Endoplasmic reticulum stress and insulin biosynthesis: a review

Abstract

Insulin resistance and pancreatic beta cell dysfunction are major contributors to the pathogenesis of diabetes. Various conditions play a role in the pathogenesis of pancreatic beta cell dysfunction and are correlated with endoplasmic reticulum (ER) stress. Pancreatic beta cells are susceptible to ER stress. Many studies have shown that increased ER stress induces pancreatic beta cell dysfunction and diabetes mellitus using genetic models of ER stress and by various stimuli. There are many reports indicating that ER stress plays an important role in the impairment of insulin biosynthesis, suggesting that reduction of ER stress could be a therapeutic target for diabetes. In this paper, we reviewed the relationship between ER stress and diabetes and how ER stress controls insulin biosynthesis.

Figure 1

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.