Resveratrol Shows no Metabolic Effect in Healthy Obese Men

High-dose resveratrol supplementation had virtually no physiological effect on obese men participating in a small, 1-month study conducted in Denmark.

The findings were published online November 28 in Diabetes by Morton M. Poulsen, an MD/PhD student from the Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark, and colleagues.

The polyphenolic compound resveratrol, a component of grapes and wine as well as other plants, has garnered attention in recent years for its potential health benefits. In rodent studies, resveratrol has appeared to mimic the protective metabolic effects of calorie restriction, including improved glucose metabolism and reduced inflammation.

Human data have been limited, however. "The present study does not support the use of resveratrol in a human clinical setting, but before ultimately defining the role of resveratrol in human metabolism, additional studies are strongly required," Poulsen told Medscape Medical News.

A total of 26 obese but otherwise healthy men were enrolled in the randomized, placebo-controlled, double-blinded, and parallel-group design study; 24 completed 4 weeks of treatment with either resveratrol or placebo.

The study dose, 500 mg trans-resveratrol 3 times daily, was 10 times higher than that used in a previous randomized study by Timmers et al, which did find improved metabolic parameters among 11 healthy obese men.

"Intuitively this should improve our possibility of observing an effect, which is, however, not the case," Poulsen said.

At 4 weeks, no significant differences between the resveratrol and placebo groups were seen in the primary outcome measure (insulin sensitivity, as assessed by the hyperinsulinemic euglycemic clamp technique). Insulin levels increased insignificantly in both groups.

There was also no effect of resveratrol on hemoglobin A1c levels; total, high-density lipoprotein, or low-density lipoprotein cholesterol levels; triglycerides; inflammatory biomarkers; leptin; or liver function tests. Measures of energy expenditure did not differ between the groups, nor did measures of c-peptide, glucagon, cortisol, adiponectin, and free fatty acids.

Resveratrol slightly increased both systolic and diastolic blood pressures, but the difference with placebo was nonsignificant. Measures of body composition also did not differ between the groups, nor did measures of ectopic or visceral fat content, Poulsen and colleagues report.

"The lack of effect disagrees with persuasive data obtained from rodent models and raises doubt about the justification of resveratrol as a human nutritional supplement in metabolic disorders," Poulsen and colleagues write.

In addition, he told Medscape Medical News, the findings agree with another recently published study by Yoshino et al showing that 75 mg/day of resveratrol did not improve metabolic parameters in nonobese postmenopausal women with normal glucose tolerance.

The difference in outcome with the Timmers study is not clear, but may be in part because of study methods. "In comparison with Timmers et al, our study design, including the statistical analysis, is stronger and we have utilized superior state-of-the-art methods, including hyperinsulinemic euglycemic clamp and 24-hour ambulatory blood pressure measurements," Poulsen told Medscape Medical News.

Atherosclerosis Benefit?

Another recent human study, a double-blind, randomized, placebo-controlled clinical trial of 44 healthy adult participants, has shown potential benefit for resveratrol with regard to primary atherosclerosis prevention, however.

The participants in this trial were randomly assigned to take either a product containing 400 mg trans-resveratrol, 400 mg grape skin extract, and 100 mg quercetin or a cellulose placebo for 30 days. Plasma was drawn from the participants and incubated with cultured human coronary artery endothelial cells. The result was a significant reduction in the expression of genes associated with inflammation and atherosclerosis for resveratrol compared with placebo.

Those findings were published online October 24 in a letter to the editor of the International Journal of Cardiology by Beamon Agarwal, MD, from the Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, and colleagues.

According to Paulsen, the Agarwal study "demonstrates interesting findings in a novel experimental in vitro assay," but the results are not comparable to his findings. "In general, there is a great gap between in vitro experimental settings and human clinical investigations."

Dr. Agarwal's coinvestigator James M. Smoliga, DVM, PhD, told Medscape Medical News that a variety of study design differences could explain the conflicting results among all the trials. Although Timmers used 150 mg resveratrol/day in a crossover design, Yoshino used 75 mg/day and Poulsen used 500 mg 3 times per day.

"With the crossover design, it appears that Timmers evaluated differences between posttreatment values within an individual. This is important since bioavailability of resveratrol varies considerably from person to person and the response to resveratrol can potentially vary from person to person," said Dr. Smoliga, associate professor of physiology, Department of Physical Therapy, High Point University, North Carolina.

As for the Yoshino trial, "I was not surprised, as I personally do not think 75 mg alone is enough to make a considerable difference," Dr. Smoliga said.

He said that the Poulsen study dose was certainly high enough, but "[o]ne thought has been that the maximal concentration of resveratrol is not the only thing that matters — the rise and fall of resveratrol concentration may also be important. In other words, there may be an advantage to having high plasma levels of resveratrol followed by a decline."

With the Poulsen study's 3-times daily regimen, "plasma and tissues levels may have been maintained relatively steadily," Dr. Smoliga said. "If spikes in resveratrol concentration are necessary to achieve its beneficial effects, the 3 times per day protocol may not be optimal to get a response."

He also noted that in the study that he conducted with Dr. Agarwal and colleagues, the combination polyphenol product they used "could have had a synergistic effect and ultimately enhanced the resveratrol's bioavailability of the actual response."

"In any case, there is clearly a need for more high quality research," he said.

The Poulsen study was supported by grants from the Danish Agency for Science Technology and Innovation, the Novo Nordisk Foundation, Karen Elise Jensen Foundation, Toyota Foundation, Elvira and Rasmus Riisfort Foundation, Ejnar Danielsens Foundation, and AP Möller Maersk Foundation. The study is also part of the research program at the Long-term Investigation of Resveratrol in Obesity (LIRMOI) Research Center, which is supported by the Danish Council for Strategic Research. The authors and Dr. Smoliga have disclosed no relevant financial relationships.

Diabetes. Published online November 28, 2012. Abstract