We appreciate the interest of Méndez-del Villar et al. (1) in our experimental work with resveratrol (2). It is true that we used a relatively low dose of resveratrol (150 mg/day) in our study, and we could not agree more that indeed more human clinical trials are needed before it can be concluded whether resveratrol can be beneficial for the treatment or prevention of type 2 diabetes. In such future studies, the working mechanism of resveratrol should be further investigated as well. On the basis of a long series of preclinical and clinical studies, we examined whether resveratrol could improve glucose homeostasis via the improvement of mitochondrial function. In that respect, we have previously shown that the dose of 150 mg/day is sufficient to improve muscle mitochondrial function (3), a finding we also confirmed in our most recent study published in Diabetes Care (2). However, this increase in mitochondrial function did not yet result in improvements in glucose homeostasis. Although we cannot exclude that an even higher dose of resveratrol could increase mitochondrial function further, the 10% increase in muscle mitochondrial function that we observed is in the range of what can be expected in human nutritional intervention studies. Therefore, we do not think that the relatively low dose was the main reason for the lack of positive effects. It should be noted that the studies included in the meta-analysis by Liu et al. (4), including the study by Méndez-del Villar et al. (5), do not report on measures of muscle mitochondrial function, and it should also be considered that resveratrol may exert positive effects on glucose homeostasis via alternative mechanisms—for example, as an antioxidant—which may indeed require higher doses.
An alternative explanation for the fact that we did not find significant effects on insulin sensitivity could be found in the type of medication used by the patients with type 2 diabetes. From our study it became apparent that patients using a relatively high dose of the oral glucose-lowering drug metformin had significantly higher levels of dihydro-resveratrol, a metabolite of resveratrol, compared with patients using lower doses (2). This indicates that there could be an interaction between metformin and the metabolism of resveratrol, potentially affecting its effectiveness. Unfortunately, not many other studies have measured plasma resveratrol and dihydro-resveratrol values for comparison. Again, future studies are needed to unravel the working mechanisms of resveratrol, including the identification of resveratrol’s bioactive compound.
Finally, we do agree that longer studies are needed, as our short-term study may have been too short to allow effects of resveratrol on mitochondrial function to translate into improvements in insulin sensitivity.
In summary, we agree with Méndez-del Villar et al. (1) that more human clinical studies are needed. Preclinical studies on resveratrol have been very promising, and as long as optimal doses, duration, and working mechanisms remain unrevealed in humans, negative human clinical trials should not discourage us from future research.
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Duality of Interest. No potential conflicts of interest relevant to this article were reported.
