Endoplasmic reticulum stress and eIF2α phosphorylation: The Achilles heel of pancreatic β cells

Abstract

BackgroundPancreatic β cell dysfunction and death are central in the pathogenesis of most if not all forms of diabetes. Understanding the molecular mechanisms underlying β cell failure is important to develop β cell protective approaches.Scope of reviewHere we review the role of endoplasmic reticulum stress and dysregulated endoplasmic reticulum stress signaling in β cell failure in monogenic and polygenic forms of diabetes. There is substantial evidence for the presence of endoplasmic reticulum stress in β cells in type 1 and type 2 diabetes. Direct evidence for the importance of this stress response is provided by an increasing number of monogenic forms of diabetes. In particular, mutations in the PERK branch of the unfolded protein response provide insight into its importance for human β cell function and survival. The knowledge gained from different rodent models is reviewed. More disease- and patient-relevant models, using human induced pluripotent stem cells differentiated into β cells, will further advance our understanding of pathogenic mechanisms. Finally, we review the therapeutic modulation of endoplasmic reticulum stress and signaling in β cells.Major conclusionsPancreatic β cells are sensitive to excessive endoplasmic reticulum stress and dysregulated eIF2α phosphorylation, as indicated by transcriptome data, monogenic forms of diabetes and pharmacological studies. This should be taken into consideration when devising new therapeutic approaches for diabetes.

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

“…EM studies on pancreatic sections of human subjects with T2D showed marked enlargement of the β‐cell ER . Histological analyses of pancreatic sections from patients with T1D and T2D and from animal models of diabetes showed dysregulation of different UPR makers, including sXBP1, phosphorylated eIF2α, ATF3, ATF6, CHOP and chaperones, for example, p58 IPK and BiP . Part of the UPR markers (ATF3, CHOP and BiP) were increased in both T1D and in T2D, whereas other markers (phosphorylated eIF2α and ATF6) seem to be decreased .…”

“…In human β‐cells, the expression of different UPR genes and chaperones is high, suggesting that β‐cells are well equipped to cope with rapid fluctuations in proinsulin synthesis and with the generation of misfolded proteins . When activation of the UPR fails to correct protein folding, it may eventually lead to apoptosis, a process called “terminal UPR.” The latter is mediated via stress kinases, such as JNK and transcription factors including CHOP/GADD153 and ATF3 .…”

“…45 Histological analyses of pancreatic sections from patients with T1D and T2D and from animal models of diabetes showed dysregulation of different UPR makers, including sXBP1, phosphorylated eIF2α, ATF3, ATF6, CHOP and chaperones, for example, p58 IPK and BiP. 24 Part of the UPR markers (ATF3, CHOP and BiP) were increased in both T1D and in T2D, [46][47][48] whereas other markers (phosphorylated eIF2α and ATF6) seem to be decreased. [49][50][51] Engin et al found that sXBP1 was decreased in islets of patients with T1D and T2D, 49,50 whereas others found that sXBP1 remained unchanged in T1D.…”

Ursodeoxycholic acid suppresses the formation of fructose/streptozotocin‐induced diabetic cataract in rats

“…Administration of STZ to rats at the end of week 2 leads to a sharp significant increase in the level of FPG in diabetic groups (week 3) compared to their respective normal controls received only the citrate buffer. During the remaining experimental period (weeks [4][5][6][7][8][9][10][11][12][13][14], the level of nonfasting plasma glucose (NFPG) was significantly lower in UDCA-treated groups than that of DM group. At the end of the experimental period (week 15), FPG levels were significantly ameliorated in both UDCA-treated groups compared to DM group, however, they are still recording significant differences compared to NC animals ( Figure 1a).…”

A2a adenosine receptor agonist improves endoplasmic reticulum stress in MIN6 cell line through protein kinase A/ protein kinase B/ Cyclic adenosine monophosphate response element‐binding protein/ and Growth Arrest And DNA‐Damage‐Inducible 34/ eukaryotic Initiation Factor 2α pathways

“…This might explain why insulin secretion was increased after A2aR activation in TM-treated MIN6 cells.Dephosphorylation of p-eIF2α is necessary to reinitiate translation of vital proteins for cell survival. During ER stress, GADD34 is overexpressed and activates protein phosphatase-1 (PP-1) to dephosphorylate p-eIF2α(Cnop, Toivonen, Igoillo-Esteve, & Salpea, 2017).…”