Figure 2.

β-cell dysfunction in diabetes. Excessive glucose levels lead to high insulin production in β-cells. Increased insulin synthesis promotes endoplasmic reticulum (ER) overload, unfolded protein response (UPR), and ER stress. Prolonged ER stress leads to apoptosis and IL-1β release through inflammasome activation. Local proinflammatory cytokines induce NFκB activation which promotes proapoptotic gene expression changes. These changes in gene expression favour Bax/Bak oligomerization and mitochondrial outer membrane permeabilization (MOMP), consequently leading to apoptosis. In addition, NFκB-dependent iNOS activation triggers ER stress and apoptosis as well. Lipotoxicity promoted by NEFAs also leads to β-cells ER stress via different mechanisms, including reactive oxygen and nitrogen species (ROS/RNS), calcium depletion (Ca²⁺), and ER to Golgi protein traffic impairment.