Nicotinamide overload may play a role in the development of type 2 diabetes

AIM: To investigate whether nicotinamide overload plays a role in type 2 diabetes. METHODS: Nicotinamide metabolic patterns of 14 diabetic and 14 non-diabetic subjects were compared using HPLC. Cumulative effects of nicotinamide and N-1-methylnicotinamide on glucose metabolism, plasma H2O2 levels and tissue nicotinamide adenine dinucleotide (NAD) contents of adult Sprague-Dawley rats were observed. The role of human sweat glands and rat skin in nicotinamide metabolism was investigated using sauna and burn injury, respectively. RESULTS: Diabetic subjects had significantly higher plasma N-1-methylnicotinamide levels 5 h after a 100-mg nicotinamide load than the non-diabetic subjects (0.89 +/- 0.13 mu mol/L vs 0.6 +/- 0.13 mu mol/L, P < 0.001). Cumulative doses of nicotinamide (2 g/kg) significantly increased rat plasma N-1-methylnicotinamide concentrations associated with severe insulin resistance, which was mimicked by N-1-methylnicotinamide. Moreover, cumulative exposure to N-1-methylnicotinamide (2 g/kg) markedly reduced rat muscle and liver NAD contents and erythrocyte NAD/NADH ratio, and increased plasma H2O2 levels. Decrease in NAD/NADH ratio and increase in H2O2 generation were also observed in human erythrocytes after exposure to N-1-methylnicotinamide in vitro. Sweating eliminated excessive nicotinamide (5.3-fold increase in sweat nicotinamide concentration 1 h after a 100-mg nicotinamide load). Skin damage or aldehyde oxidase inhibition with tamoxifen or olanzapine, both being notorious for impairing glucose tolerance, delayed N-1-methylnicotinamide clearance. CONCLUSION: These findings suggest that nicotinamide overload, which induced an increase in plasma N-1-methylnicotinamide, associated with oxidative stress and insulin resistance, plays a role in type 2 diabetes. (C) 2009 The WIG Press and Baishideng. All rights reserved.