Resveratrol is a substance found in many plants, including grapes and red wine, which is widely used as a nutritional supplement. Studies in cells and lower animals show that resveratrol has many potential benefits, including prolonging lifespan, preventing cancer and heart disease and normalization of glucose metabolism. Although use of this agent shows great promise in the treatment and/or prevention of diabetes, there have been no studies reported to date in humans. As an initial step, this proposal is for a 6 week pilot study of resveratrol treatment in older adults with impaired glucose tolerance (IGT) in order to explore its effects on post-meal blood glucose metabolism. Preliminary studies will also be conducted to explore how resveratrol works by studying cellular function (in muscle samples obtained from study participants) and by testing resveratrol's effect on blood vessel function.

A. Introduction and Specific Aims Resveratrol (RSV), a plant-derived polyphenol and potential activator of the mammalian sirtuin, Sirt1, has demonstrated promising effects on insulin secretion, insulin sensitivity and glucose tolerance and has extended the lifespan of obese mice. RSV is in common use as a nutritional supplement, but formal studies in humans are limited and-in particular-the metabolic effects of RSV in humans have yet to be carefully tested. The convergence of a worldwide epidemic of diabetes combined with a marked increase in the proportion of the elderly underscore the need to develop new approaches to improve glucose intolerance. We therefore propose a study of RSV treatment in older subjects with impaired glucose tolerance (IGT) to determine if there is improvement in glucose tolerance and markers of insulin resistance, mitochondrial biogenesis and vascular function. This proposal builds on our findings in a recently-completed NIH P01 on cardiovascular disease markers in older adults with IGT. It is our hypothesis that RSV has the potential to exert important metabolic effects that can be directly and safely tested in human subjects. The growing body of pre-clinical evidence, as well as our own preliminary data, provide strong support for formal tests of RSV effects on several important metabolic parameters. These proposed studies constitute a critical step in investigating the therapeutic potential of RSV, as well as providing insight into relevant mechanisms.

Specific Aims: We propose a 6-week randomized, double-blind, placebo controlled cross-over study of RSV in older adults (age 50-80 years, n=38) with IGT, with the following aims:

Specific Aim 1: To assess the effects of RSV (2g/day) on mixed meal tolerance in subjects with age-related glucose intolerance. In our previous studies, we developed a standard mixed meal protocol to evaluate postprandial changes in glucose, insulin and lipids. We will apply this protocol to study a cohort of older adults with impaired glucose tolerance in a double-blind, placebo controlled cross-over study of RSV treatment. Metabolic outcomes will include post-meal glucose area under the curve (AUC), calculated estimates of insulin sensitivity and insulin secretion and circulating levels of free fatty acids and triglycerides. This study will be the first to document RSV effects on glucose intolerance in humans and will provide critical information needed to inform future clinical and mechanistic investigations. We hypothesize that treatment with RSV will result in improvement in mixed meal tolerance, via effects on insulin secretion, insulin action or both, in subjects with age-related glucose intolerance.

Specific Aim 2: To assess the effects of RSV on age-related decline in mitochondrial biogenesis. In animal models, RSV has been shown to enhance mitochondrial biogenesis, which may occur through activation of Sirt1, which is an important regulator of cellular energy metabolism via PGC-1α (peroxisome-proliferator-activated receptor-γ coactivator-1 alpha). We will assess this directly by measuring mitochondrial mRNA expression and DNA copy number in muscle obtained from participants after treatment with RSV compared with placebo. Studies of mitochondrial morphology and enzyme activity will be performed in collaboration with Dr. Sreekumaran Nair (Mayo Clinic), who is an expert in mitochondrial physiology. We hypothesize that treatment with RSV will result in improvement in mitochondrial number and function, which is a potential mechanism for improvement in insulin sensitivity that may occur with RSV treatment.

Specific Aim 3: To assess the effects of RSV on fasting and post-meal endothelial function. Since treatment with RSV has also been reported to have beneficial cardiovascular effects, including improved vascular reactivity, we will study in vivo endothelial function. We will use reactive hyperemia peripheral arterial tonometry to assess endothelial dependent vasodilation in study subjects before and after treatment with RSV, in both the fasting and postprandial state. Augmentation index, a measure of arterial stiffness will also be assessed. We hypothesize that chronic treatment with RSV will result in improvement in endothelial function through direct vascular effects, which may be mediated via enhanced nitric oxide availability, reduced oxidative stress and/or as a consequence of improvement in glucose metabolism.

Inclusion Criteria:

• impaired glucose tolerance

Exclusion Criteria:

• history of estrogen-dependent neoplasm
• use of certain drugs: high dose statins, warfarin, antiepileptics
• current treatment with anti-diabetes medications
• impaired liver or kidney function

During full 16 week study period