A preexistent hypoxic gene signature predicts impaired islet graft function and glucose homeostasis

James Cantley, Stacey N. Walters, Min Ho Jung, Anita Weinberg, Mark J. Cowley, Tess P. Whitworth, Warren Kaplan, Wayne J. Hawthorne, Philip J. O'Connell, Gordon Weir, Shane T. Grey

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25 Citations (Scopus)

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. Hypoxiapreexposed 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 HIFdependent switch to glycolysis with subsequent poor glycemic control and loss of GSIS. Early intervention to reverse or prevent these hypoxia-induced metabolic gene changes may improve clinical islet transplantation.

Original languageEnglish
Pages (from-to)2147-2159
Number of pages13
JournalCell Transplantation
Volume22
Issue number11
DOIs
Publication statusPublished - 1 Nov 2013

Keywords

  • Glycolysis
  • Hypoxia
  • Hypoxia-inducible factor-1α (HIF-1α)
  • Islet transplantation

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    Cantley, J., Walters, S. N., Jung, M. H., Weinberg, A., Cowley, M. J., Whitworth, T. P., Kaplan, W., Hawthorne, W. J., O'Connell, P. J., Weir, G., & Grey, S. T. (2013). A preexistent hypoxic gene signature predicts impaired islet graft function and glucose homeostasis. Cell Transplantation, 22(11), 2147-2159. https://doi.org/10.3727/096368912X658728