Plasma Lipids-Dependent Vitamin E Metabolism During Dynamic Hyperlipidemia

Official title

Plasma Lipids-dependent Vitamin E Metabolism During Dynamic Hyperlipidemia

Overview

Background: Obesity is known to lead to diseases such as diabetes and high cholesterol (or fats) in the blood (hyperlipidemia). But no one knows why. Researchers think that high levels of fat in the blood may block important nutrients, such as vitamin E, from reaching places they are needed in the body. Objective: To learn how high-fat meals affect levels of vitamin E in the blood. Eligibility: People aged 18 to 65 with high blood fat levels. Healthy volunteers are also needed. Design: Participants will have 3 or 4 clinic visits in 3 months. The last visit will require them to stay in the clinic for 2 nights. Participants will be screened. They will have a physical exam and blood tests. After this visit, all participants must stop taking any dietary supplements. Those who use them must also stop taking any drugs to lower their blood sugar and blood fats. These participants will have an extra visit for blood tests after 60 days. The next visit will include 2 imaging scans: Magnetic resonance imaging (MRI) of the abdomen. This scan will check for fat in the liver. Dual-energy X-ray absorptiometry (DEXA). This scan measures the levels of body fat. On day 1 of the clinic stay, participants will have 2 set meals, with nothing but water after 10 pm. On day 2, they will drink high-fat shakes at 8 am, noon, and 4 pm. They will have blood draws every hour for 17 hours, and then every 2 hours until 7 am. The blood will be taken from a tube inserted into a vein and left in place for the day. On day 3, they will go home.

Detailed description

Study Description:

A controlled interventional study of effects of postprandial hypertriglyceridemia from three consecutive high-fat vitamin E-stripped meals on the dynamics of plasma vitamin E concentrations in subjects with baseline normo- and hyperlipidemia, to explore the concept of vitamin E sequestration by fats in plasma.

Objectives:

Primary Objective: Compare effects of postprandial hypertriglyceridemia (PHTG) on plasma/lipoprotein vitamin E dynamics in subjects between baseline normo- and hyperlipidemia.

Secondary Objectives: Compare effects of postprandial hypertriglyceridemia (PHTG) on other fat-soluble vitamins (gamma-tocopherol, phylloquinone \[K1\]; menaquinone \[K2\]; 25-OH vitamin D; retinol \[A\]) and related vitamers (beta-carotene, lycopene lutein/zeaxanthin) between subjects with baseline normo- and hyperlipidemia.

Tertiary/Exploratory Objectives:

1. Compare effects of individual high-fat meals on the dynamics of vitamin E, gamma-tocopherol, phylloquinone \[K1\], menaquinone \[K2\], 25-OH vitamin D, retinol \[A\], and other carotenoids between subjects with baseline normo- and hyperlipidemia. 2. Compare effects of postprandial hypertriglyceridemia (PHTG) and resultant vitamin E dynamics on: red blood cell (RBC) membrane deformability, fluidity, and oxygen exchange capacity (p50); RBC vitamin E, plasma vitamin C, plasma dehydroascorbic acid; fasting glucose and insulin; oxidized LDL, coenzyme Q10, and plasma adipokine profile between subjects with baseline normo- and hyperlipidemia; 3. Explore effects of postprandial hypertriglyceridemia on small RNAs including microRNAs, tRNAs, and PIWI-interacting RNAs. 4. Explore the influence of genetic variance on the metabolism of vitamin E and other fat-soluble vitamins and related vitamers in subjects with baseline normo- and hyperlipidemia.

Endpoints:

Primary Endpoint: AUC (Area Under the Curve) of vitamin E plasma from hour 1 to hour 23, by cohort.

Secondary Endpoints: AUC of gamma-tocopherol, phylloquinone \[K1\], menaquinone \[K2\], 25-OH vitamin D and retinol \[A\] from hour 1 to hour 23, by cohort.

Tertiary/Exploratory Endpoints:

1. Between the timepoints that reflect consuming 3 high-fat meals, AUC of vitamin E, gamma-tocopherol, phylloquinone \[K1\], menaquinone \[K2\], 25-OH vitamin D, retinol \[A\], and other carotenoids will be separately calculated for each participant. 2. Over the course of inpatient visit, RBC membrane deformability/fluidity, p50, RBC vitamin E, plasma vitamin C, plasma dehydroascorbic acid, blood glucose, insulin, c-peptide, oxidized LDL, coenzyme Q10 and serum adipokine profiles in each subject. 3. Over the course of inpatient visit, small RNAs including microRNAs, tRNAs, and PIWI-interacting RNAs. 4. Genetic variance (single nucleotide polymorphisms, SNPs)- dependent change in lipid-soluble vitamin dynamics over the course of inpatient visit in each subject.

