Original Article
Copyright ©2009 The WJG Press and Baishideng. All rights reserved.
World J Gastroenterol. Dec 7, 2009; 15(45): 5674-5684
Published online Dec 7, 2009. doi: 10.3748/wjg.15.5674
Nicotinamide overload may play a role in the development of type 2 diabetes
Shi-Sheng Zhou, Da Li, Wu-Ping Sun, Ming Guo, Yong-Zhi Lun, Yi-Ming Zhou, Fu-Cheng Xiao, Li-Xin Jing, Shen-Xia Sun, Li-Bin Zhang, Ning Luo, Fu-Ning Bian, Wei Zou, Lai-Bin Dong, Zhi-Gang Zhao, Sheng-Fan Li, Xiao-Jie Gong, Zeng-Guo Yu, Chang-Bin Sun, Cong-Long Zheng, Dong-Ju Jiang, Zheng-Ning Li
Shi-Sheng Zhou, Da Li, Wu-Ping Sun, Yong-Zhi Lun, Fu-Cheng Xiao, Li-Xin Jing, Shen-Xia Sun, Ning Luo, Fu-Ning Bian, Sheng-Fan Li, Xiao-Jie Gong, Zeng-Guo Yu, Chang-Bin Sun, Cong-Long Zheng, Institute of Basic Medical Sciences, Medical College, Dalian University, Dalian 116622, Liaoning Province, China
Ming Guo, Zheng-Ning Li, College of Environmental and Chemical Engineering, Dalian University, Dalian 116622, Liaoning Province, China
Yi-Ming Zhou, Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Okazaki 444-8787, Japan
Li-Bin Zhang, Department of Physiology, Xinxiang Medical College, Xinxiang 453003, Henan Province, China
Wei Zou, Department of Life Sciences, Liaoning Normal University, Dalian 116029, Liaoning Province, China
Lai-Bin Dong, Department of Neurology, PLA No. 91 Hospital, Jiaozuo 454003, Henan Province, China
Zhi-Gang Zhao, Dong-Ju Jiang, Department of Medicine, PLA No. 210 Hospital, Dalian 116021, Liaoning Province, China
Author contributions: Zhou SS was responsible for the study concept, design, direction and supervision, drafted the manuscript, and obtained funding; Li D, Sun WP, Lun YZ, Zhou YM, Xiao FC, Jing LX, Sun SX, Zhang LB, Luo N, Bian FN, Zou W, Gong XJ, Yu ZG, Sun CB and Zheng CL contributed to the program initiation, data acquisition and analysis/discussion, as well as writing and editing the manuscript; Guo M directed the HPLC separation and analysis; Dong LB, Zhao ZG, Li SF and Jiang DJ acquired the clinical cases and patient consent, and assisted in data collection; Li ZN synthesized the compounds.
Supported by National Natural Science Foundation of China, No. 30570665; the Foundation of Dalian Technology Bureau, No. 2008E13SF182; and the Foundation of Key Laboratory of Education Department of Liaoning Province, No. 2009S005
Correspondence to: Shi-Sheng Zhou, Professor, PhD, MD, Institute of Basic Medical Sciences, Medical College, Dalian University, Dalian 116622, Liaoning Province, China. zhouss@ymail.com
Telephone: +86-411-87402740 Fax: +86-411-87402053
Received: September 21, 2009
Revised: October 26, 2009
Accepted: November 3, 2009
Published online: December 7, 2009
Abstract

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 N1-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 N1-methylnicotinamide levels 5 h after a 100-mg nicotinamide load than the non-diabetic subjects (0.89 ± 0.13 μmol/L vs 0.6 ± 0.13 μmol/L, P < 0.001). Cumulative doses of nicotinamide (2 g/kg) significantly increased rat plasma N1-methylnicotinamide concentrations associated with severe insulin resistance, which was mimicked by N1-methylnicotinamide. Moreover, cumulative exposure to N1-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 N1-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 N1-methylnicotinamide clearance.

CONCLUSION: These findings suggest that nicotinamide overload, which induced an increase in plasma N1-methylnicotinamide, associated with oxidative stress and insulin resistance, plays a role in type 2 diabetes.

Keywords: Type 2 diabetes; Nicotinamide; N1-methylnicotinamide; Insulin resistance; Oxidative stress; Liver; Sweat glands