Nicotinamide overload may play a role in the development of type 2 diabetes.
OBJECTIVE
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 H(2)O(2) 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 micromol/L vs 0.6 +/- 0.13 micromol/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 H(2)O(2) levels. Decrease in NAD/NADH ratio and increase in H(2)O(2) 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.


CONCLUSIONS
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.
Zhou
Shi-Sheng
SS
Institute of Basic Medical Sciences, Medical College, Dalian University, Dalian, Liaoning Province, China. zhouss@ymail.com
Li
Da
D
Sun
Wu-Ping
WP
Guo
Ming
M
Lun
Yong-Zhi
YZ
Zhou
Yi-Ming
YM
Xiao
Fu-Cheng
FC
Jing
Li-Xin
LX
Sun
Shen-Xia
SX
Zhang
Li-Bin
LB
Luo
Ning
N
Bian
Fu-Ning
FN
Zou
Wei
W
Dong
Lai-Bin
LB
Zhao
Zhi-Gang
ZG
Li
Sheng-Fan
SF
Gong
Xiao-Jie
XJ
Yu
Zeng-Guo
ZG
Sun
Chang-Bin
CB
Zheng
Cong-Long
CL
Jiang
Dong-Ju
DJ
Li
Zheng-Ning
ZN
D000328:Adult; D000368:Aged; D042931:Aldehyde Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009243:NAD / Q000378:metabolism; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012307:Risk Factors; D013542:Sweat / Q000737:chemistry; D055815:Young Adult
D001786:Blood Glucose; D007328:Insulin; D016877:Oxidants; D009243:NAD; D009536:Niacinamide; D006861:Hydrogen Peroxide; D042931:Aldehyde Oxidase; C024058:N(1)-methylnicotinamide