Although resveratrol has widely been studied for its potential health benefits, little is known about its metabolic effects in humans. Our aims were to determine whether the polyphenol resveratrol improves insulin sensitivity in type 2 diabetic patients and to gain some insight into the mechanism of its action. After an initial general examination (including blood chemistry), nineteen patients enrolled in the 4-weeklong double-blind study were randomly assigned into two groups: a resveratrol group receiving oral 2 £ 5 mg resveratrol and a control group receiving placebo. Before and after the second and fourth weeks of the trial, insulin resistance/sensitivity, creatinine-normalised ortho-tyrosine level in urine samples (as a measure of oxidative stress), incretin levels and phosphorylated protein kinase B (pAkt):protein kinase B (Akt) ratio in platelets were assessed and statistically analysed. After the fourth week, resveratrol significantly decreased insulin resistance (homeostasis model of assessment for insulin resistance) and urinary ortho-tyrosine excretion, while it increased the pAkt:Akt ratio in platelets. On the other hand, it had no effect on parameters that relate to b-cell function (i.e. homeostasis model of assessment of b-cell function). The present study shows for the first time that resveratrol improves insulin sensitivity in humans, which might be due to a resveratrol-induced decrease in oxidative stress that leads to a more efficient insulin signalling via the Akt pathway.Key words: Resveratrol: Type 2 diabetes: Insulin sensitivity: Oxidative stress: Akt Despite the rather high average daily fat intake in France, compared with other European countries, epidemiological surveys document a relatively low rate of cardiovascular mortality. This phenomenon, which is often called the French paradox, is thought to be explained by a fairly high red wine consumption by the French (1,2) . Red wine is known to be rich in various polyphenolic compounds that might have a variety of health benefits. Among these polyphenols, the stilbene derivative resveratrol seems to be the most vigorously studied, which is probably due to the fact that it apparently affects a wide array of physiological and biochemical processes as shown in animal and cell culture studies (3) . On the other hand, human studies with conclusive results on resveratrol are regrettably lacking.Resveratrol is considered to have beneficial effects on the cardiovascular system, as it has been found to improve vasodilatation (4) , ischaemic preconditioning (5,6) , both of which seem to be the result of the activation of the endothelial NO synthase enzyme (7) , and to inhibit both platelet aggregation (3) and vascular smooth muscle cell proliferation (8) . In addition, resveratrol has also been demonstrated to show anti-inflammatory (9) and anti-tumour activities (3) , and it might even have considerable anti-ageing properties as it provokes changes in cell signalling that mimics those found upon energy restriction (3) .Oxidative stress, whi...

The difference between para-tyrosine levels of the groups is probably due to renal impairment, while there is indirect evidence for an increased tubular secretion or production of ortho-tyrosine in the kidney in diabetic patients with or without CKD.

Background/Aims: In type 1 diabetes (T1D), type 2 diabetes (T2D) and metabolic syndrome (MetS), the associated complex metabolomic changes in the involvement of carnitine metabolism in total carnitine ester level has already been documented; here we extended the investigations to the individual acylcarnitines. Methods: The fasting serum acylcarnitine concentrations were determined in 49 T1D, 38 T2D and 38 MetS patients and 40 controls by isotope dilution electrospray ionization tandem mass spectrometry. Results: The acylcarnitine profiles of the 3patient groups shared elements with the controls. Considerably higher levels of almost all short-chain acylcarnitines (p < 0.05) and lower levels of some long-chain acylcarnitines were detected in T2D and MetS patients. The amounts of C3 and C4 carnitine were higher and most of the medium-chain and long-chain acylcarnitine levels were lower (p < 0.05) in T1D and MetS patients than in the controls. In T1D and T2D, the levels of C3 and C4 acylcarnitines were markedly elevated and some long-chain acylcarnitines were lower than the controls (p < 0.05). Moreover, significantly lower concentrations of free- and total carnitine were observed in T1D patients (p < 0.05). Conclusions: Profound alterations were detected in acylcarnitine profiles in the 3 patient groups. Similarities in the patterns suggest different degrees of involvement of the same metabolic systems in a systems biology approach.

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