Effects of proinsulin misfolding on β‐cell dynamics, differentiation and function in diabetes

Abstract

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.

Unfolded protein response is involved in geniposide‐regulating glucose‐stimulated insulin secretion in INS‐1 cells

“…24,25 It has been proposed that, in the presence of high glucose, unsuppressed translation that leads to exuberant proinsulin biosynthesis does not increase proinsulin misfolding but is associated with beta cell death. 26,27 At present, geniposide prohibited PERK phosphorylation induced by high glucose, and both PERK siRNA and inhibitor prevented the role of geniposide on GSIS, suggesting that PERK might be an essential player of geniposide-regulating GSIS.…”

“…PERK, also known as eIF2α kinase‐3, was the first of the ER stress sensors found to be tightly linked to beta cell function, which played a crucial role on the protein translation, and has emerged as a critically negative regulatory step for proinsulin biosynthesis . It has been proposed that, in the presence of high glucose, unsuppressed translation that leads to exuberant proinsulin biosynthesis does not increase proinsulin misfolding but is associated with beta cell death . At present, geniposide prohibited PERK phosphorylation induced by high glucose, and both PERK siRNA and inhibitor prevented the role of geniposide on GSIS, suggesting that PERK might be an essential player of geniposide‐regulating GSIS.…”

The healthy exocrine pancreas contains preproinsulin-specific CD8 T cells that attack islets in type 1 diabetes

“…These antigen-specific CD8 + T cells are present in large numbers in the nondiabetic exocrine pancreas (with higher numbers in aab + donors), arguing against a defective thymic selection of CD8 T cells and systemic regulatory mechanisms as fundamental disease drivers. Last, their increased accumulation in pancreatic islets after clinical diagnosis suggests mechanisms that selectively “unmask” beta cells to the immune system such as up-regulation of MHC class I ( 14 ) possibly mediated by a viral trigger ( 38 ) as well as accumulation of proinsulin, potentially caused by beta cell metabolic stress ( 15 , 39 , 40 ), resulting in their recognition, functional impairment, and ultimately demise ( 34 ). Our findings strongly argue the case for a more beta cell–centric rather than a systemic therapeutic approach to tackle the complicated problem of T1D ( 41 ).…”

Role of Proinsulin Self-Association in MutantINSgene-induced Diabetes of Youth

“…Increasing evidence indicates that proinsulin misfolding and ER stress not only are the molecular basis of MIDY, but may also play an important role in the development and progression of type 1 and type 2 diabetes (2,(24)(25)(26)(27). Increased proinsulin misfolding has been recently reported in b-cells with either defects in the ER folding environment (28)(29)(30), or defective ER export machinery (18), or proinsulin oversynthesis due to insulin resistance in rodent and human type 2 diabetes islets (19).…”