题名：Influence of chronic hyperglycemia on the loss of the unfolded protein response in transplanted islets.
作者：WALTERS SN; LUZURIAGA J; CHAN JY; GREY ST; LAYBUTT DR;
来源：J Mol Endocrinol. 2013 Sep 6;51(2):225-32. doi: 10.1530/JME-13-0016. Print 2013. [ IF= 0.00 ] ]
摘要：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.