Vitamin E Pharmacokinetics and Biomarkers in Normal and Obese Women
Condition: Diabetes; Fatty Liver; Obesity; Healthy Volunteers
MeSH terms: Fatty Liver
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

        -  Vitamin E is an antioxidant that reduces the damaging effects of oxygen in the body.
           Most American men (90%) and women (96%) do not get enough vitamin E from their diets;
           however, the amount of vitamin E needed by the body has been studied only in men, not
           women. In addition, it is unknown whether another antioxidant, vitamin C, helps vitamin
           E in protecting the body. Because vitamin E is a fat-soluble vitamin, how much body fat
           a person has could affect the amount of vitamin E needed for protection.

      Objectives: This study has three arms to examine vitamin E requirements:

        -  To determine the amount of fat required to get the best vitamin E absorption from a
           meal.

        -  To determine the amount (i.e., best dose) of vitamin E that must be consumed before it
           can be measured in the blood.

        -  To examine how vitamin E and vitamin C work together in the body, in conjunction with
           diet and vitamin supplements.

      Eligibility:

        -  Arms 1 and 2: Women between the ages of 18 and 40 years who have a normal weight and
           body mass index (BMI) of 27 or less.

        -  Arm 3: Women between the ages of 18 and 40 years who have a normal weight (BMI 27), who
           are overweight (BMI > 27), or who are overweight (BMI > 27) and have non
           insulin-dependent diabetes.

      Design:

        -  Arm 1: Five studies, each lasting 1 month with 1 month off between studies (total study
           = 10 months). Participants will take 500 1,000 mg of vitamin C twice daily for 2 weeks
           before admission to the clinical center for 1 week.

        -  Study 1: Participants will eat breakfast containing a known amount of fat, after which
           they will take a vitamin E pill as well as receive an IV injection of vitamin E. Other
           foods contain only negligible amounts of vitamin E. Blood and urine samples will measure
           levels of vitamin E and other substances.

        -  Studies 2 5: Outpatient visits will consist of the same tests as in Study 1; however,
           the amount of fat in the breakfast will range from 0% to 40% in random order. During one
           of the studies, an adipose tissue biopsy will be collected to determine how much vitamin
           E is in the tissues.

        -  Arm 2: Five studies, each lasting 1 month with 1 month off between studies (total study
           = 10 months). Preparation for Arm 2 is the same as in Arm 1. The proportion of fat,
           muscle, and water in the body will also be measured.

        -  Study 1: Participants will eat breakfast containing 30% fat, after which they will take
           a vitamin E pill as well as receive an IV injection of vitamin E. Conditions and
           procedures are the same as in Arm 1.

        -  Studies 2 5: Outpatient visits will consist of the same tests as in Study 1; however,
           the amount of vitamin E in the breakfast will range from 2 to 30 mg in random order.

        -  Arm 3: Outpatient (2 to 6 weeks) and inpatient studies (4 to 6 weeks).

        -  Outpatient study: Participants will take 500 1,000 mg of vitamin C daily and provide
           blood and urine samples, as well as an adipose tissue sample.

        -  Inpatient studies: Two vitamin E inpatient studies. Before these begin, participants
           vitamin C blood levels will be reduced by means of a diet low in vitamin C. Blood tests
           will determine how quickly vitamin C leaves the body. Once the vitamin C level is
           reduced, the first vitamin E study will begin.

      Study A: The procedure for this study is the same as in Arm 2, Study 1.

      Study B: The procedure for this study is the same as in Study A, except that the participants
      blood vitamin C levels will be higher.
    

Detailed description: 
      Vitamin E (alpha-tocopherol) is essential for humans but determining human dietary
      requirements has proved difficult. The recommended dietary allowance (RDA) for vitamin E is
      not met by 96% of American women, without apparent harm. Because vitamin E is an antioxidant,
      optimum consumption of vitamin E may improve the health of obese women who experience high
      levels of inflammation and oxidative stress. We hypothesize that vitamin E functions as an
      antioxidant is related to its tissue stores, and that delivery to tissue stores can be
      calculated from plasma vitamin E turnover kinetics from slow release pools. We propose
      turnover kinetics as a new means to estimate vitamin E recommended dietary allowance. We will
      study vitamin E pharmacokinetics using dual stable-isotope labeled (deuterium)
      alpha-tocopherols administered orally and intravenously to healthy nonobese, overweight and
      overweight non-insulin requiring diabetic women. Blood samples will be collected at intervals
      and vitamin E measured by mass spectrometry. Because ascorbic acid (vitamin C) concentrations
      may alter alpha-tocopherol pharmacokinetics, subjects will be studied first at low and then
      high steady state plasma vitamin C concentrations. Before this main study, two preliminary
      trials will be performed. In preliminary trial 1, fat content for optimal absorption will be
      assessed because fat-content of a meal may alter vitamin E absorption. The fat content in
      preliminary trial 1 will be 0 - 40% of calories in the breakfast meal during which vitamin E
      will be administered. In preliminary trial 2, optimal fat content from preliminary trial 1
      will be used, and the vitamin E dose will be varied. Vitamin E dose amount could
      non-specifically alter vitamin E kinetics. We will therefore determine the largest dose (2-30
      mg) that does not non-specifically increase vitamin E turnover, with fat held constant.
      Additionally, we will measure vitamin E pharmacokinetics as a function of lipid peroxidation
      biomarkers to provide direct data that can be used to predict vitamin E requirements for
      women, and to set new recommendations for vitamin E intakes. We will explore new
      alpha-tocopherol functions, specifically whether gene transcription in human subjects is
      regulated by vitamin E status in relation to vitamin C status. Because vitamin E turnover may
      be affected by vitamin C concentrations, we will use a vitamin C depletion-repletion study
      design to investigate the relationship between vitamin C status and vitamin E turnover.
    

Intervention name(s): Alpha tocopherol; Vitamin E; Vitamin C
Intervention type(s): Drug; Other; Other
Intervention description(s): intravenous deuterated vitamin E at doses of 2mg, 5mg, 7.5mg, 10mg and 30mg.; Deuterated vitamin E, oral and intravenous, at doses of 2mg, 5mg, 7.5mg, 10mg and 30mg.; Oral vitamin C, one gram daily.
Intervention MeSH terms: Vitamins; Vitamin E; Tocopherols; Tocotrienols; alpha-Tocopherol
Allocation: Non-Randomized
Intervention model: Factorial Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Non-Insulin Dependent Diabetes; Antioxidant; Lipid Peroxidation; Alpha-Tocopherol; Non-Alcoholic Fatty Liver Disease; Health Volunteer; HV; Normal Weight; Overweight; Type 2 Diabetes