Pilot Study of Resveratrol in Older Adults With Impaired Glucose Tolerance
Condition: Impaired Glucose Tolerance
MeSH terms: Glucose Intolerance
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): resveratrol; Placebo
Intervention type(s): Dietary Supplement; Drug
Intervention description(s): resveratrol 500 mg capsules, 3 capsules (1500 mg) orally twice a day for 6 weeks; 3 placebo capsules orally twice a day for 6 weeks
Other intervention name(s): RevGenetics; X500 Resveratrol
Intervention MeSH terms: Resveratrol
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: resveratrol; glucose intolerance; insulin resistance; endothelial function