Previous studies have postulated the association between oxidative stress and Type 2 diabetes. Considering the long pre-diabetic period with IGR (impaired glucose regulation) and its high risk of developing diabetes, to test this hypothesis, we have investigated oxidative stress pathways and DNA damage in patients with IGR and newly diagnosed Type 2 diabetes. The study population consisted of 92 subjects with NGT (normal glucose tolerance), 78 patients with IGR and 113 patients with newly diagnosed diabetes. Plasma MDA (malondialdehyde) and TAC (total antioxidative capacity) status, erythrocyte GSH content and SOD (superoxide dismutase) activity were determined. A comet assay was employed to evaluate DNA damage. Compared with subjects with NGT, patients with IGR had reduced erythrocyte SOD activity. Patients with diabetes had a higher plasma MDA concentration, but a lower plasma TAC level and erythrocyte SOD activity, than the NGT group. Correlation analysis revealed a strong positive association between IR (insulin resistance) and MDA concentration, but negative correlations with TAC status and SOD activity. With respect to beta-cell function, a positive association with TAC status and an inverse correlation with GSH respectively, were observed. The comet assay revealed slight DNA damage in patients with IGR, which was increased in patients with diabetes. Significant correlations were observed between DNA damage and hyperglycaemia, IR and beta-cell dysfunction. In conclusion, the results of the present study suggest that hyperglycaemia in an IGR state caused the predominance of oxidative stress over antioxidative defence systems, leading to oxidative DNA damage, which possibly contributed to pancreatic beta-cell dysfunction, IR and more pronounced hyperglycaemia. This vicious circle finally induced the deterioration to diabetes.

Short-term diabetes caused hyperglycemia and intensified oxidative stress in renal mitochondrial demonstrated by higher MDA and lower GSH levels than control group, accompanied by increased mRNA expression and activity of HO-1 and Mn-SOD, and augmented GSH-Px activity. Low dose of MG administration ameliorated hyperglycemia, inhibited HO-1 and Mn-SOD mRNA expression and reduced HO-1, Mn-SOD, GSH-Px activities. Diabetic mice did not demonstrate early symptoms of diabetic nephropathy until 8th week, characterized by hyperglycemia, hyperlipidemia, and renal damage. A progressive increment in MDA level and decrease in GSH level, as well as reduced mRNA expression and activity of Mn-SOD and HO-1 in the kidney were observed. Low dose of MG attenuated diabetic nephropa- thy symptoms partially, inhibited lipid peroxidation, up-regulated HO-1 and Mn-SOD mRNA expression, and increased HO-1 activity. Conclusions The study confirmed the involvement of oxidative stress in the development of diabetes mediated by the pro- and antioxidant role of HO-1, and pointed to the possible anti-oxidative mechanism of the anti-diabetic and nephroprotective action of MG.

Momordica grosvenori (MG), a traditional medicinal herb in China used as a substitute sugar for obese and diabetic patients, exhibited an enhancement of immunity. Heme oxygenase-1 (HO-1) is among the acute phase proteins that play an important role in the inflammatory process and have antiinflammatory activities with their antioxidant properties. The hypothesis that MG could modulate an imbalance of the cellular immune system and prevent the progression of diabetes mellitus, via induction of HO-1 protein expression was investigated. Diabetes was induced in male Balb/c mice by intraperitoneal injection of alloxan (200 mg/kg). The mice were randomly assigned to non-diabetic and diabetic groups, and further subdivided according to their treatments: control (distilled water), low dose MG (150 mg/kg) and high dose MG (300 mg/kg), which were administered by gavage in 24 h cycles over a 30 day period. MG administration effectively regulated the immune imbalance in diabetic mice, principally by upregulating the CD4(+) T lymphocyte subsets, and remodeling the intracellular cytokine profiles (reducing the expression of pro-inflammatory Th1 cytokines towards a beneficial Th2 pattern), ascribed to its induction and upregulation of HO-1. In conclusion, MG exhibited antidiabetic effects and may be used as a new natural drug for the treatment of diabetes.