Endoplasmic Reticulum Stress and Insulin Biosynthesis: A Review

Mi-Kyung Kim,Keun-Gyu Park,In-Kyu Lee,Hye-Soon Kim

doi:10.1155/2012/509437

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.

Highlights

These findings suggested that sustained activation of IRE1α may decrease insulin biosynthesis at the transcriptional level
Many studies have reported that endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of diabetes and that the unfolded protein response (UPR) has an important role in regulating pancreatic beta cell functions
It has been suggested from experimental evidence that ER stress mediates glucolipotoxicity-induced suppression of insulin biosynthesis (Figure 1)

Summary

Introduction

Exendin-4 increased ATF4 and CHOP expression and potentiated the induction of GADD34 and PP1c activity, resulting in decreased phosphorylation of eIF2α and a faster recovery from translational repression These findings show that GLP-1 receptor signaling modulates the ER stress response, leading to enhanced pancreatic beta cell survival [48]. By contrast, sustained activation of IRE1 signaling by chronic high glucose exposure causes ER stress, leading to the suppression of insulin mRNA expression. These findings suggested that sustained activation of IRE1α may decrease insulin biosynthesis at the transcriptional level. Another study has suggested that sustained production of spliced XBP-1 (XBP-1s) induces beta cell dysfunction by decreasing insulin gene expression, leading to apoptosis [53]. Chronic hyperglycemia has deleterious effects on beta cell function, as shown in primary cultured rat and human islet cells and in beta cell lines [64]

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Conclusions