Hypoxia inducible factor-1α (HIF-1α) is required for β-cell survival in Type 1 diabetes (T1D) caused by immunological insults — ASN Events
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  3. Hypoxia inducible factor-1α (HIF-1α) is required for β-cell survival in Type 1 diabetes (T1D) caused by immunological insults

Hypoxia inducible factor-1α (HIF-1α) is required for β-cell survival in Type 1 diabetes (T1D) caused by immunological insults (#99)

Amit Lalwani 1 , Joanna Warren 2 , Rebecca Stokes 1 , David Liuwantara 1 , Wayne Hawthorne 3 , Philip O'Connell 3 , Maria Craig 4 , Michael Swarbrick 1 , Cecile King 2 , Jenny Gunton 1 3
  1. Westmead Institute for Medical Research, Westmead, NSW, Australia
  2. Mucosal Autoimmunity, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  3. Westmead Hospital, University of Sydney, Sydney, NSW, Australia
  4. University of New South Wales, Sydney, NSW, Australia

Background: Our previous studies show that HIF-1α is important for β-cell survival and function in islet-transplantation but however; its significance in T1D is unknown.

Aim: To determine the role of HIF-1α in T1D onset caused by insults such as coxsackieviruses (CV), multiple low-dose streptozotocin (MLDS) and interleukin-1β (IL-1β).

Methods: NOD mice with β-cell-specific HIF-1α deletion (βHIF-1α) and floxed-controls were studied. For CV, mice were inoculated with 105 pfu of CVB4 or CVB1. Days 7 (peak), 21 (clearance) post-infection (dpi) and long-term were assessed. For MLDS, mice received 20mg/kg streptozotocin on days 1 to 5. For IL-1β, human islets from healthy donors and mouse islets were treated ± 10 pg/mL for 1, 2 or 24-hours.

Results: At 7dpi, CVB4 infected βHIF-1α mice had higher pancreatic viral-load and elevated islet-infiltrates that constituted of higher percentages of CD3+ T-cells (p=0.0095) and CD19+ B-cells (p=0.019). By 21dpi virus was cleared. In the long-term study, florid-T1D developed in 13/22 βHIF-1α mice (59%), versus 0/11 of controls (0%, p≤0.001) by 32 weeks. Adoptive-transfer studies confirmed T1D, with 100% of NOD-SCID recipients of diabetic βHIF-1α splenocytes developing T1D. In ongoing studies, CVB1 induced florid-T1D in 4/9 β-HIF-1α mice (44%), versus 0/5 of controls (0%, p≤0.0001) by 11 weeks. When exposed to CVB4 orally by gavage, 3/6 β-HIF-1α mice (50%) thus far have developed florid-T1D versus 0/5 controls (0%). Following MLDS, βHIF-1α mice had increased BGLs, glucose intolerance by 1 week, and 8/8 mice (100%) developed florid-T1D versus 5/15 mice for controls (33%, p=0.0015). Human islets treated with IL-1β showed increased expression of pro-apoptotic markers BAX (1.7 fold, p≤0.01) and BAK1 (2.9 fold, p≤0.01) after 24-hours, versus controls. βHIF-1α mouse islets showed decreased expression of anti-apoptotic gene Bcl-xl (3.9 fold, p≤0.0001) and β-cell survival gene Pdx1 (11.1 fold, p≤0.0001) after 2-hours, versus control islets.

Conclusion: These findings suggest that β-cell HIF-1α is a common-regulator of β-cell susceptibility to T1D. This has important implications for the role of β-cells in T1D-development and suggests that increasing β-cell HIF-1α may protect against T1D development.

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