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https://hdl.handle.net/2440/120800
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Type: | Journal article |
Title: | A preexistent hypoxic gene signature predicts impaired islet graft function and glucose homeostasis |
Author: | 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. |
Citation: | Cell Transplantation, 2013; 22(11):2147-2159 |
Publisher: | Cognizant Communication Corporation |
Issue Date: | 2013 |
ISSN: | 0963-6897 1555-3892 |
Statement of Responsibility: | James Cantley, Stacey N. Walters, Min-Ho Jung, Anita Weinberg, Mark J. Cowley, P. Tess Whitworth, Warren Kaplan, Wayne J. Hawthorne, Philip J. O'connell, Gordon Weir, Shane T. Grey |
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. |
Keywords: | Islet transplantation; hypoxia; glycolysis; hypoxia-inducible factor-1α (HIF-1α) |
Rights: | © 2013 Cognizant Comm. Corp. |
DOI: | 10.3727/096368912X658728 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/427695 http://purl.org/au-research/grants/nhmrc/427828 |
Published version: | http://dx.doi.org/10.3727/096368912x658728 |
Appears in Collections: | Aurora harvest 4 Medicine publications |
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