The role of the unfolded protein response in diabetes mellitus

The endoplasmic reticulum (ER) plays a key role in the synthesis and modification of secretory and membrane proteins in all eukaryotic cells. Under normal conditions, these proteins are correctly folded and assembled in the ER. However, when cells are exposed to environmental factors such as overproduction of ER proteins, viral infections, or glucose deprivation, the secretory and membrane proteins can accumulate in unfolded or misfolded forms in the lumen of the ER, and consequently, cause stress in the ER. To maintain cellular homeostasis, cells induce several responses to ER stress. In mammalian cells, ER stress responses are induced by a diversity of signal pathways. There are three ER-located transmembrane proteins that play important roles in mammalian ER stress responses: activating transcription factor 6, inositol-requiring protein 1, and protein kinase RNA-like endoplasmic reticulum kinase. ER stress is linked to various diseases, including diabetes. This review highlights the particular importance of ER stress-responsive molecules in insulin biosynthesis, glyconeogenesis, insulin resistance, glucose intolerance, and pancreatic beta-cell apoptosis. An understanding of the pathogenic mechanism of diabetes from the aspect of ER stress is crucial in formulating therapeutic strategies.