Effect of Nicotinamide Riboside on Ketosis, Fat Oxidation & Metabolic Rate

Study Description:

This is a randomized, double-blind, placebo-controlled crossover study of adults with overweight or obesity to determine whether nicotinamide riboside supplementation increases sleeping energy expenditure and fat oxidation rate during a ketogenic diet.

Objectives:

Primary Aim 1: Determine whether sleeping energy expenditure increases after transitioning to a low carbohydrate ketogenic diet as compared to a baseline high carbohydrate run-in diet in men

Primary Aim 2: Determine whether sleeping energy expenditure is affected by NR supplementation during a ketogenic diet in men

Secondary Aim 1: Determine whether fat oxidation during sleep increases after transitioning to a low carbohydrate ketogenic diet as compared to a baseline high carbohydrate run-in diet in men

Secondary Aim 2: Determine whether fat oxidation during sleep is affected by NR supplementation during a ketogenic diet from the baseline run-in diet in men

Exploratory Aims: Exploratory comparison of the above endpoints between men and women without MODY2.

Exploratory comparison of the above diet-related endpoints between patients with MODY2 and those obtained during the Placebo period in other participants.

Several exploratory measurements are planned to help comprehensively phenotype the effects of the diets and nicotinamide riboside supplementation and are intended to be hypothesis-generating. We will assess the following:

• Liver TG
• Daily ketosis, insulin secretion, and protein utilization
• Rates of ketogenesis and lipolysis
• Physical activity and sleep assessment
• Body composition assessment
• Fasting and postprandial blood measurements of various metabolites, hormones, cytokines, markers of inflammation , and other circulating signaling factors.
• Microbiome composition
• Hunger and satiety before and after meals
• Eating rate
• Chronotype and sleep quality
• Usual food intake
• 24-h and exercise energy expenditure

Endpoints:

Primary:

Mean change in sleeping energy expenditure between the ketogenic diet and the baseline run-in diet

Mean difference in sleeping energy expenditure between NR and placebo during the ketogenic diet

Secondary:

Mean change in sleeping fat oxidation rate between the ketogenic diet and the baseline run-in diet Mean difference in fat oxidation rate between NR and placebo during the ketogenic diet

Exploratory:

• H magnetic resonance spectroscopy
• 24hr urine ketones, C-peptide, nitrogen
• Stable isotope infusions of 13C beta-hydroxybutyrate and 2H glycerol
• Daily accelerometry and wireless EEG headband
• DXA scans
• Fasting and postprandial blood concentrations of various metabolites, hormones, cytokines, inflammatory markers and other circulating signaling factors
• Blood glucose variability and mean concentration as measured by Continuous Glucose Monitoring
• Daily fasting glucose and beta-hydroxybutyrate concentrations by finger-prick
• Microbiome composition
• Hunger and satiety visual analogue scores
• Meal duration
• Pittsburg sleep quality index, morningness-eveningness questionnaire, and subjective sleep visual analogue scores
• Usual food intake as measured by Food frequency questionnaire
• 24-h and exercise energy expenditure from respiratory chamber

• INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

• Meet one of the following:

• Adult males aged 18-65 years
• Pre-menopausal adult females aged 18-50 years
• Adult males aged 18-65 years with diagnosed maturity-onset diabetes of the young type 2 (MODY2) or pre-menopausal adult females aged 18-50 years with diagnosed MODY2
• Weight stable (< +/- 5 % body weight change over past 6 months) as determined by volunteer report
• Body mass index (BMI) >= 25 kg/m^2 (of >=18.5 kg/m^2 for patients with MODY2)
• Able to cycle at a moderate rate and intensity with a HR equal to or greater than 0.3x(220-age-HRrest)+HRrest but not exceeding 0.4x(220-age-HRrest)+HRrest with no signs of arrhythmia

Exclusion criteria

An individual who meets any of the following criteria will be excluded from participation in this study:

• Taking prescription medications or other drugs or supplements that may influence energy metabolism or nutrient digestion or absorption (including, but not limited to, diet/weight-loss medication or other medications at the discretion of the PI and/or study team)
• Indicators of liver disease; combination of both albumin < 2.8 mg/mL and bilirubin > 3 mg/mL
• Individuals with significant medical comorbidities (e.g., non-MODY2 diabetes, NYHA Class >II heart failure, or CKD Stage II or worse, or American Society of Anesthesiologists Physical Status Class 3 or above)
• Individuals taking prescription medications to treat hypertension in participants without MODY2
• Participating in a regular exercise program (> 2h/week of vigorous activity) as determined by volunteer report
• Positive pregnancy test (only for people who can get pregnant)
• Hematocrit < 40% (men only)
• Hematocrit <37% (women only)
• Caffeine consumption > 300 mg/day as determined by volunteer report
• Alcohol consumption > 3 drinks per day for men or > 2 drinks per day for women as determined by volunteer report
• Regular use of tobacco (smoking or chewing), e-cigarettes (a.k.a. vapes), nicotine patches, or illicit drugs over past 6 months as determined by volunteer report. Subjects may also be excluded based on a urine drug test.
• Psychological conditions as determined by volunteer report such as (but not limited to) eating disorders, depression, bipolar disorders, that would be incompatible with safe and successful participation in this study, as determined by investigators
• Volunteers with strict dietary concerns (e.g. vegetarian or kosher diet, food allergies) or a reported dislike of a significant fraction of the study foods
• Unwilling or unable to comply with or perform all study procedures (e.g. cycling or activities of daily living), or unavailability for the duration of the study, as determined by participant or investigator discretion
• Unwilling or unable to adhere to Lifestyle Considerations throughout study duration, as determined by participant or investigator discretion
• Volunteers unwilling or unable to give informed consent
• Participants with a measured Resting Energy Expenditure (REE) more than 30% above or below the predicted REE based on Mifflin St Jeor equation