期刊
DIABETES OBESITY & METABOLISM
卷 20, 期 -, 页码 95-103出版社
WILEY
DOI: 10.1111/dom.13379
关键词
beta-cells; apoptosis; diabetes; ER stress; insulin secretion; proliferation; proinsulin misfolding
资金
- Israel Science Foundation [ISF-347/12]
- Israel Science Foundation-Legacy Biomedical Science Partnership [ISF-1563/14ISF-2323/17]
ER stress due to proinsulin misfolding has an important role in the pathophysiology of rare forms of permanent neonatal diabetes (PNDM) and probably also of common type 1 (T1D) and type 2 diabetes (T2D). Accumulation of misfolded proinsulin in the ER stimulates the unfolded protein response (UPR) that may eventually lead to apoptosis through a process called the terminal UPR. However, the beta-cell ER has an incredible ability to cope with accumulation of misfolded proteins; therefore, it is not clear whether in common forms of diabetes the accumulation of misfolded proinsulin exceeds the point of no return in which terminal UPR is activated. Many studies showed that the UPR is altered in both T1D and T2D; however, the observed changes in the expression of different UPR markers are inconsistent and it is not clear whether they reflect an adaptive response to stress or indeed mediate the beta-cell dysfunction of diabetes. Herein, we critically review the literature on the effects of proinsulin misfolding and ER stress on beta-cell dysfunction and loss in diabetes with emphasis on beta-cell dynamics, and discuss the gaps in understanding the role of proinsulin misfolding in the pathophysiology of diabetes.
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