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

TY - JOUR

T1 - A preexistent hypoxic gene signature predicts impaired islet graft function and glucose homeostasis

AU - Cantley, James

AU - Walters, Stacey N.

AU - Jung, Min Ho

AU - Weinberg, Anita

AU - Cowley, Mark J.

AU - Whitworth, Tess P.

AU - Kaplan, Warren

AU - Hawthorne, Wayne J.

AU - O'Connell, Philip J.

AU - Weir, Gordon

AU - Grey, Shane T.

PY - 2013/11/1

Y1 - 2013/11/1

N2 - 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.

AB - 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.

KW - Glycolysis

KW - Hypoxia

KW - Hypoxia-inducible factor-1α (HIF-1α)

KW - Islet transplantation

UR - https://www.scopus.com/pages/publications/84886439822

U2 - 10.3727/096368912X658728

DO - 10.3727/096368912X658728

M3 - Article

C2 - 23127310

AN - SCOPUS:84886439822

SN - 0963-6897

VL - 22

SP - 2147

EP - 2159

JO - Cell Transplantation

JF - Cell Transplantation

IS - 11

ER -