Cadmium-Induced Structural Destabilization of the Insulin–Zinc Complex Underlies the Paradox of Elevated but Dysfunctional Insulin

Abstract Chronic cadmium (Cd) exposure, even in environmental conditions, has been associated with metabolic disorders such as dyslipidemia, insulin resistance, and type 2 diabetes. However, the molecular mechanisms underlying Cd-induced endocrine–metabolic 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, β-cell proliferation, insulin secretion, and the biofunctionality of insulin-Cd complex. Male Wistar rats were exposed orally to CdCl₂ (15 or 32 ppm) for three months. zoometric, glycemic, and lipid parameters were evaluated, along with markers of glucose-stimulated insulin secretion (GSIS), β-cell proliferation (Ki-67), and survival (Bcl-2). Crystallographic, spectroscopic (UV–Vis, FTIR), and in silico analyses characterized the coordination chemistry of Zn²⁺ and Cd²⁺ 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 β-cell function. Isolated islets showed exaggerated second-phase insulin release and increased Ki-67 with reduced Bcl-2 immunoreactivity, suggesting compensatory β-cell proliferation under subtoxic stress. Spectroscopic and theoretical analyses support the possibility that Cd²⁺ substitutes Zn²⁺ within insulin coordination sites, leading to structural perturbations. In vivo, insulin–Cd 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.