sydney, Sydney, NSW, Australia
Jennifer Chen
Center for Diabetes, Obesity, and Endocrinology (CDOE), The Westmead Institute for Medical Research (WIMR), The University of Sydney, Sydney, NSW, Australia
D. Ross Laybutt
Islet Biology, Garvan Institute of Medical Research, Sydney, NSW, Australia
Maria E. Craig
Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; The Children’s Hospital at Westmead, Sydney, NSW, Australia; School of Women’s and Children’s Health, University of New South Wales, Kensington, NSW, Australia
Michael M. Swarbrick
Center for Diabetes, Obesity, and Endocrinology (CDOE), The Westmead Institute for Medical Research (WIMR), The University of Sydney, Sydney, NSW, Australia; School of Medical Sciences, University of New South Wales, Kensington, NSW, Australia
Cecile King
Mucosal Autoimmunity, Garvan Institute of Medical Research, Sydney, NSW, Australia
Jenny E. Gunton
Center for Diabetes, Obesity, and Endocrinology (CDOE), The Westmead Institute for Medical Research (WIMR), The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; St Vincent’s Clinical School, University of New South Wales, Kensington, NSW, Australia; Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, NSW, Australia; Corresponding author
Summary: 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-1α (HIF-1α) from β cells increases the susceptibility of non-obese diabetic (NOD) mice to environmentally triggered T1D from coxsackieviruses and the β cell toxin streptozotocin. Similarly, knockdown of HIF-1α in human islets leads to a poorer response to coxsackievirus infection. Studies in coxsackievirus-infected islets demonstrate that lack of HIF-1α leads to impaired viral clearance, increased viral load, inflammation, pancreatitis, and loss of β cell mass. These findings show an important role for β cells and, specifically, lack of β cell HIF-1α in the development of T1D. These data suggest new strategies for the prevention of T1D. : Lalwani et al. describe a role for β cell hypoxia-inducible factor-1α (HIF1a) in determining whether β cell injury is followed by resolution and normal function or ongoing injury, autoimmunity, and type 1 diabetes. Keywords: type 1 diabetes, coxsackievirus, beta-cell, apoptosis, autoimmunity, streptozotocin, inflammation
