The main findings in the present study are (1) the lean GK had marked hyperglycemia with well-preserved endothelium function at early and later stages, while the obese OLETF showed mild hyperglycemia but significant endothelium dysfunction and hyperinsulinemia at early stage; (2) the GK showed elevated vessel eNOS and HO protein and OLETF decreased vessel eNOS; (3) insulin injection corrected hyperglycemia in GK but induced endothelium dysfunction and intima hyperplasia; (4) hyperglycemia/hyperosmolarity in vitro upregulated vasodilating eNOS/HO-1. Here, HMOX1 is linked to Hyperinsulinemia.