Interventions

• Dietary supplement High fat liquid shake
  Three consecutive high-fat vitamin E-stripped meals

Primary outcome measures

• AUC (Area Under the Curve) of vitamin E plasma from hour 1 to hour 23 by cohort. [Time frame: From hour 1 to hour 23]

Secondary outcome measures (1)

• AUC of gamma-tocopherol, phylloquinone [K1]; menaquinone [K2]; 25-OH vitamin D; retinol [A] from hour 1 to hour 23 by cohort. [Time frame: From hour 1 to hour 23]

Eligibility criteria

• INCLUSION CRITERIA

Cohort 1

• Males and females between the ages of 18 to 65
• BMI 18.5 - 26.9 kg/m\^2
• Subject understands the protocol and provides written, informed consent in addition to a willingness to comply with specified follow-up instructions and evaluations
• Normotensive, not on medications for hypertension
• Not on glucose-lowering or lipid-lowing medications
• Screening labs with baseline HbA1c <5.7%, baseline fasting triglyceride < 150 mg/dL and LDL <100 mg/dL
• Liver fat <2%

Cohort 2

• Males and females between the ages of 18 to 65
• BMI >26 kg/m\^2 and <36 kg/m\^2
• Subject understands the protocol and provides written, informed consent in addition to a willingness to comply with specified follow-up instructions and evaluations.
• Screening labs with baseline HbA1c <= 7.5%, agree to be off or stop oral glucose-lowering medications (metformin), baseline fasting triglyceride < 500 mg/dL and LDL <190 mg/dL, agree to be off or stop oral lipid-lowing medications for 4-10 weeks prior to the inpatient visit.
• Liver fat <2%

Exclusion criteria

• For women: pregnancy or currently breastfeeding
• Subjects <18-year-old. This age group has a broad spectrum of hormonal profiles, due to development and puberty, which significantly increases the heterogenicity of the study subjects.
• Subjects >65-year-old. This age group has significantly increased risk of cardiovascular diseases. To minimize the risk from temporarily suspending lipid- and glucose-lowering medications and stress from serial blood draws, we exclude these individuals.
• Heavy alcohol user (males with >2 drinks per day or >14 drinks per week; female with >1 drinks per day or >7 drinks per week)
• Current smoker, or former smoker who quit smoking <15 years ago
• Subjects with weight changes greater than 20% baseline body weight over the past 3 months
• Subjects with lactose intolerance unwilling to take lactase
• Subjects with type 1 diabetes
• Subjects with hemoglobin <11 g/dL or hematocrit <33%
• Subjects with abnormal liver function test results
• Subjects with liver fat >= 2% on abdominal MRI
• Subjects with a history of pancreatitis, diabetes ketoacidosis, hyperosmolar hyperglycemic state, advanced atherosclerosis, cardiovascular diseases, kidney diseases, or liver diseases
• Subjects with fat malabsorption including: history of gastrointestinal surgery, pancreatic insufficiency, inflammatory bowel disease, celiac disease, moderate-to-severe irritable bowel syndrome, and pathologic mutations impacting lipoprotein metabolism
• Subjects on glucocorticoids >1 week (not including topical glucocorticoids)
• Subjects with HIV
• Subjects with uncontrolled psychiatric and/or behavioral disorders
• Subjects taking diabetes medications other than metformin
• Anticipated surgery during the study period
• Subjects with severe medication-resistant claustrophobia
• Subjects who are unwilling to stop medications, vitamins and/or dietary supplements that investigators have requested to be held
• Subjects participating in any other clinical study without informing investigators
• Any other reason or clinical condition that the investigators judge would interfere with study participation and/or be unsafe for a participant or staff member

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Basic science

Study locations

United States · 1 center

• National Institutes of Health Clinical Center — Bethesda

Publications

• Traber MG, Leonard SW, Ebenuwa I, Violet PC, Wang Y, Niyyati M, Padayatty S, Tu H, Courville A, Bernstein S, Choi J, Shamburek R, Smith S, Head B, Bobe G, Ramakrishnan R, Levine M. Vitamin E absorption and kinetics in healthy women, as modulated by food and by fat, studied using 2 deuterium-labeled alpha-tocopherols in a 3-phase crossover design. Am J Clin Nutr. 2019 Nov 1;110(5):1148-1167. doi: 1 PMID 31495886

Identifiers

NCT: NCT07715890 · 10002623 · 002623-H

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