Recent clinical reports indicate that impaired glucose tolerance is a common phenomenon in primary aldosteronism. Aldosterone stimulates nuclear-factor kappa-B (NF-B) and activating-protein (AP-1) to cause oxidative injury. Elevated oxidative stress impairs insulin-signaling. We recently showed that the heme oxygenase (HO) system lowers blood pressure (BP) in deoxycorticosterone-acetate (DOCA-salt) hypertension, a model of primary aldosteronism. However, the effect of the HO system on insulin sensitivity in this model remains largely unclear. Here we report the effects of the HO-inducer (hemin) and the HO-blocker [chromium mesoporphyrin (CrMP)] on insulin sensitivity/glucose metabolism. Our experimental design included the following groups: (A) controls [(i) surgery-free or normal Sprague-Dawley (SD), (ii) uninephrectomized (UnX)-Sham, (iii) UnX-salt (0.9%NaCl+0.2%KCl) and (iv) UnX-DOCA]; (B) DOCA-salt; (C) hemin+DOCA-salt; (D) hemin+CrMP+DOCA-salt; (E) CrMP+DOCA-salt, (F) vehicle-treated rats and (G) normal-SD+hemin. DOCA-salt-hypertensive rats were normoglycemic. Hemin therapy lowered BP, increased plasma insulin and the insulin-sensitizing protein, adiponectin, with slight but significant reduction of glycemia, while CrMP abolished the hemin effects. Furthermore, hemin improved intraperitoneal glucose (IPGTT) and insulin tolerance (IPITT), suggesting that although DOCA-salt-hypertensive rats were normoglycemic, insulin-signaling may be impaired. In contrast, the HO-inhibitor, CrMP, aggravated insulin resistance and exacerbated IPGTT and IPITT. Interestingly, the enhanced insulin-sensitization in hemin-treated animals was accompanied by reduced urinary/gastrocnemius muscle 8-isoprostane, inflammatory/oxidative transcription factors like NF-B, AP-1, c-Jun-NH2-terminal kinase and heme content, whereas HO-1, HO-activity, cGMP and plasma/gastrocnemius muscle anti-oxidants including bilirubin, ferritin, superoxide dismutase, catalase and the total anti-oxidant capacity were increased. Similarly, hemin enhanced pancreatic HO, cGMP and cAMP, but suppressed 8-isoprostane and attenuated pancreatic histopathological lesions including fibrosis, interstitial edema, acinar-cell necrosis, vacuolization and mononuclear cell-infiltration, with corresponding improvement of insulin production. Our results suggest that impaired insulin-signaling may be a forerunner to hyperglycemia in aldosteronism. By preserving pancreatic morphology, potentiating insulin-signaling and lowering BP, the HO-system may prevent metabolic/cardiovascular complications in aldosteronism.