In both type 1 and
type 2 diabetes, pancreatic islet dysfunction results in part from
cytokine-mediated
inflammation. The ubiquitous
eukaryotic translation initiation factor 5A (eIF5A), which is the only
protein to contain the
amino acid hypusine, contributes to the production of proinflammatory
cytokines. We therefore investigated whether eIF5A participates in the inflammatory cascade leading to islet dysfunction during the development of diabetes. As described herein, we found that eIF5A regulates iNOS levels and that eIF5A depletion as well as the inhibition of hypusination protects against
glucose intolerance in inflammatory mouse models of diabetes. We observed that following knockdown of eIF5A expression, mice were resistant to beta cell loss and the development of
hyperglycemia in the low-dose
streptozotocin model of diabetes. The depletion of eIF5A led to impaired translation of iNOS-encoding
mRNA within the islet. A role for the
hypusine residue of eIF5A in islet inflammatory responses was suggested by the observation that inhibition of
hypusine synthesis reduced translation of iNOS-encoding
mRNA in rodent beta cells and human islets and protected mice against the development of
glucose intolerance the low-dose
streptozotocin model of diabetes. Further analysis revealed that
hypusine is required in part for nuclear export of iNOS-encoding
mRNA, a process that involved the export
protein exportin1. These observations identify the
hypusine modification of eIF5A as a potential therapeutic target for preserving islet function under inflammatory conditions.