Jeanne M. Walker, Patricia Eckardt, Jose O. Aleman, Joel Correa da Rosa, Yupu Liang, Tadasu Iizumi, Stephane Etheve, Martin J. Blaser, Jan L. Breslow, Peter R. Holt

Walker et al., J Clin Transl Res 2018; 4(2): 4

Published online: December 7, 2018

Abstract

Background and Aim: The metabolic syndrome (MetS) is a pathological condition comprised of abdominal obesity, insulin resistance, hypertension and hyperlipidemia. It has become a major threat globally, resulting in rapidly increasing rates of diabetes, coronary heart disease and stroke. The polyphenol resveratrol (RES) is believed to improve glucose homeostasis and insulin resistance by activating sirtuin, which acetylates and co-activates downstream targets and affects glucose and lipid homeostasis in the liver, insulin secretion in the pancreas, and glucose uptake in skeletal muscle. We studied the effects of RES on insulin resistance, glucose homeostasis and concomitant effects on adipose tissue metabolism and fecal microbiota in insulin resistant subjects with the metabolic syndrome. 

Methods: Twenty-eight obese men with the metabolic syndrome were studied during a 35-day stay in the Rockefeller University Hospital metabolic unit. Subjects were randomized to receive resveratrol 1 gram orally twice daily or placebo, while kept weight stable and consuming a Western style diet. At baseline, and after 30 days of resveratrol or placebo administration, subjects underwent testing that included a euglycemic, hyperinsulinemic clamp, 2- hour oral glucose tolerance test, resting energy expenditure (REE), daily blood pressure monitoring, abdominal adipose tissue biopsy, and fecal and blood collections. 

Results: RES induced no changes in insulin resistance, but reduced the 120-minute time point and the area under the curve for glucose concentration in the two-hour glucose tolerance test (GTT). In post hoc analysis, Caucasian subjects showed a significant improvement in insulin sensitivity and glucose homeostasis after GTT, whereas non-Caucasians showed no similar effects. Levels of fasting plasma RES and its primary metabolite dihydroresveratrol (DHR) were variable, and did not explain the racial differences in glucose homeostasis. RES administration to Caucasian subjects lead to an increase in several taxa including Akkermansia mucinophila. 

Conclusions: Resveratrol 2 grams administered orally to obese men with metabolic syndrome and insulin resistance marginally altered glucose homeostasis. However, in a small group of Caucasians, insulin resistance and glucose homeostasis improved. No concomitant changes in adipose tissue metabolism occurred, but fecal microbiota showed RES-induced changes. 

Relevance for patients: The metabolic syndrome increases the risk of diabetes, heart disease and stroke. A major component of the syndrome is insulin resistance, resulting in systemic inflammation and hyperinsulinemia. The primary treatment consists of lifestyle changes, improved diet and increased physical activity. This is often unsuccessful. In this study, RES was well tolerated. In Caucasian men it significantly improved insulin sensitivity and glucose homeostasis. Similar results were found in studies that consisted exclusively of Caucasian men. However, RES presents a novel addition to the current treatment of the MetS and its sequelae.

DOI: http://dx.doi.org/10.18053/jctres.04.201802.004

Author affiliation

1 The Rockefeller University Hospital, Rockefeller University, New York, NY, United States
2 Laboratory of Biochemical Genetics and Metabolism, Rockefeller University, New York, NY, United States3 New York University School of Medicine, Department of Medicine, New York, NY, United States4 DSM Nutritional Products LTD, Kaiseraugst, Switzerland

*Corresponding author:

Jeanne M. Walker
The Rockefeller University Hospital, 1230 York Avenue, Box 317, New York, N.Y. 10065. United States
Tel. +1 212-327-7270
Email: walkerj@rockefeller.edu 

Handling editor:

Michal Heger
Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

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