Grape Polyphenols Prevent Fructose-Induced Oxidative Stress and Insulin Resistance in First-Degree Relatives of Type 2 Diabetic Patients

OBJECTIVE

To assess the clinical efficacy of nutritional amounts of grape polyphenols (PPs) in counteracting the metabolic alterations of high-fructose diet, including oxidative stress and insulin resistance (IR), in healthy volunteers with high metabolic risk.

RESEARCH DESIGN AND METHODS

Thirty-eight healthy overweight/obese first-degree relatives of type 2 diabetic patients (18 men and 20 women) were randomized in a double-blind controlled trial between a grape PP (2 g/day) and a placebo (PCB) group. Subjects were investigated at baseline and after 8 and 9 weeks of supplementation, the last 6 days of which they all received 3 g/kg fat-free mass/day of fructose. The primary end point was the protective effect of grape PPs on fructose-induced IR.

RESULTS

In the PCB group, fructose induced 1) a 20% decrease in hepatic insulin sensitivity index (P < 0.05) and an 11% decrease in glucose infusion rate (P < 0.05) as evaluated during a two-step hyperinsulinemic-euglycemic clamp, 2) an increase in systemic (urinary F2-isoprostanes) and muscle (thiobarbituric acid–reactive substances and protein carbonylation) oxidative stress (P < 0.05), and 3) a downregulation of mitochondrial genes and decreased mitochondrial respiration (P < 0.05). All the deleterious effects of fructose were fully blunted by grape PP supplementation. Antioxidative defenses, inflammatory markers, and main adipokines were affected neither by fructose nor by grape PPs.

CONCLUSIONS

A natural mixture of grape PPs at nutritional doses efficiently prevents fructose-induced oxidative stress and IR. The current interest in grape PP ingredients and products by the global food and nutrition industries could well make them a stepping-stone of preventive nutrition.The Western diet, dominated by ultra-processed products rich in saturated fats and sugar, including high-fructose corn syrup, and poor in micronutrients (1), is a major contributor to the worldwide “diabesity” epidemic. In addition to contributing to calorie overconsumption, the unique metabolism of fructose (2) and its marked effect on systemic oxidative stress (3) could give it a pivotal role in the pathophysiology of insulin resistance (IR) and the metabolic syndrome (4).The “French Paradox,” defined as a low incidence of coronary heart disease despite consumption of a diet rich in saturated fat (5), has stimulated interest in investigating whether grape polyphenols (PPs) may offer antioxidant-consequential health benefits (6–8) including improved insulin sensitivity (9), although this effect remains debated (10). If this outcome were to be confirmed in humans, then supplementation of highly processed foods with grape PPs may prove to be a promising strategy to stem the tide of chronic metabolic diseases, which, furthermore, would be quite easy to implement, since PPs are currently marketed in the form of dyes and tannins that can be used safely in relatively large amounts in sugary foods (11).We thus designed a randomized double-blinded controlled study to assess the clinical efficacy of nutritional amounts of grape PPs in counteracting the metabolic effects of high-fructose diet (HFrD) to substantiate the hypothesis that by neutralizing oxidative stress, grape PPs can prevent fructose-induced IR.