High-dose resveratrol supplementation in obese men: an investigator-initiated, randomized, placebo-controlled clinical trial of substrate metabolism, insulin sensitivity, and body composition

Abstract

Obesity, diabetes, hypertension, and hyperlipidemia constitute risk factors for morbidity and premature mortality. Based on animal and in vitro studies, resveratrol reverts these risk factors via stimulation of silent mating type information regulation 2 homolog 1 (SIRT1), but data in human subjects are scarce. The objective of this study was to examine the metabolic effects of high-dose resveratrol in obese human subjects. In a randomized, placebo-controlled, double-blinded, and parallel-group design, 24 obese but otherwise healthy men were randomly assigned to 4 weeks of resveratrol or placebo treatment. Extensive metabolic examinations including assessment of glucose turnover and insulin sensitivity (hyperinsulinemic euglycemic clamp) were performed before and after the treatment. Insulin sensitivity, the primary outcome measure, deteriorated insignificantly in both groups. Endogenous glucose production and the turnover and oxidation rates of glucose remained unchanged. Resveratrol supplementation also had no effect on blood pressure; resting energy expenditure; oxidation rates of lipid; ectopic or visceral fat content; or inflammatory and metabolic biomarkers. 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.

Trial registration: ClinicalTrials.gov NCT01150955.

Figures

FIG. 1.

Insulin sensitivity and glucose metabolism. Glucose metabolism was examined before and after 4 weeks of resveratrol or placebo supplementation. Black bars and black dots indicate placebo group (n = 12) and white bars and white dots indicate the resveratrol group (n = 12). Results are presented as group means ± SEM. Insulin sensitivity was assessed by a hyperinsulinemic euglycemic clamp. The participants were clamped at a blood glucose level of ∼5 mmol/L with an insulin infusion of 0.5 mU/kg/min. A and B: The GIR before and after intervention, respectively. P values reflect between-group differences assessed by two-way repeated-measures ANOVA. C: The corresponding whole-body insulin sensitivity, the M value, defined as the mean GIR during the last 30 min of the clamp. P value reflects the potential treatment effect analyzed by two-way repeated-measures ANOVA. D: Glucose Rd. E: EGP. F: Nonoxidative glucose disposal. *A statistically significant within-group effect of the insulin stimulation evaluated by a paired t test. Overall comparisons of potential treatment effects were performed by two-way repeated-measures ANOVA in the basal and clamp situations, respectively. NS, nonsignificant.

FIG. 2.

Blood pressure. Ambulatory blood pressure was measured automatically by a portable device every 20th minute over 24 h. Results are presented as box plots of the absolute changes from baseline after 4 weeks of placebo (n = 12) or resveratrol (n = 12) supplementation, respectively. The box boundaries indicate the 25th–75th percentile range, and error bars represent the 5th–95th percentiles. Solid and dotted lines represent median and mean, respectively. Resveratrol supplementation tends to increase both systolic and diastolic blood pressure; however, the elevations are not significant when compared with the placebo group by two-way repeated-measures ANOVA (systolic, P = 0.39; diastolic, P = 0.36).

FIG. 3.

Body composition. Absolute changes in essential body composition parameters after 4 weeks of placebo (n = 12) or resveratrol supplementation (n = 12). The box boundaries indicate the 25th–75th percentile range, and error bars represent the 5th–95th percentiles. Solid and dotted lines represent median and mean, respectively. A–D were assessed by whole-body dual-energy X-ray absorptiometry; E and F were quantified by MR imaging based on repetitive axial slices from the proximal border of the left kidney to the femur neck; nine were evaluable in each group. Two-way repeated-measures ANOVA revealed no statistically significant differences between groups.

FIG. 4.

Ectopic lipid. Relative changes in ectopic lipid deposition from baseline after 4 weeks of placebo or resveratrol supplementation, respectively. Results are generated by 1H-MR spectroscopy and raw data processing provides an estimate of the ratio of lipid to water (LWR) within the tissue. The box boundaries indicate the 25th–75th percentile range, and error bars represent the 5th–95th percentiles. Solid and dotted lines represent median and mean, respectively. Two-way repeated-measures ANOVA revealed no statistically significant differences between groups. A: Changes in hepatic lipid content; 11 were evaluable in each group. B: Changes in intramyocellular lipid (IMCL) content; 10 were evaluable in each group.

FIG. 5.

Gene expression and protein phosphorylation. Intracellular protein levels and relative mRNA expression in muscle (A–D) and adipose (E and F) tissue biopsies taken before and after 4 weeks' treatment with placebo (n = 12) or resveratrol (n = 12). Biopsies were taken before and during (20 min after initiation) a hyperinsulinemic euglycemic clamp. Black bars indicate the placebo group and white bars indicate the resveratrol group. Results are presented as group means ± SEM, and overall comparisons of potential treatment effects were performed by two-way repeated-measures ANOVA in the basal and clamp situations, respectively. A: Phosphorylation of the intracellular kinase AMP-activated protein kinase (AMPK) assessed by Western blot analysis in muscle tissue. B: Total acetylation of lysine residues assessed by Western blot analysis in muscle tissue. C: Relative GLUT4 mRNA expression in muscle tissue assessed by RT-PCR. D: Relative peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α) mRNA expression in muscle tissue assessed by RT-PCR. E: Relative tumor necrosis factor (TNF)-α mRNA expression in subcutaneous adipose tissue assessed by RT-PCR. F: Relative nuclear factor (NF)-κB mRNA expression in subcutaneous adipose tissue assessed by RT-PCR. *In C, we found an overall treatment effect in the clamp situation, and a post hoc test revealed a statistically significant (P < 0.05) decreased expression of GLUT4 in the resveratrol group.