Dysregulated glucose homeostasis, oxidative stress, and chronic inflammation are causes of insulin resistance and pathological progression. During inflammation and oxidative stress, reactive oxygen and nitrogen species are generated and act as signaling molecules, e.g., for immune cell recruitment and activation. Moreover, reactive species interact with biomolecules and induce post-translational modifications, causing functional changes or altered immunogenicity, as known from the context of autoimmune disorders. Varying the reactive species in the micromilieu leads to different variants of oxidatively modified insulin (oxIns) that may alter cell recognition and cell-molecular signaling pathways. Mimicking a reactive species-rich inflammatory environment using cold physical gas plasma technology, we found different sensitivities to argon plasma-induced redox stress in murine immune cells, which were linked to Nrf2 signaling. Focusing on the stress-related Nrf2 signaling pathway and pro-inflammatory NF-κB response, we further used THP-1-NF-κB reporter monocytes and TK6 lymphoblast cell line models. Inflammation markers and cell growth-related signaling molecules were investigated after incubation with five differently oxidized insulin variants. Oxidized insulin was not toxic, but modulated gene expression of GLUT4, Nrf2, and HMOX1, and correlated with Akt and Erk expression for all oxIns variants. Furthermore, modulation of NF-κB signaling by oxIns was detected in THP-1-NF-κB cells, which correlated with cell size, MHC-II surface marker expression, IL-18 secretion, and Akt signaling. These data provide evidence of dedicated recognition of oxidized insulin by cells, which may modify insulin signaling and pathophysiology.