Living Dangerously: Protective and Harmful ER Stress Responses in Pancreatic β-Cells

Abstract

Type 2 diabetes (T2D) is a growing cause of poor health, psychosocial burden, and economic costs worldwide. The pancreatic β-cell is a cornerstone of metabolic physiology. Insulin deficiency leads to hyperglycemia, which was fatal before the availability of therapeutic insulins; even partial deficiency of insulin leads to diabetes in the context of insulin resistance. Comprising only an estimated 1 g or <1/500th of a percent of the human body mass, pancreatic β-cells of the islets of Langerhans are a vulnerable link in metabolism. Proinsulin production constitutes a major load on β-cell endoplasmic reticulum (ER), and decompensated ER stress is a cause of β-cell failure and loss in both type 1 diabetes (T1D) and T2D. The unfolded protein response (UPR), the principal ER stress response system, is critical for maintenance of β-cell health. Successful UPR guides expansion of ER protein folding capacity and increased β-cell number through survival pathways and cell replication. However, in some cases the ER stress response can cause collateral β-cell damage and may even contribute to diabetes pathogenesis. Here we review the known beneficial and harmful effects of UPR pathways in pancreatic β-cells. Improved understanding of this stress response tipping point may lead to approaches to maintain β-cell health and function.

Vitamin K-dependent γ-carboxylation regulates calcium flux and adaptation to metabolic stress in β-cells

“…Based on these observations, we hypothesized that the capacity of islet cells to respond and adapt to ER stress might be deficient in the absence of γ-carboxylation, potentially leading to impaired β-cell function. In support of this notion, we found that a network of genes previously implicated in the β-cell response to ER stress, including Ddit3 (CHOP), Atf4 , Eif2ak3 (PERK) , Herpud1 , Trib3 , Pdia4 , Ppp1r1a and Atp2a2 (SERCA2) (Johnson et al, 2014; Sharma et al, 2021), was down-regulated in absence of γ-carboxylation (Fig. 1D).…”

Nutrient Regulation of Pancreatic Islet β-Cell Secretory Capacity and Insulin Production

“…Collectively, the primary function of the ER stress response program is to sense client protein overload through the loss of available chaperone protein binding (i.e., accumulation of misfolded proteins) and adjust ER folding capacity via the activation of transcriptional and translational programs that modulate the expression of ER chaperones, PDIs, and glycosylation enzymes [ 100 , 106 , 111 ]. A detailed discussion of the contribution of these sensors to β-cell function and their transcriptional programs is beyond the scope of this review and was expertly reviewed elsewhere [ 99 , 112 ].…”

Sex differences in islet stress responses support female beta cell resilience

“…Given the prolonged protein synthesis repression in males following ER stress, we next quantified cell death, another ER stress-associated phenotype ( 80 ), in male and female islets. Using a kinetic cell death analysis, we observed no significant increase in apoptosis in female islet cells with 0.1 μM or 1.0 μM Tg treatment compared with controls after 84-hours (Figure 3C).…”

“…This suggests sex differences in ER stress-associated phenotypes occur prior to male-female differences in peripheral insulin sensitivity. Indeed, islets isolated from males and females with equivalent sensitivity also show a sex difference in protein synthesis repression, a classical ER stress-associated phenotype ( 80 ). While estrogen affects insulin biosynthesis via ERα ( 49 ), future studies will need to determine whether estrogen contributes to the ability of female islets to restore protein synthesis to basal levels faster than male islets following ER stress.…”