Influence of chronic hyperglycemia on the loss of the unfolded protein response in transplanted islets
Chronic hyperglycemia contributes to beta-cell dysfunction in diabetes and with islet transplantation, but the mechanisms remain unclear. Recent studies demonstrate that the unfolded protein response (UPR) is critical for beta-cell function. Here, we assessed the influence of hyperglycemia on UPR gene expression in transplanted islets. Streptozotocin-induced diabetic or control nondiabetic mice were transplanted under the kidney capsule with syngeneic islets either sufficient or not to normalize hyperglycemia. Twenty-one days after transplantation, islet grafts were excised and RT-PCR was used to assess gene expression. In islet grafts from diabetic mice, expression levels of many UPR genes of the IRE1/ATF6 pathways, which are important for adaptation to endoplasmic reticulum stress, were markedly reduced compared with that in islet grafts from control mice. UPR genes of the PERK pathway were also downregulated. The normalization of glycemia restored the changes in mRNA expression, suggesting that chronic hyperglycemia contributes to the downregulation of multiple arms of UPR gene expression. Similar correlations were observed between blood glucose and mRNA levels of transcription factors involved in the maintenance of beta-cell phenotype and genes implicated in beta-cell function, suggesting convergent regulation of UPR gene expression and beta-cell differentiation by hyperglycemia. However, the normalization of glycemia was not accompanied by restoration of antioxidant or pro-inflammatory cytokine mRNA levels, which were increased in islet grafts from diabetic mice. These studies demonstrate that chronic hyperglycemia contributes to the downregulation of multiple arms of UPR gene expression in transplanted mouse islets. Failure of the adaptive UPR may contribute to beta-cell dedifferentiation and dysfunction in diabetes.
|Authors||Walters, S. N.; Luzuriaga, J.; Chan, J. Y.; Grey, S. T.; Laybutt, D. R.;|
|Responsible Garvan Author|
|Publisher Name||JOURNAL OF MOLECULAR ENDOCRINOLOGY|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/23833251|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/11873|