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However, the molecular mechanisms underlying Cd-induced endocrine\u2013metabolic disruption remain unclear. Using a multidisciplinary approach that combines in vivo, in vitro, and in silico analyses, we examined the effects of environmentally relevant Cd concentrations on lipids and glucose homeostasis, \u03b2-cell proliferation, insulin secretion, and the biofunctionality of insulin-Cd complex. Male Wistar rats were exposed orally to CdCl\u2082 (15 or 32 ppm) for three months. zoometric, glycemic, and lipid parameters were evaluated, along with markers of glucose-stimulated insulin secretion (GSIS), \u03b2-cell proliferation (Ki-67), and survival (Bcl-2). Crystallographic, spectroscopic (UV\u2013Vis, FTIR), and in silico analyses characterized the coordination chemistry of Zn\u00b2\u207a and Cd\u00b2\u207a within insulin complexes, and the biological activity of insulin-Cd was assessed in diabetic models. Cd exposure produced a dose-dependent increase in zoometric and biochemical parameters, accompanied by hyperinsulinemia and impaired \u03b2-cell function. Isolated islets showed exaggerated second-phase insulin release and increased Ki-67 with reduced Bcl-2 immunoreactivity, suggesting compensatory \u03b2-cell proliferation under subtoxic stress. Spectroscopic and theoretical analyses support the possibility that Cd\u00b2\u207a substitutes Zn\u00b2\u207a within insulin coordination sites, leading to structural perturbations. In vivo, insulin\u2013Cd conjugates exhibited diminished hypoglycemic efficacy despite elevated circulating insulin levels, indicating reduced bioactivity. In conclusion, Cd exposure at the experimental concentrations used in this study is associated with structural perturbations of insulin and markedly reduced biological activity, providing a plausible mechanism for Cd-induced metabolic dysfunction.<\/jats:p>","DOI":"10.1007\/s12011-026-05255-7","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T23:08:14Z","timestamp":1785280094000},"page":"8250-8266","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cadmium-Induced Structural Destabilization of the Insulin\u2013Zinc Complex Underlies the Paradox of Elevated but Dysfunctional Insulin"],"prefix":"10.1007","volume":"204","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4500-0648","authenticated-orcid":false,"given":"Diana","family":"Moroni-Gonz\u00e1lez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0545-8232","authenticated-orcid":false,"given":"Israel","family":"Quiroga-Montes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5536-458X","authenticated-orcid":false,"given":"Fabi\u00e1n","family":"Galindo-Ram\u00edrez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8891-0505","authenticated-orcid":false,"given":"Celso Enrique","family":"Cortes-Romero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0377-0943","authenticated-orcid":false,"given":"Eduardo","family":"Brambila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7940-6059","authenticated-orcid":false,"given":"Victor Enrique","family":"Sarmiento-Ortega","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5679-1671","authenticated-orcid":false,"given":"Samuel","family":"Trevi\u00f1o","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"5255_CR1","doi-asserted-by":"publisher","unstructured":"Moroni-Gonz\u00e1lez D, Sarmiento-Ortega VE, Diaz A et al (2023) Pancreatic Antioxidative Defense and Heat Shock Proteins Prevent Islet of Langerhans Cell Death After Chronic Oral Exposure to Cadmium LOAEL Dose. 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