Insulin-mediated signal transduction is positively correlated to
adiponectin,
adenosine monophosphate-activated
protein kinase (AMPK), and glucose-transporter-4 (GLUT4) but negatively to oxidative/inflammatory mediators such as
nuclear factor-kappaB, activating-
protein (AP)-1, AP-2, and
c-Jun-N-terminal-kinase. Although hemeoxygenase (HO) suppresses oxidative insults, its effects on
insulin-sensitizing agents like AMPK and GLUT4 remains unclear and were investigated using Goto-Kakizaki rats (GK), a nonobese
insulin-resistant type-2 diabetic model. HO was induced with
hemin or inhibited with
chromium mesoporphyrin (CrMP). The application of
hemin to GK rats evoked a 3-month
antidiabetic effect, whereas the HO-inhibitor, CrMP, exacerbated
hyperglycemia and nullified
insulin-signaling/
glucose metabolism. Interestingly, the
antidiabetic was accompanied by a paradoxical increase of
insulin alongside the potentiation of
insulin-sensitizing agents such as
adiponectin, AMPK, and GLUT4 in the gastrocnemius muscle. Furthermore,
hemin enhanced mediators/regulators of
insulin signaling like cGMP and cAMP and suppressed oxidative insults by up-regulating HO-1, HO activity,
superoxide dismutase,
catalase, and the total
antioxidant capacity in the gastrocnemius muscle. Accordingly, oxidative markers/mediators including
nuclear factor-kappaB,
AP-1, AP-2,
c-Jun-N-terminal-kinase, and
8-isoprostane were abated, whereas CrMP annulled the cytoprotective and
antidiabetic effects of
hemin. Correspondingly, ip
glucose tolerance,
insulin tolerance, and homeostasis model assessment
insulin resistance analyses revealed improved
glucose tolerance, reduced
insulin intolerance, enhanced
insulin sensitivity, and reduced
insulin resistance in
hemin-treated GK rats. In contrast, CrMP, abolished the
insulin-sensitizing effects and restored and/or exacerbated
insulin resistance. Our study unveils a 3-month enduring
antidiabetic effect of
hemin and unmasks the synergistic interaction among the HO system,
adiponectin, AMPK, and GLUT4 that could be explored to enhance
insulin signaling and improve
glucose metabolism in
insulin-resistant diabetes.