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Perturbed red blood cell (RBC) homeostasis and diminished nitric oxide (NO) availability contribute to endothelial dysfunction, a hallmark of cardiometabolic disorders; however, underlying pathophysiological mechanisms remain elusive. Here, we investigated RBC signaling pathways in a murine model of metabolic disease, focused on NO. T2DM\u2010RBCs had elevated levels of cytosolic NO, intracellular calcium ions (Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ), and reactive oxygen species. Acute stimulation with exogenous insulin had no effect on NO content. Whereas insulin exposure caused Ca\n                    <jats:sup>2+<\/jats:sup>\n                    entry into healthy RBCs, T2DM\u2010RBCs were insensitive. Using RBCs isolated from human blood, we confirmed that insulin had no effect on RBC\u2010NO, despite prompting Ca\n                    <jats:sup>2+<\/jats:sup>\n                    uptake. Ca\n                    <jats:sup>2+<\/jats:sup>\n                    uptake with insulin exposure was sensitive to inhibition of mechanosensitive ion channels, as well as Ca\n                    <jats:sup>2+<\/jats:sup>\n                    chelation. Furthermore, co\u2010incubation of RBCs with the piezo\u2010type mechanosensitive ion channel component 1 (Piezo1) channel agonist Yoda1 and insulin did not produce compounded Ca\n                    <jats:sup>2+<\/jats:sup>\n                    uptake, raising the possibility of crosstalk between insulin and Piezo1. The hyperinsulinemia associated with T2DM may exacerbate normal Piezo1\u2010dependent Ca\n                    <jats:sup>2+<\/jats:sup>\n                    uptake into RBCs, contributing to RBC dysfunction and circulatory complications in T2DM. The significance of RBC signaling in the pathophysiology of cardiometabolic disorders is still emerging. Individuals carrying mutations in the\n                    <jats:italic>PIEZO1<\/jats:italic>\n                    gene exhibit hematological aberrations and hereditary anemia, supporting the importance of Piezo1 in RBC homeostasis. Furthermore, a shift in RBC\u2013NO metabolism favoring nitrosative stress may contribute to circulatory complications observed in metabolic diseases such as T2DM. Collectively, the emerging relevance of RBC signaling pathways may provide novel avenues for targeted drug development.\n                  <\/jats:p>","DOI":"10.1111\/febs.70157","type":"journal-article","created":{"date-parts":[[2025,6,8]],"date-time":"2025-06-08T09:00:32Z","timestamp":1749373232000},"page":"5457-5474","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Insulin facilitates entry of calcium ions into human and murine erythrocytes via Piezo1: a newly identified mechanism with implications for type 2 diabetes"],"prefix":"10.1111","volume":"292","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2394-6547","authenticated-orcid":false,"given":"Lennart","family":"Kuck","sequence":"first","affiliation":[{"name":"Biorheology Research Laboratory Griffith University  Gold Coast Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tia 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