Figure 4.

Chronic hyperglycemia disrupts endoplasmic reticulum (ER) homeostasis. When disruption of homeostasis occurs within the ER, the ER initiates the adaptive ER-stress responses such as the unfolded protein response (UPR) and autophagy. Lysosomes engulf portions of damaged ER during micro ERphagy, whereas the autophagy machinery is involved in macro ERphagy. Activation of the adaptive stress responses alleviates stress and restores homeostasis. However, unresolvable UPR activation due to chronic hyperglycemia exhausts the ER stress response, impairs autophagy, and promotes apoptosis.