In type-2 diabetes (T2D), postprandial and fasting hyperglycaemia are important predictors of cardiovascular diseases, however, few drugs are currently available to simultaneously suppress these conditions. Here, we report an enduring anti-diabetic effect of the heme oxygenase (HO) inducer, hemin, on Goto-Kakizaki rats (GK), a non-obese insulin-resistant T2D model. HO breaks down the heme-moiety generating antioxidants (biliverdin/bilirubin, ferritin) and carbon monoxide which stimulate insulin secretion. Hemin induces HO-1 to potentiate HO-activity and the HO-derived products. Chronically applied hemin (30 mg/kg i.p.) for a month reduced and maintained fasting glucose at physiological levels for 3 months. Before therapy, glucose levels were 9.3±0.3 mmol/L, n=14. At 1, 2 and 3 months post-therapy, we recorded 6.7±0.13, 5.9±0.2 and 7.2±0.2 mmol/L respectively. Hemin was also effective against postprandial hyperglycaemia (14.6±1.1 vs. 7.5±0.4 mmol/L, n=14, p<0.01), and the effect remained sustained for 3 months after therapy. The reduction of hyperglycaemia was accompanied by enhanced HO-1, HO-activity and cGMP of the soleus muscle, alongside increased plasma bilirubin, ferritin, SOD, total anti-oxidant capacity and insulin levels, whereas markers/mediators of oxidative stress like urinary-8-isoprostane and soleus muscle nitrotyrosine, NF-B, AP-1 and AP-2 were abated. Furthermore, inhibitors of insulin-signaling including soleus muscle glycogen-synthase-kinase-3 and c-Jun-N-terminal-kinase were reduced, while the insulin-sensitizing adipokine, adiponectin, alongside adenosine monophosphate-activated-protein-kinase were increased. Correspondingly, hemin improved glucose tolerance (IPGTT), suppressed insulin intolerance (IPITT), reduced insulin resistance and overturned the inability of insulin to enhance glucose-transporter-4 (GLUT4), a protein required for glucose uptake. Hemin also upregulated HO-1/HO-activity, cGMP and lowered glucose in euglycemic Sprague-Dawley control rats albeit less-intensely, suggesting greater selectivity of the HO system in diabetic conditions. In conclusion, reduced oxidative stress alongside the concomitant and paradoxical enhancement of insulin secretion and insulin-sensitizing pathways may account for the 3-month enduring anti-diabetic effect. The synergistic interaction between HO, adiponectin and GLUT4 may be explored against insulin-resistant diabetes.