Melatonin ameliorates low-grade inflammation and oxidative stress in young Zucker diabetic fatty rats

The aim of this study was to investigate the effects of melatonin on low-grade inflammation and oxidative stress in young male Zucker diabetic fatty (ZDF) rats, an experimental model of metabolic syndrome and type 2 diabetes mellitus (T2DM). ZDF rats (n=30) and lean littermates (ZL) (n=30) were used. At 6wk of age, both lean and fatty animals were subdivided into three groups, each composed of 10 rats: naive (N), vehicle treated (V), and melatonin treated (M) (10mg/kg/day) for 6wk. Vehicle and melatonin were added to the drinking water. Pro-inflammatory state was evaluated by plasma levels of interleukin-6 (IL-6), tumor necrosis factor- (TNF-), and C-reactive protein (CRP). Also, oxidative stress was assessed by plasma lipid peroxidation (LPO), both basal and after Fe2+/H2O2 inducement. ZDF rats exhibited higher levels of IL-6 (112.4 +/- 1.5pg/mL), TNF- (11.0 +/- 0.1pg/mL) and CRP (828 +/- 16.0 mu g/mL) compared with lean rats (IL-6, 89.9 +/- 1.0, P<0.01; TNF-, 9.7 +/- 0.4, P<0.01; CRP, 508 +/- 21.5, P<0.001). Melatonin lowered IL-6 (10%, P<0.05), TNF- (10%, P<0.05), and CRP (21%, P<0.01). Basal and Fe2+/H2O2-induced LPO, expressed as malondialdehyde equivalents (mu mol/L), were higher in ZDF rats (basal, 3.2 +/- 0.1 versus 2.5 +/- 0.1 in ZL, P<0.01; Fe2+/H2O2-induced, 8.7 +/- 0.2 versus 5.5 +/- 0.3 in ZL; P<0.001). Melatonin improved basal LPO (15%, P<0.05) in ZDF rats, and Fe2+/H2O2- induced LPO in both ZL (15.2%, P<0.01) and ZDF rats (39%, P<0.001). These results demonstrated that oral melatonin administration ameliorates the pro-inflammatory state and oxidative stress, which underlie the development of insulin resistance and their consequences, metabolic syndrome, diabetes, and cardiovascular disease.