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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.
Full 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.
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Inclusion criteria
Men and women, aged 23 to 60 years
Fasting plasma triglycerides between 2.0 and 5.0 mmol/l
Body mass index 25 kg/m2 to 35 kg/m2
Minimum body weight 64kg
Hemoglobin above 130g/L.
Research volunteers must be able to provide informed consent and be willing to comply with protocol requirements.
HOMA-IR (a measure of insulin resistance calculated from fasting blood glucose and insulin) >4.0.
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Exclusion criteria
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Interventional model
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8 participants in 2 patient groups, including a placebo group
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Data sourced from clinicaltrials.gov
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