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

Cell Transplant. 2013;22(11):2147-59. doi: 10.3727/096368912X658728. Epub 2012 Oct 31.


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 GSIS. Early intervention to reverse or prevent these hypoxia-induced metabolic gene changes may improve clinical islet transplantation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Blood Glucose / metabolism
  • Cell Hypoxia*
  • Diabetes Mellitus, Experimental / surgery
  • Female
  • Glycolysis
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Insulin / metabolism
  • Insulin Secretion
  • Islets of Langerhans / cytology*
  • Islets of Langerhans / metabolism
  • Islets of Langerhans Transplantation*
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • L-Lactate Dehydrogenase / genetics
  • L-Lactate Dehydrogenase / metabolism
  • Lactate Dehydrogenase 5
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Transcriptome
  • Transplantation, Homologous


  • Blood Glucose
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Insulin
  • Isoenzymes
  • L-Lactate Dehydrogenase
  • Lactate Dehydrogenase 5