Endoplasmic reticulum (ER) stress is characterized by the accumulation of unfolded and misfolded proteins in
the ER lumen. Unfolded and misfolded protein accumulation interferes with the ER function and triggers ER stress response.
Thus, ER stress response, also called unfolded protein response (UPR), is an adaptive process that controls the
protein amount in the ER lumen and the downstream protein demand. In normal conditions, the role of ER stress is to
maintain ER homeostasis, restore ER function, and protect stressed cells from apoptosis, by coordinating gene expression,
protein synthesis, and accelerating protein degradation through several molecular pathways. However, prolonged ER
stress response plays a paradoxical role, which leads to cell damage, apoptosis, and concomitant tissue injuries. A number
of tissue alterations are involved with diabetes mellitus progress and its comorbidities via ER stress. However, certain
pharmacological agents affecting ER stress have been identified. In this review, we summarized the relationship between
ER stress and insulin resistance development. Moreover, we aim to explain how ER stress influences type 2 diabetes mellitus
(T2DM) development. In addition, we reviewed the literature on ER stress and UPR in three kinds of tissue injuries
induced by T2DM. Finally, a retrospective analysis of the effects of anti-diabetes medications on ER stress is presented.