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.
Highlights
Over the past 20 years the proof-of-principle of reversing the diabetic state with islet transplantation has been established, serious limitations remain [1]
Human beta cells in a transplant site had unfolded protein response (UPR) changes in gene expression that protect against the proapoptotic effects of unfolded proteins
The results show an endoplasmic reticulum (ER) stress response in these beta cells but indicate that it is likely serving a protective role rather than a destructive one
Summary
Over the past 20 years the proof-of-principle of reversing the diabetic state with islet transplantation has been established, serious limitations remain [1]. There seems to be little capacity for regeneration and there is a presumed increase in the rate of apoptosis. These problems can be partially attributed to the effects of host immune rejection, autoimmunity, and immunosuppressive drugs. Glucose toxicity [3] and the abnormal transplant environment [4] are likely to contribute to the altered functional capacity of transplanted beta cells. There 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
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