title: A preexistent hypoxic gene signature predicts impaired islet graft function and glucose homeostasis.
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 GSIS. Early intervention to reverse or prevent these hypoxia-induced metabolic gene changes may improve clinical islet transplantation.
authors.affiliation: Diabetes and Obesity Research Program, Garvan Institute, Darlinghurst, New South Wales, Australia.
authors.forename: James
authors.initials: J
authors.lastname: Cantley
authors.forename: Stacey N
authors.initials: SN
authors.lastname: Walters
authors.forename: Min-Ho
authors.initials: MH
authors.lastname: Jung
authors.forename: Anita
authors.initials: A
authors.lastname: Weinberg
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Cowley
authors.forename: Tess P
authors.initials: TP
authors.lastname: Whitworth
authors.forename: Warren
authors.initials: W
authors.lastname: Kaplan
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Hawthorne
authors.forename: Philip J
authors.initials: PJ
authors.lastname: O'Connell
authors.forename: Gordon
authors.initials: G
authors.lastname: Weir
authors.forename: Shane T
authors.initials: ST
authors.lastname: Grey
mesh_terms: D000328:Adult; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015687:Cell Hypoxia; D003921:Diabetes Mellitus, Experimental / Q000601:surgery; D005260:Female; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology* / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D059467:Transcriptome; D014184:Transplantation, Homologous
chemical_list: D001786:Blood Glucose; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D007527:Isoenzymes; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5