Regulation of Intestinal and Hepatic Lipoprotein Secretion by Resveratrol
Condition: Dyslipidaemia; Insulin Resistance
MeSH terms: Insulin Resistance; Dyslipidemias
Study type: Interventional
Phase: Phase 2

Summary: 
      Resveratrol, an ingredient of red wine and available in Canada in highly purified form as an
      over-the-counter health supplement, has been shown to have a number of health benefits. Data
      from in vitro and animal studies suggest that it has beneficial effects on insulin
      sensitivity and lipid lowering. The investigators are not aware, however, of any mechanistic
      studies that have examined the effect of highly purified resveratrol in vivo on lipoprotein
      metabolism in humans. Given the potential therapeutic benefit of resveratrol in correcting
      the metabolic abnormalities of insulin resistant individuals the investigators plan to
      examine the effects of resveratrol on intestinal and hepatic lipoprotein production in
      humans.
    

Detailed description: 
      Subjects will receive resveratrol (Transmax 1 x 500mg tablets bid for one week followed by 2
      x 500mg bid for the second week (Biotivia Longevity Biologicals, New York, NY, USA) or
      placebo and advised to start taking the tablets 14 days prior to the first lipoprotein
      kinetics study.

      For the lipoprotein kinetics study subjects will receive an infusion of stable isotope
      enriched leucine and a bolus of stable isotope enriched glycerol in order to measure the
      rates of fatty acid synthesis, apolipoprotein and triglyceride turnover respectively. This in
      vivo stable isotope enrichment methodology has been widely established and used by
      investigators around the world for more than 30 years to examine the metabolism of various
      metabolites in humans.

      On the first day of the 2 day admission to hospital for the lipoprotein kinetics study,
      following an overnight fast, at approximately noon on day 1 of the study the subject will be
      admitted to hospital and will have a 30ml fasting blood sample drawn for analysis of plasma
      glucose, total plasma cholesterol, LDL-cholesterol, HDL cholesterol, triglycerides (TG), free
      fatty acids (FFA), insulin, cytokines, stable isotope enrichment and a more detailed analysis
      of triglyceride rich lipoprotein (TRL) composition (lipid and apolipoprotein content). The
      subject will be allowed to eat regular meals during the day but will fast overnight after
      7pm.

      At 4am the subject will begin to ingest the first of 17 identical small hourly aliquots of a
      liquid formula called Great Shake Plus (Hormel), each hourly dose equivalent to 1/17th of
      their estimated daily caloric requirement calculated by the Harris-Benedict formula. Apart
      from the shake the subject will not eat until the end of the study at 7pm that night. This
      will provide a steady state fed state for the subsequent assessment of lipoprotein turnover
      kinetics. At 7am 2 iv's will be inserted into a superficial vein in each forearm, one for
      infusion and one for sampling.

      At 7 am (the investigators will refer to this time point as 0hr of the lipoprotein turnover
      study), the lipoprotein turnover study will begin. An iv bolus of deuterated-glycerol
      (d5-glycerol, 75 micromol/kg) will be administered, followed by a primed-constant infusion of
      deuterated leucine (L-[5,5,5-2H3]-leucine; d3-leucine, 98%, Cambridge Isotope Laboratories,
      Andover, MA, USA)(10 micromol/kg bolus followed by 10 micromol/kg/hr for 10 hours). Blood
      samples will be collected prior to and at regular time intervals for 10 hours after the iv
      bolus of d3-glycerol (for 13C-triglyceride palmitate enrichment to assess de novo
      lipogenesis) and start of the constant infusion of d3-leucine (for assessment of lipoprotein
      kinetics). Insulin sensitivity will be assessed by calculation of HOMA-IR.
    

Intervention name(s): Resveratrol
Intervention type(s): Drug
Intervention description(s): 500mg bid for one week followed by 1 gram bid for one week prior to lipoprotein study.
Intervention MeSH terms: Resveratrol
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: Dyslipidaemia; Insulin resistance; Type 2 Diabetes