An accomplice more than a mere victim: The impact of β-cell ER stress on type 1 diabetes pathogenesis

DNA damage to β cells in culture recapitulates features of senescent β cells that accumulate in type 1 diabetes

“…Luminex assays for secreted NOD mouse β cell SASP factors [ 7 ] on conditioned media showed dramatically increased secretion of Serpine1 and Igfbp3 from senescent NIT1 cells as compared with controls whereas none of these factors were secreted by late-stage senescent MIN6 cells ( Figure 3 C,D). We also determined whether induction of senescence would impact the UPR, a different β cell stress response implicated in T1D [ 4 ]. We validated antibodies for UPR mediators phospho-IRE1α Ser724 (activated IRE1α) and total IRE1α, PERK and ATF6α (90 kDa uncleaved form) by western blot on primary human islets treated with 1 μM Thapsigargin for 5 h, which led to increased levels of these UPR factors ( Supplementary Fig.…”

“…However there was a ∼50% decrease in GCG expression and a similar decrease in the corresponding glucagon processing enzyme gene PCSK2 [ 52 ] in senescent islets from Donor 2 but not Donor 1 ( Figure 4 F), revealing inter-donor variability. In addition, genes involved in ER stress and UPR [ 4 ] were not significantly changed between control and bleomycin treatment ( Supplementary Fig. 4C ).…”

“…While much of our understanding of T1D stems from investigations of the immune system, recent work has implicated stress responses in β cells as an additional factor driving disease progression and onset [ 2 , 3 ]. For instance, β cells experience unmitigated endoplasmic reticulum (ER) stress and activate the terminal unfolded protein response (UPR) leading to apoptosis during the development of T1D [ 4 ]. Small molecule therapeutics that block terminal UPR have shown promise in clinical trials of new onset T1D patients by slowing the decline in C-peptide production after diagnosis [ 5 , 6 ].…”

Adaptation to chronic ER stress enforces pancreatic β-cell plasticity

“…implicate ER stress and maladaptive UPR in the pathogenesis of type 1 and type 2 diabetes (T1D and T2D) [9][10][11][12][13][14][15][16][17][18] . Indeed, mutations in genes that influence ER stress responses, including those encoding the major UPR elements PERK, eIF2α, CHOP, XBP1, IRE1α, and WSF1, frequently result in loss of β-cell function and/or death in experimental models and humans 3,[19][20][21] . In this study, we investigated the molecular underpinnings of reversible chronic and episodic ER stress and their effects on β-cell adaptation.…”

Endoplasmic Reticulum Stress and Dysregulated Autophagy in Human Pancreatic Beta Cells

“…These KIRAs ameliorated ER stress-induced hyperactivation and endoribonuclease activity of IRE1α and degradation of ER-localized mRNAs. Evidence for the pharmacologic targeting of ER stress and plausible mechanisms have been reviewed elsewhere [ 11 , 12 , 27 , 28 ].…”