Plasma Lipids-Dependent Vitamin E Metabolism During Dynamic Hyperlipidemia

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:

• 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.
• 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;
• Explore effects of postprandial hypertriglyceridemia on small RNAs including microRNAs, tRNAs, and PIWI-interacting RNAs.
• 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:

• 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.
• 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.
• Over the course of inpatient visit, small RNAs including microRNAs, tRNAs, and PIWI-interacting RNAs.
• Genetic variance (single nucleotide polymorphisms, SNPs)- dependent change in lipid-soluble vitamin dynamics over the course of inpatient visit in each subject.

• 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