Endoplasmic reticulum stress in insulin resistance and diabetes

The endoplasmic reticulum is the main intracellular Ca2+ store for Ca2+ release during cell signaling. There are different strategies to avoid ER Ca2+ depletion. Release channels utilize first Ca2+-bound to proteins and this minimizes the reduction of the free luminal [Ca2+]. However, if release channels stay open after exhaustion of Ca2+-bound to proteins, then the reduction of the free luminal ER [Ca2+] (via STIM proteins) activates Ca2+ entry at the plasma membrane to restore the ER Ca2+ load, which will work provided that SERCA pump is active. Nevertheless, there are several noxious conditions that result in decreased activity of the SERCA pump such as oxidative stress, inflammatory cytokines, and saturated fatty acids, among others. These conditions result in a deficient restoration of the ER [Ca2+] and lead to the ER stress response that should facilitate recovery of the ER. However, if the stressful condition persists then ER stress ends up triggering cell death and the ensuing degenerative process leads to diverse pathologies; particularly insulin resistance, diabetes and several of the complications associated with diabetes. This scenario suggests that limiting ER stress should decrease the incidence of diabetes and the mobility and mortality associated with this illness.