Fig. 4

Integrated stress response (ISR). The ISR signaling pathway initiates when distinct stressors activate at least one member of a family of four serine/threonine kinases—PERK, PKR, HRI, GCN2, and these activations will converge to induce phosphorylation of eIF2a on serine. At least two of the four serine/threonine kinases activated by distinct stressors—PKR and PERK—can downregulate the insulin signaling pathway through serine phosphorylation of insulin receptor substrates, attenuating insulin action. Specifically for COVID-19, fragments of viral RNA can activate PKR, which will induce IRS-1 serine phosphorylation and consequently insulin resistance