A pre-existent hypoxic gene signature predicts impaired islet graft function and glucose homeostasis
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, beta cell physiology, as well as molecular changes were examined. Expression of hypoxia-response genes in human islets pre- and post-transplant was examined by microarray. Hypoxia-pre-exposed 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 pre-exposure stabilized HIF-1alpha with a concomitant increase in hypoxic-response genes including LDHA; a molecular gene set which would favor glycolysis and lactate production and impair glucose sensing. Indeed, static incubation studies showed hypoxia-exposed islets exhibited dysregulated glucose responsiveness with elevated basal insulin secretion. Isolated human islets, prior to transplantation, express a characteristic hypoxiaresponse gene expression signature, including high levels of LDHA, which is maintained post transplant. Hypoxic pre-exposure 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.
|Authors||Cantley, J.; Walters, S. N.; Jung, M. H.; Weinberg, A.; Cowley, M. J.; Whitworth, P. T.; Kaplan, W.; Hawthorne, W. J.; O'Connell, P. J.; Weir, G.; Grey, S. T.;|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/23127310|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/11315|