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

doi:10.1016/j.celrep.2019.04.086

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

Cell Rep. 2019 May 21;27(8):2370-2384.e6. doi: 10.1016/j.celrep.2019.04.086.

Authors

Affiliations

¹ 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.
² Mucosal Autoimmunity, Garvan Institute of Medical Research, Sydney, NSW, Australia.
³ National Pancreas Transplant Unit (NPTU), Westmead Hospital, Sydney, NSW, Australia.
⁴ Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; National Pancreas Transplant Unit (NPTU), Westmead Hospital, Sydney, NSW, Australia.
⁵ Laboratory of Metabolism, National Cancer Institute, Bethesda, MD, USA.
⁶ Center for Diabetes, Obesity, and Endocrinology (CDOE), The Westmead Institute for Medical Research (WIMR), The University of Sydney, Sydney, NSW, Australia.
⁷ Islet Biology, Garvan Institute of Medical Research, Sydney, NSW, Australia.
⁸ 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.
⁹ 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.
¹⁰ 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. Electronic address: jenny.gunton@sydney.edu.au.

Abstract

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.

Keywords: apoptosis; autoimmunity; beta-cell; coxsackievirus; inflammation; streptozotocin; type 1 diabetes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Diabetes Mellitus, Type 1 / prevention & control*
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / pharmacology
Hypoxia-Inducible Factor 1, alpha Subunit / therapeutic use*
Male
Mice

Substances

Hypoxia-Inducible Factor 1, alpha Subunit

Abstract

Publication types

MeSH terms

Substances

Grants and funding