Recent clinical reports indicate that
impaired glucose tolerance is a common phenomenon in primary
aldosteronism.
Aldosterone stimulates
NF-kappaB and activating protein-1 (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 10 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.
Hemin therapy lowered BP and 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 and
insulin tolerance, 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
glucose and
insulin tolerance. Interestingly, the enhanced
insulin sensitization in
hemin-treated animals was accompanied by reduced urinary/gastrocnemius muscle 8-iso-prostaglandin F(2alpha) (8-isoprostane), inflammatory/oxidative
transcription factors like
NF-kappaB,
AP-1, JNK, and
heme content, whereas HO-1, HO-activity, cGMP, and plasma/gastrocnemius muscle
antioxidants including
bilirubin,
ferritin, SOD,
catalase, and the total
antioxidant 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 and cardiovascular complications in
aldosteronism.