The effects of trans-resveratrol on insulin resistance, inflammation, and microbiota in men with the metabolic syndrome: a pilot randomized, placebo controlled clinical trial

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 coactivates 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 MetS. Methods: A total of 28 obese men with the MetS were studied during a 35-day stay in the Rockefeller University Hospital metabolic unit. Subjects were randomized to receive RES 1 g orally twice daily or placebo while kept weight stable and consuming a western-style diet. At baseline, and after 30 days of RES or placebo administration, subjects underwent testing that included a euglycemic, hyperinsulinemic clamp, 2-h oral glucose tolerance test (GTT), resting energy expenditure, 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-min time point and the area under the curve for glucose concentration in the 2-h 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 were variable and did not explain the racial differences in glucose homeostasis. RES administration to Caucasian subjects leads to an increase in several taxa including Akkermansia muciniphila. Conclusions: RES 2 g administered orally to obese men with MetS 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 MetS 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.

The Role of Histone Acetylation and the Microbiome in Phytochemical Efficacy for Cardiovascular Diseases

“…Additionally, curcumin attenuated colon inflammation in this study but increased sirtuin expression to a lesser extent [114]. Of further interest, reseveratrol was shown to increase SCFA-producing microbiota in metabolically compromised men [115]. As SCFA HDAC inhibitors have been shown to attenuate cardiac remodeling and improve cardiac function [14], these data suggest that resveratrol protects the heart by a microbiome-epigenome-dependent mechanism.…”

“…As SCFA HDAC inhibitors have been shown to attenuate cardiac remodeling and improve cardiac function [14], these data suggest that resveratrol protects the heart by a microbiome-epigenome-dependent mechanism. However, resveratrol did not affect any clinical endpoint in men with metabolic syndrome, although it should be noted that the study length may have been too short to see any improvements [115].…”

At the Intersection of Gut Microbiome and Stroke: A Systematic Review of the Literature

“…Anti-diabetic and anti-inflammatory medications affect the gut microbiota. For instance, polyphenol resveratrol given to obese Caucasians improved glucose homeostasis and insulin resistance along with a reduction in microbial diversity and an increase in Akkersmansia muciniphila (16). Similar results were not observed in obese African Americans, Afro-Latinos, and African American/Asian; indicating that polyphenol resveratrol intervention may exhibit ethnicity-dependent effects on glucose metabolism.…”

Benefits and Implications of Resveratrol Supplementation on Microbiota Modulations: A Systematic Review of the Literature

“…The latest studies confirm the ability of RSV to interact with intestinal MB and derivatives of their metabolism, such as short-chain fatty acids and intraluminal lipids, playing an essential role in improving the clinical aspects of the metabolic syndrome [ 16 , 53 , 54 , 55 ]. In particular, the metabolic syndrome (MS) is a recurrent disease worldwide, characterized by hyperlipidemia, abdominal obesity, insulin resistance, and hypertension, with consequent development of systemic inflammatory diseases, diabetes, coronary heart disease, stroke, and cancer [ 56 , 57 , 58 ]. Studies show that the oral administration of RSV, activating SIRT-1, influences both glucose metabolism and lipid metabolism, inhibiting their accumulation.…”

“…Studies show that the oral administration of RSV, activating SIRT-1, influences both glucose metabolism and lipid metabolism, inhibiting their accumulation. RSV inhibits the process of the formation and accumulation of fat in the white adipose tissue, while, in glucose metabolism, it intervenes in several mechanisms [ 57 , 59 ]. Oral administration of RSV in humans improves insulin secretion and insulin resistance by protecting pancreatic β cells from oxidative stress, suppresses glucagon production after meals by improving insulin metabolism, and reduces fasting blood sugar and A1C hemoglobin [ 60 , 61 ].…”