Excess Nicotinamide Induces Reactive Oxygen Species Generation, Insulin Resistance, and Epigenetic Change in Rats and Humans

Abstract

The implementation of grain fortification with niacin, commonly in the form of nicotinamide, has significantly increased niacin per capita consumption in U.S. from 1930s. Nicotinamide is the precursor of NAD and NADP, which participate in many biological reactions. Therefore, nicotinamide homeostasis is vitally important for the body. This study is to investigate the effects of excess nicotinamide on ROS generation, insulin resistance, and epigenetic change, which are hallmarks of type 2 diabetes.

We found acute nicotinamide overload increased ROS generation, insulin resistance, and reduced muscle glycogen level in adult rats. Besides these effects, long-term nicotinamide overload led to oxidative stress in kidney and liver, increased their DNA damage, and decreased their global DNA methylation profile. We further demonstrated that decreasing nicotinamide degradation and excretion level was crucial for the ROS generation- and insulin resistance-inducing effects using an impaired skin detoxification rat model.

Using oral glucose tolerance test (OGTT), we observed that in healthy volunteers, nicotinamide addition induced higher levels of ROS generation and insulin resistance in the early phase, followed by hypoglycemia in the late phase. Compared to controls, diabetic patients showed a disturbed nicotinamide degradation pattern, characterized by higher plasma N¹-methylnicotinamide (NMN) levels and lower urinary degraded metabolite, N¹-methyl-2-pyridone-5-carboxamide (2-Py).

Mechanistically nicotinamide degradation process was associated with ROS generation; excess nicotinamide led to higher ROS generation causing kidney and liver damage. We also found that excess nicotinamide disturbed the monoamine neurotransmitters degradation and DNA methylation by competing for the biological methyl-donor, betaine in the body.

In summary, our results indicate that excess nicotinamide may play an important role in type 2 diabetes.