Submitted on September 22, 2008
Revised on December 9, 2008
Accepted on January 24, 2009
The heme oxygenase system enhances insulin sensitivity and glucose metabolism in streptozotocin-induced diabetes
Joseph Fomusi Ndisang1* and Ashok Jadhav2
1 University of Saskatchewan College of Medicine
2 University of Saskatchwan College of Medicine
* To whom correspondence should be addressed. E-mail: jon056{at}mail.usask.ca.
Hyperglycaemia-induced oxidative stress is a common phenomenon in diabetes. Since oxidative stress depletes adiponectin and insulin levels, we investigated whether an upregulated heme oxygenase (HO) system would attenuate the oxidative destruction of adiponectin/insulin, and improve insulin sensitivity and glucose metabolism in streptozotocin (STZ)-induced type-1 diabetes. HO was upregulated with hemin (15 mg/kg i.p.) or inhibited with chromium mesoporphyrin (CrMP, 4 µmol/kg i.p.). Administering hemin to STZ-diabetic rats reduced hyperglycaemia and improved glucose metabolism whereas, the HO inhibitor, CrMP annulled the anti-diabetic effects and/or exacerbated fasting/postprandial hyperglycaemia. Interestingly, the anti-diabetic effects of hemin lasted for 2 months after termination of therapy, and were accompanied by enhanced HO-1 and HO activity of the soleus muscle, alongside the potentiation of plasma anti-oxidants like bilirubin, ferritin and superoxide dismutase, with corresponding elevation of the total anti-oxidant-capacity. Importantly, hemin abated c-Jun-N-terminal-kinase (JNK), a substance known to inhibit insulin biosynthesis, and suppressed markers/mediators of oxidative stress including 8-isoprostane, nuclear-factor-kappaB (NF-
B), activating-protein (AP-1) and AP-2 of the soleus muscle. Furthermore, hemin therapy significantly attenuated pancreatic histopathological lesions including acinar-cell necrosis, interstitial edema, vacuolization, fibrosis and mononuclear cell-infiltration. Correspondingly, hemin increased plasma insulin, and potentiated agents implicated in insulin-sensitization and insulin-signaling such as adiponectin, adenosine monophosphate-activated protein kinase (AMPK), cAMP, cGMP, glucose-transporter-4 (GLUT4), a protein required for glucose uptake. These were accompanied by improved glucose tolerance (IPGTT), decreased insulin intolerance (IPITT), and reduced insulin resistance (HOMA-IR index), whereas CrMP nullified the hemin-dependent anti-diabetic and insulin-sensitizing effects. In conclusion, by concomitantly enhancing insulin and paradoxically potentiating insulin sensitivity, this study unveils a novel, unique and long-lasting anti-diabetic characteristic of upregulating HO with hemin that could be explored against insulin-resistant and insulin-dependent diabetes.
