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, b-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-1a 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 glucose-stimulated insulin secretion (GSIS). Early intervention to reverse or prevent these hypoxia-induced metabolic gene changes may improve clinical islet transplantation.

Extracellular hemoglobin combined with an O2‐generating material overcomes O2 limitation in the bioartificial pancreas

“…Nevertheless, we showed that low oxygen tension significantly damages NPI function, metabolism and viability from 2 to 7 days of culture. In keeping with the literature describing the impact of ischemia or hypoxia on human pancreatic islets (Brandhorst et al, ; Cantley et al, ; Giuliani et al, ; Hals, Rokstad, Strand, Oberholzer & Grill, ; Lai et al, ; Moritz et al, ), our results suggest that the innovative oxygen supply strategy developed in the present study may also meet the challenges of hypoxia during allotransplantation of macroencapsulated human pancreatic islets.…”

The control of insulin secretion by adipokines: current evidence for adipocyte-beta cell endocrine signalling in metabolic homeostasis

“…Finally, another potential mechanism by which resistin may impact on beta cell function is by enhancing blood flow to the pancreas (Danielsson et al 2009). Beta cell function is negatively impacted by hypoxia (Cantley et al , 2013 and hypoxia-inducible factor 1a activation (Cantley et al 2009); therefore, as nutrient stimulation can lead to a transient decrease in oxygen tension (Bensellam et al 2012), resistin may help to sustain adequate islet perfusion and oxygenation during times of high-metabolic demand. Furthermore, as the development of an adequate beta cell mass is highly dependent on vascular perfusion (Reinert et al 2013), resistin may potentially play a role in beta cell development and expansion.…”

Intraportal Islet Oxygenation

“…There are recent data indicating that early hypoxic exposure may result in a persistent change in the human islet cell gene signature and longer-lasting loss of glucose-stimulated insulin secretion. 21,22 This becomes even more important if the islet does not completely revascularize, since this would mean that the islet would rely on passive oxygen transport for several days or weeks and possibly indefinitely. It is generally believed that revascularization takes 7-10 days.…”