Endoplasmic Reticulum Stress and Insulin Biosynthesis: A Review
Possible mechanisms of insulin biosynthesis by endoplasmic reticulum (ER) stress. Insulin biosynthesis is affected by ER stress through different mechanisms, such as activation of the following pathways: transcription factor 6 (ATF6), inositol-requiring 1 (IRE1)/X-box-binding-protein-1 (XBP-1), and protein-kinase-RNA (PKR-) like ER kinase (PERK). The exposure of beta cells to high glucose chronically induces ER stress, resulting in the activation of ATF6. Activation of ATF6 impairs insulin gene expression. Long-term exposure to high glucose induces IRE1α activation and XBP-1 splicing, leading to the suppression of insulin mRNA expression and to increases in the degradation of insulin mRNA. In addition, downstream of PERK, ATF4, and CHOP inhibit proinsulin synthesis via translational attenuation mediated by PP1c and GADD34. Numbers in parentheses are the references cited in this paper.