Pathological β-Cell Endoplasmic Reticulum Stress in Type 2 Diabetes: Current Evidence

Abstract

The notion that in diabetes pancreatic β-cells express endoplasmic reticulum (ER) stress markers indicative of increased unfolded protein response (UPR) signaling is no longer in doubt. However, what remains controversial is whether this increase in ER stress response actually contributes importantly to the β-cell failure of type 2 diabetes (akin to 'terminal UPR'), or whether it represents a coping mechanism that represents the best attempt of β-cells to adapt to changes in metabolic demands as presented by disease progression. Here an intercontinental group of experts review evidence for the role of ER stress in monogenic and type 2 diabetes in an attempt to reconcile these disparate views. Current evidence implies that pancreatic β-cells require a regulated UPR for their development, function and survival, as well as to maintain cellular homeostasis in response to protein misfolding stress. Prolonged ER stress signaling, however, can be detrimental to β-cells, highlighting the importance of "optimal" UPR for ER homeostasis, β-cell function and survival.

Keywords: ATF6 (activating transcription factor 6); IRE1 (inositol-requiring enzyme 1); PERK (PKR-like endoplasmic reticulum kinase); endoplasmic reticulum; insulin; stress; unfolded protein response.

Figure 1

Pathways leading to β-cell ER stress and failure. (A) Genetic and non-genetic causes of human β-cell ER stress in diabetes. Patients with EIF2AK3 and EIF2B1 mutations that result in impaired signaling downstream of PERK develop young-onset diabetes, as do patients with EIF2S3, DNAJC3 and PPP1R15B mutations that result in excessive PERK signaling. Homozygous WFS1, YIPF5, TANGO1, MANF and IER3IP1 mutations also cause excessive UPR. Burst symbol indicates loss-of-function mutation causing monogenic diabetes, with red color indicating excessive and blue insufficient UPR signaling. For GWAS variants associated with T2D risk (indicated by tilde), the direction of effect is most often not known (black color). (B) Potential dysregulated β-cell responses to nutritional/metabolic challenge. UPR function is required for normal β-cell physiology, sustaining β-cell health and survival (green arrow). In conditions of insufficient UPR signaling relative to the prevailing ER stress (blue arrow), β-cells will fail. Conversely, excessive UPR signaling will cause β-cell dysfunction and death (red arrow). Currently available data provide evidence for both red and blue scenarios taking place in β-cells in T2D. ERAD ER-associated degradation, FFAs free fatty acids, IAPP islet amyloid polypeptide, RIDD regulated IRE1-dependent decay.