In rodent models of diet-induced obesity, a high dose of resveratrol (400 mg/kg/d) improves insulin sensitivity and lowers body weight [10
], which has increased the interest and the speculation about its potential use as an anti-diabetic agent in humans. However, applying a lower dose of resveratrol (~ 22.5 mg/kg/d) appeared insufficient to produce weight loss, although it still improved glucose tolerance [9
]. In fact, low doses of resveratrol are shown to prolong survival in obese mice while simultaneously increasing body weight [29
]. One observation that is made, is that animals supplemented with a high dose of resveratrol are capable of increasing their energy expenditure, based on their ability to increase their running distance or tolerate cold longer compared to their untreated controls. However, whether these observations underlie the reduction in body weight is not clear, as voluntary exercise is actually lower in the resveratrol-treated group and body temperature is not detectably changed under basal conditions [10
]. Nevertheless, recent work has shown that a one-year intervention with resveratrol at a dose of 200 mg/kg/d seems to cause an increase in basal metabolic rate and total daily energy expenditure in the non-human primate Microcebus murinus
]; indicating that resveratrol might have the potency to enhance energy expenditure thereby promoting weight loss.
In 2007 already, a cross-sectional study found that supplemental resveratrol is taken by 2/3 of people who routinely consume multiple dietary supplements, and this number may be increasing as studies describing resveratrol's health effects have reached the lay public through ample coverage in popular media. Because of the increasing public interest, and the favourable health effects in lower organisms, there is urgent need for studies examining the therapeutic potential of resveratrol in humans, especially since the prevalence of chronic metabolic diseases is reaching epidemic proportions worldwide.
To date, the number of published clinical trials that have examined the effect of resveratrol on insulin sensitivity are still limited and several trials are currently still ongoing (see Table for an overview of all published peer-reviewed clinical trials on resveratrol). However, none of the peer-reviewed human clinical trials have addressed the ability of resveratrol to serve as a weight loss compound. In 2009 a clinical study Elliott et al. [51
] reported for the first time the effect of resveratrol on type 2 diabetes patients at doses of 2.5 and 5 g/day for 28 days. The levels of fasting and postprandial glucose and insulin serum levels were statistically significantly decreased at the dose of 5g/day, but few experimental details were provided in that work. In 2011, Brasnyo et al. [52
] found that a four-week intervention with resveratrol in type 2 diabetic men significantly improved insulin sensitivity. Thus, supplementing trans-resveratrol twice daily at a dose of 5 mg decreased insulin resistance (computed by the homeostatic model assessment of insulin resistance HOMA-IR), lowered blood glucose levels and delayed the glucose peak following a standardized meal in type 2 diabetic men (n=10) compared with placebo (n=9) [52
]. The authors suggested that a decreased oxidative stress might underlie these effects, as significant reductions in 24 h urinary creatinine-normalized ortho-tyrosine concentrations and an increased Akt phosphorylation in blood platelets was observed after the fours weeks of supplementation. Ghamin et al. [53
] reported on the other hand that fasting glucose, insulin or HOMA-IR scores remained unchanged following a six-week supplementation of 40 mg resveratrol (in P. cuspidatum
extract) in healthy volunteers. In that respect it might be noteworthy to mention that also normal healthy mice on a chow-diet fail to improve their insulin sensitivity upon resveratrol supplementation [10
], arguing that resveratrol might only be effective under metabolic stress conditions such as obesity or diabetes. Recently, a small pilot study was carried out that showed the potential of resveratrol treatment to improve glucose tolerance, insulin sensitivity and vascular function [17
]. For this intervention the authors chose to study the effects of resveratrol in subjects with impaired glucose tolerance that have definite but not yet severe metabolic dysregulation, and therefore may be most amenable to intervention. After four weeks of resveratrol supplementation with a daily dose of 1, 1.5 or 2g, post meal plasma glucose was lowered in IGT subjects at doses between 1 and 2 g/day, whereas the insulin response remained unchanged [17
]. Furthermore, a trend towards an improved post meal endothelial function was reported.
Summary of peer reviewed published clinical trials*
We also investigated the metabolic effects of resveratrol in obese men [54
] and were able to support the notion that resveratrol might have a similar mechanism of action in obese humans as in high-fat fed animals. Supplementation with resveratrol for 30 days induced health effects that were comparable to the effects of calorie restriction. Resveratrol reduced sleeping and resting metabolic rate in the absence of body weight changes. Furthermore, skeletal muscle mitochondrial function and fat oxidative capacity improved and fasting plasma glucose and insulin values were decreased by resveratrol. Gene set enrichment analysis revealed that resveratrol activated similar pathways in humans compared to mice, as mitochondrial pathways related to ATP production and oxidative phosphorylation were upregulated and inflammatory pathways were downregulated. In accordance to the rodent data, we confirmed that resveratrol supplementation induced an increase in skeletal muscle SIRT1 protein levels. These results are especially encouraging since Rutanen et al. showed that low SIRT1 expression could contribute to the disturbance in energy balance, that is already present in offspring of type 2 diabetes, by reducing mitochondrial function [55
Though limited data is available on resveratrol's efficacy in chronic metabolic diseases in humans, the clinical trials that are available show much promise that resveratrol might be applied to improve general health status and prevent chronic disease in humans. However, further research is warranted to increase our understanding of the physiological responses of resveratrol before widespread use in humans can be promoted. Future research should aim to explore the relationship between dose – bioavailability- and efficacy and further define the pleiotrophic mechanisms of actions in humans. Furthermore, chronic studies are an absolute must, as it is still unclear if resveratrol supplementation on the longer term is beneficial for overall health status.