Making the most
of niacin treatment

Published April 03 2017

A ball-and-stick model of niacin

Niacin, better known as vitamin B3, acutely lowers plasma levels of free fatty acids, which helps to deter insulin resistance. However, tolerance to niacin is known to develop over time and can cause FFA levels go back up to, or even become higher than, pretreatment levels. Long-term use of niacin also is associated with worsening of glycemic control, casting doubt on the value of the niacin treatment. In a recent study published in the Journal of Lipid Research, a team led by Tobias Kroon at the Swedish University of Agricultural Sciences and AstraZeneca in Sweden explored strategies to develop a niacin-dosing regimen that would maximize metabolic control and minimize tolerance to niacin in a rat model of Type 2 diabetes.

Niacin is known to lower plasma FFA levels by functioning as an agonist to G-protein–coupled receptors that regulate lipolysis. In diabetics, high amounts of FFA, triglycerides and glucose logjam into the blood after a meal and overwhelm the insulin machinery, leading to insulin resistance. Kroon’s team wondered how niacin could be made to work most efficiently to lower these high amounts of FFA and glucose in blood.

To find out, Kroon and colleagues conducted a two-part study. The first part examined the effects of a sudden or gradual withdrawal of niacin treatment on metabolism. The second part used the better withdrawal strategy alongside feeding or fasting periods to identify the most synergistic treatment regimen.

For the first part, the investigators delivered niacin via subcutaneous implants to the rats for 12 hours. They gave half of the animals an infusion of glucose to simulate a meal. The other half didn’t receive any glucose. At the 13th hour, they either abruptly stopped the niacin treatment or gradually stepped it down until completely terminating it at the 16th hour.

The investigators analyzed the metabolic responses by measuring plasma levels of FFA, glucose, insulin and triglycerides. As the team had hypothesized, plasma FFA rebounds were lowest among animals that experienced a gradual termination of niacin treatment during glucose infusion. Plasma insulin levels showed the same trend. They concluded that niacin treatment should be terminated gradually while the animals are in the fed state.

For the second part of the study, the investigators treated two sets of animals with niacin for five days — one in the feeding phase, the other in the fasting phase — followed by gradual termination of the treatment. A set of control animals received saline treatment. The investigators found that the plasma FFA and triglyceride levels as well as triglycerides in the heart and liver were lowest among animals that experienced treatment during the feeding phase. Glucose control also improved markedly in those animals. The master regulatory genes responsible for de novo lipogenesis were downregulated in the liver of these animals.

While the exact reason behind this phenomenon is unknown, the investigators believe it has something to do with the fact that reduced FFA supply resulting from niacin treatment provided much-needed insulin sensitivity during feeding, when there is an influx of dietary carbohydrate in the system.

“The main challenge (with niacin treatment) that we overcame in our work was finding this magic right way,” says Kroon. At the moment, niacin is prescribed to be taken at bedtime, which, for most people, is the fasting phase. “The data raise the question of whether alternative dosing schedules in humans might improve the current clinical use of niacin,” explains Kroon, although he cautions, “The ultimate proof of these ideas will require future studies in people with diabetes.”

Sapeck Agrawal Sapeck Agrawal is a science writer.