Examination of Endoplasmic Reticulum Stress, the Unfolded Protein Response and Autophagy in Iron Overload-Induced Insulin Resistance

Identification of new mechanisms mediating insulin sensitivity is important to allow validation of corresponding therapeutic targets. In this study, I first used a cellular model of skeletal muscle cell iron overload and found endoplasmic reticulum (ER) stress and insulin resistance occurred after iron treatment. Insulin sensitivity was assessed using cells engineered to express an Akt biosensor, based on nuclear Foxo localization, as well as western blotting for insulin signaling proteins. Use of salubrinal to elevate eIF2a phosphorylation and promote the unfolded protein response (UPR) attenuated iron-induced insulin resistance. Salubrinal induced autophagy flux and its beneficial effects on insulin sensitivity were not observed in autophagy-deficient cells generated by overexpressing a dominant-negative Atg5 mutant or via knockout of ATG7. This indicated the beneficial effect of salubrinal-induced UPR activation was autophagy-dependent. I translated these observations to an animal model of systemic iron overload-induced skeletal muscle insulin resistance. Administration of salubrinal as pre-treatment enhanced eIF2a phosphorylation and induced autophagy in skeletal muscle. This attenuated insulin resistance upon systemic iron administration. Together, my results show that salubrinal elicited an eIF2a-autophagy axis leading to improved skeletal muscle insulin sensitivity both in vitro and in mice.