A Preexistent Hypoxic Gene Signature Predicts Impaired Islet Graft Function and Glucose Homeostasis

Author:

Cantley James12,Walters Stacey N.23,Jung Min-Ho4,Weinberg Anita23,Cowley Mark J.25,Whitworth P. Tess12,Kaplan Warren26,Hawthorne Wayne J.7,O'connell Philip J.7,Weir Gordon4,Grey Shane T.23

Affiliation:

1. Diabetes and Obesity Research Program, Garvan Institute, Darlinghurst, New South Wales, Australia

2. St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, New South Wales, Australia

3. Immunology Program, Garvan Institute, Darlinghurst, New South Wales, Australia

4. Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA

5. Cancer Program, Garvan Institute, Darlinghurst, New South Wales, Australia

6. Peter Wills Bioinformatics Centre, Garvan Institute, Darlinghurst, New South Wales, Australia

7. The Centre for Transplant and Renal Research, Westmead Hospital, Westmead, New South Wales, Australia

Abstract

We examined whether hypoxic exposure prior to the event of transplantation would have a positive or negative effect upon later islet graft function. Mouse islets exposed to hypoxic culture were transplanted into syngeneic recipients. Islet graft function, β-cell physiology, as well as molecular changes were examined. Expression of hypoxia-response genes in human islets pre- and posttransplant was examined by microarray. Hypoxia-preexposed murine islet grafts provided poor glycemic control in their syngeneic recipients, marked by persistent hyperglycemia and pronounced glucose intolerance with failed first- and second-phase glucose-stimulated insulin secretion in vivo. Mechanistically, hypoxic preexposure stabilized HIF-1α with a concomitant increase in hypoxic-response genes including LDHA, and a molecular gene set, which would favor glycolysis and lactate production and impair glucose sensing. Indeed, static incubation studies showed that hypoxia-exposed islets exhibited dysregulated glucose responsiveness with elevated basal insulin secretion. Isolated human islets, prior to transplantation, express a characteristic hypoxia-response gene expression signature, including high levels of LDHA, which is maintained posttransplant. Hypoxic preexposure of an islet graft drives a HIF-dependent switch to glycolysis with subsequent poor glycemic control and loss of glucose-stimulated insulin secretion (GSIS). Early intervention to reverse or prevent these hypoxia-induced metabolic gene changes may improve clinical islet transplantation.

Publisher

SAGE Publications

Subject

Transplantation,Cell Biology,Biomedical Engineering

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