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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 β-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 β-cell dysfunction of diabetes. Herein, we critically review the literature on the effects of proinsulin misfolding and ER stress on β-cell dysfunction and loss in diabetes with emphasis on β-cell dynamics, and discuss the gaps in understanding the role of proinsulin misfolding in the pathophysiology of diabetes.
This article was published in the following journal.
Name: Diabetes, obesity & metabolism
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The middle segment of proinsulin that is between the N-terminal B-chain and the C-terminal A-chain. It is a pancreatic peptide of about 31 residues, depending on the species. Upon proteolytic cleavage of proinsulin, equimolar INSULIN and C-peptide are released. C-peptide immunoassay has been used to assess pancreatic beta cell function in diabetic patients with circulating insulin antibodies or exogenous insulin. Half-life of C-peptide is 30 min, almost 8 times that of insulin.
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A pancreatic polypeptide of about 110 amino acids, depending on the species, that is the precursor of insulin. Proinsulin, produced by the PANCREATIC BETA CELLS, is comprised sequentially of the N-terminal B-chain, the proteolytically removable connecting C-peptide, and the C-terminal A-chain. It also contains three disulfide bonds, two between A-chain and B-chain. After cleavage at two locations, insulin and C-peptide are the secreted products. Intact proinsulin with low bioactivity also is secreted in small amounts.
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