Protective Unfolded Protein Response in Human Pancreatic Beta Cells Transplanted into Mice

Abstract

BackgroundThere is great interest about the possible contribution of ER stress to the apoptosis of pancreatic beta cells in the diabetic state and with islet transplantation.Methods and FindingsExpression of genes involved in ER stress were examined in beta cell enriched tissue obtained with laser capture microdissection (LCM) from frozen sections of pancreases obtained from non-diabetic subjects at surgery and from human islets transplanted into ICR-SCID mice for 4 wk. Because mice have higher glucose levels than humans, the transplanted beta cells were exposed to mild hyperglycemia and the abnormal environment of the transplant site. RNA was extracted from the LCM specimens, amplified and then subjected to microarray analysis. The transplanted beta cells showed an unfolded protein response (UPR). There was activation of many genes of the IRE-1 pathway that provide protection against the deleterious effects of ER stress, increased expression of ER chaperones and ERAD (ER-associated protein degradation) proteins. The other two arms of ER stress, PERK and ATF-6, had many down regulated genes. Downregulation of EIF2A could protect by inhibiting protein synthesis. Two genes known to contribute to apoptosis, CHOP and JNK, were downregulated.ConclusionsHuman beta cells in a transplant site had UPR changes in gene expression that protect against the proapoptotic effects of unfolded proteins.

Influence of chronic hyperglycemia on the loss of the unfolded protein response in transplanted islets

“…With treatment periods of 24-96 h, UPR activation is thought to contribute to hyperglycemia-mediated inhibition of insulin synthesis and secretion in vitro (Seo et al 2008, Zhang et al 2009) and in vivo (Tang et al 2012). In the longer term, upregulation of protective UPR genes of the IRE1 pathway is associated with the mild hyperglycemia imposed on human islets transplanted into mouse recipients, which have slightly higher blood glucose levels than humans (Kennedy et al 2010). However, in type 2 diabetes, CHOP protein levels are increased and may contribute to b-cell apoptosis (Akerfeldt et al 2008, Cunha et al 2008, Song et al 2008, suggesting failure of the adaptive UPR.…”

KAT2B Is Required for Pancreatic Beta Cell Adaptation to Metabolic Stress by Controlling the Unfolded Protein Response

“…By analyzing fresh human islets isolated from four T2D donors and four normoglycemic subjects (see Table S4 for donor information), we confirmed that KAT2B expression was decreased in T2D ( Figure 5G). Some UPR er pathways are defective in human T2D islets; Engin et al, 2014;Kennedy et al, 2010). In this respect, KAT2B expression, ABCC8, SLC30A8, CPE, PDX1, and UPR er genes DDIT3 (CHOP), HERPUD2, HSP90B1 (GRP94), EDEM1, and DNAJC3 (p58IPK) were concomitantly decreased in T2D islets ( Figure 5H).…”

“…A growing body of evidence suggests that alteration in the expression of UPR er genes may lead to b cell failure and contribute to diabetes development (Cnop et al, 2012;Rabhi et al, 2014). Recent studies in mouse and human diabetic islets implicate altered expression of these markers (Chan et al, 2013;Engin et al, 2014;Kennedy et al, 2010;Laybutt et al, 2007). However, the upstream regulators responsible for the modulation of UPR er gene expression are currently unknown.…”

A Reevaluation of the Role of the Unfolded Protein Response in Islet Dysfunction: Maladaptation or a Failure to Adapt?

“…Congruent with this presumption, hyperglycemia induced by glucose infusion in Wistar rats activates an adaptive UPR in islets, as determined by increased expression of XBP1s and the ER chaperones BiP and GRP94 (40). Similarly, mild hyperglycemia imposed on human islets when transplanted into mouse recipients also results in the activation of an adaptive UPR (41). These effects on the UPR are likely due to an increased demand for insulin rather than hyperglycemia per se (32,42).…”