Regulation of Intestinal and Hepatic Lipoprotein Secretion by Resveratrol

This study has been completed.
Sponsor:
Collaborator:
Canadian Institutes of Health Research (CIHR)
Information provided by (Responsible Party):
University Health Network, Toronto
ClinicalTrials.gov Identifier:
NCT01451918
First received: October 11, 2011
Last updated: May 5, 2014
Last verified: May 2012
  Purpose

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.


Condition Intervention Phase
Dyslipidaemia
Insulin Resistance
Drug: Resveratrol
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Regulation of Intestinal (and Hepatic) Lipoprotein Secretion by Resveratrol

Resource links provided by NLM:


Further study details as provided by University Health Network, Toronto:

Primary Outcome Measures:
  • Examine the effect of resveratrol on ApoB 100 and ApoB 48 production in humans [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
    10 hour lipoprotein turnover study as described above following 2 weeks treatment with resveratrol or placebo.


Secondary Outcome Measures:
  • Assess the change in insulin sensitivity with resveratrol treatment [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
    HOMA-IR calculated from fasting insulin and fasting glucose will be used to assess change in insulin sensitivity before and after 2 weeks of resveratrol treatment.


Enrollment: 8
Study Start Date: October 2011
Study Completion Date: September 2013
Primary Completion Date: September 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Resveratrol Drug: Resveratrol
500mg bid for one week followed by 1 gram bid for one week prior to lipoprotein study.
Placebo Comparator: Placebo Drug: Resveratrol
500mg bid for one week followed by 1 gram bid for one week prior to lipoprotein study.

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.

  Eligibility

Ages Eligible for Study:   23 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Men and women, aged 23 to 60 years
  2. Fasting plasma triglycerides between 2.0 and 5.0 mmol/l
  3. Body mass index 25 kg/m2 to 35 kg/m2
  4. Minimum body weight 64kg
  5. Hemoglobin above 130g/L.
  6. Research volunteers must be able to provide informed consent and be willing to comply with protocol requirements.
  7. HOMA-IR (a measure of insulin resistance calculated from fasting blood glucose and insulin) >4.0.

    .

Exclusion Criteria:

  1. Subject has a history of hepatitis/hepatic disease that has been active within the previous two years.
  2. Any significant active (over the past 12 months) disease of the gastrointestinal, pulmonary, neurological, renal (Cr > 1.5 mg/dL), genitourinary, hematological systems, or has severe uncontrolled treated or untreated hypertension (sitting diastolic BP > 90 or systolic >140) or proliferative retinopathy
  3. Any dehydration or excessive vomiting
  4. History of diabetes or 75g OGTT indicative of diabetes.
  5. Cancer or history of cancer
  6. Any history of a MI or clinically significant, active, cardiovascular history including a history of arrhythmia's or conduction delays on ECG, unstable angina, or decompensated heart failure.
  7. Any active medical illness
  8. Any laboratory values: AST > 2x ULN; ALT > 2x ULN TSH>5mU/l or <0.01 mU/l
  9. Any clinically relevant abnormal blood/urine screening test results that are outside of the normal reference range and are significant to the investigator will be excluded
  10. Any current hormonal disorder or history or hormonal disorders
  11. Any bleeding disorders or autoimmune conditions
  12. Any allergies to any of the ingredients in the study product or placebo ie: hypersensitivity to resveratrol, grapes, red wine, red wine polyphenols and microcrystalline microcellulose
  13. Current addiction to alcohol or substances of abuse as determined by the investigator.
  14. Mental incapacity, unwillingness or language barrier precluding adequate understanding or cooperation
  15. Taking any prescription or non-prescription medications at the time of the study
  16. Taking any natural health products during the course of the study
  17. Having donated blood three months prior to and three months post study procedures
  18. A pregnancy test will be performed 1 to 3 days prior to each study in all female subjects (visit #4, and visit #7 before taking study drug). Those who test positive for pregnancy will be excluded.
  19. If you are breast-feeding or lactating you will be excluded from the study.
  20. Women taking the oral contraceptive pill will be excluded from the study.
  21. All current smokers or those who have smoked more than 1 pack per day for 5 years or more.
  22. Those with ferritin levels below 50 ug/L will be excluded
  23. Study Participants who experience serious adverse event or who no longer satisfy the inclusion /exclusion criteria during the trial will be withdrawn
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01451918

Locations
Canada, Ontario
Toronto General Hospital
Toronto, Ontario, Canada
Sponsors and Collaborators
University Health Network, Toronto
Canadian Institutes of Health Research (CIHR)
Investigators
Principal Investigator: Gary Lewis, MD UHN Toronto
  More Information

No publications provided by University Health Network, Toronto

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: University Health Network, Toronto
ClinicalTrials.gov Identifier: NCT01451918     History of Changes
Other Study ID Numbers: RESV10-0537-A
Study First Received: October 11, 2011
Last Updated: May 5, 2014
Health Authority: Canada: Health Canada

Keywords provided by University Health Network, Toronto:
Dyslipidaemia
Insulin resistance
Type 2 Diabetes

Additional relevant MeSH terms:
Insulin Resistance
Dyslipidemias
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Lipid Metabolism Disorders
Resveratrol
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Inflammatory Agents
Therapeutic Uses
Antirheumatic Agents
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Enzyme Inhibitors
Platelet Aggregation Inhibitors
Hematologic Agents
Antimutagenic Agents
Anticarcinogenic Agents
Central Nervous System Agents

ClinicalTrials.gov processed this record on September 30, 2014