The Heme Oxygenase System Abates Hyperglycemia in Zucker Diabetic Fatty Rats by Potentiating Insulin-Sensitizing Pathways

Emerging evidence indicates that aldosterone causes oxidative stress by stimulating proinflammatory/oxidative mediators, including nuclear factor-κB, activating protein (AP-1), and c-Jun N-terminal kinase. Thus, in insulin-resistant type 2 diabetes (T2D), oxidative stress generated by hyperglycemia and aldosterone would potentiate the oxidative destruction of tissue and important regulators of glucose metabolism like adiponectin and insulin. Although heme oxygenase (HO)-1 is cytoprotective, its effects on T2D have not been fully characterized. Here we report an enduring antidiabetic effect of the HO inducer, hemin, on Zucker diabetic-fatty rat (ZDF), a model of insulin-resistant T2D. Chronically applied hemin to ZDF reduced and maintained significantly low fasting and postprandial hyperglycemia for 4 months after therapy. The antidiabetic effect was accompanied by enhanced HO activity, catalase, cyclic GMP, bilirubin, ferritin, total antioxidant capacity, and insulin. In contrast, reduced aldosterone alongside markers/mediators of oxidative stress, including 8-isoprostane, c-Jun N-terminal kinase, nuclear factor-κB, AP-1, and AP-2 were observed. Interestingly, in hemin-treated ZDF, inhibitory proteins of insulin-signaling, such as glycogen synthase kinase-3 and protein-tyrosine phosphastase-1B were reduced, whereas agents that promote insulin signaling including adiponectin, cAMP, AMP-activated protein kinase, aldolase-B, and glucose transporter-4 (GLUT4), were robustly increased. Correspondingly, hemin improved ip glucose tolerance, reduced insulin intolerance, and lowered insulin resistance (homeostasis model assessment of insulin resistance), and the inability of insulin to enhance GLUT4 was overturned. These results suggest that the suppression of hyperglycemia and aldosterone-induced oxidative stress alongside the potentiation of insulin-sensitizing pathways may account for the 4-month enduring antidiabetic effect. The synergistic interaction between the HO system, aldolase-B, adiponectin, AMP-activated protein kinase, and GLUT4 may be explored for novel strategies against postprandial/fasting hyperglycemia and insulin-resistant T2D.