Precision Nutrition and Metabolic Function

Overview

The purposes of this study are: 1) to determine the mechanisms responsible for the development of cardiometabolic complications in some, but not all people with obesity; 2) determine the best dietary approach for cardiometabolic health; and 3) understand why some people have a stable metabolic phenotype over time whereas cardiometabolic health improves or worsens in others.

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Other
    • Masking: None (Open Label)
  • Study Primary Completion Date: October 1, 2029

Detailed Description

Excess adiposity causes alterations in metabolic function including impaired glucose homeostasis and insulin resistance, which are important risk factors for type 2 diabetes (T2D) and cardiovascular disease (CVD). Not all people with obesity experience the typical metabolic complications associated with obesity. Approximately 25% of people with obesity are protected from the adverse metabolic effects of excess fat accumulation and are considered to be metabolically healthy based on their normal response to insulin. The mechanism(s) responsible for the differences in metabolic function among people with obesity is not known, but is likely to be multifactorial including dietary intake. The risk for developing T2D and CVD is also well known to increase with age, however, not all people that are metabolically healthy convert to a metabolically unhealthy phenotype over time. The mechanisms responsible for the stability of health status in some, but not all adults, are unclear. The overall goals of this study are to: i) determine the mechanisms responsible for the development of cardiometabolic complications in participants who will be carefully characterized into 3 distinct groups [metabolically normal lean, metabolically normal obese and metabolically abnormal obese], ii) to determine the optimal dietary approach for cardiometabolic health independent of weight change in people with metabolically abnormal obesity, and iii) perform a comprehensive longitudinal assessment of cardiometabolic health to understand why some people have a stable metabolic phenotype over time whereas cardiometabolic health improves or worsens in others.

Interventions

  • Behavioral: Mediterranean diet
    • A Mediterranean-type diet will be consumed for 4 to 8 weeks in the weight stable state with all meals provided.
  • Behavioral: Low-carbohydrate, ketogenic diet
    • A low-carbohydrate, ketogenic diet will be consumed for 4 to 8 weeks in the weight stable state with all meals provided.
  • Behavioral: Low-fat diet
    • A low-fat diet will be consumed for 4 to 8 weeks in the weight stable state with all meals provided.
  • Other: Annual follow-up testing for 5 years
    • Annual follow-up testing with no restrictions on dietary intake during periods between annual testing.

Arms, Groups and Cohorts

  • Other: Metabolically normal lean
    • Metabolically normal lean – Lean individuals that have good glucose (sugar) control, normal plasma triglyceride (fat) levels and a low liver fat content.
  • Other: Metabolically normal obese
    • Metabolically normal obese – Persons with obesity that have good glucose (sugar) control, normal plasma triglyceride (fat) levels and a low liver fat content.
  • Experimental: Metabolically abnormal obese – Mediterranean diet
    • Metabolically abnormal obese – Persons with obesity with glucose levels higher than recommended and a moderate to high amount of fat in the liver randomized to the Mediterranean diet group.
  • Experimental: Metabolically abnormal obese – Low-carbohydrate ketogenic diet
    • Metabolically abnormal obese – Persons with obesity with glucose levels higher than recommended and a moderate to high amount of fat in the liver randomized to the low-carbohydrate, ketogenic diet group.
  • Experimental: Metabolically abnormal obese – Low-fat diet
    • Metabolically abnormal obese – Persons with obesity with glucose levels higher than recommended and a moderate to high amount of fat in the liver randomized to the low-fat diet group.

Clinical Trial Outcome Measures

Primary Measures

  • Insulin sensitivity
    • Time Frame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
    • Whole-body insulin sensitivity will be assessed by using the hyperinsulinemic-euglycemic clamp procedure
  • Change in insulin sensitivity
    • Time Frame: Before and after 4-8 weeks of weight maintenance in metabolically abnormal obese subjects randomized to follow a Mediterranean, low-carbohydrate or low-fat diet
    • Whole-body insulin sensitivity will be assessed by using the hyperinsulinemic-euglycemic clamp procedure
  • Change in insulin sensitivity
    • Time Frame: Performed annually for 5 years
    • Whole-body insulin sensitivity will be assessed by using the hyperinsulinemic-euglycemic clamp procedure

Secondary Measures

  • 24-hour glucose concentrations
    • Time Frame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
    • Plasma glucose concentrations will be evaluated from frequent blood samples over a 24 h period
  • Change in 24-hour glucose concentrations
    • Time Frame: Before and after 4-8 weeks of weight maintenance in metabolically abnormal obese subjects randomized to follow a Mediterranean, low-carbohydrate or low-fat diet
    • Plasma glucose concentrations will be evaluated from frequent blood sampling over a 24 h period
  • Change in 24-hour glucose concentrations
    • Time Frame: Performed annually for 5 years
    • Plasma glucose concentrations will be evaluated from frequent blood sampling over a 24 h period
  • 24-hour hormone concentrations
    • Time Frame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
    • Plasma hormone concentrations will be evaluated from frequent blood sampling over a 24 h period
  • Change in 24-hour hormone concentrations
    • Time Frame: Before and after 4-8 weeks of weight maintenance in metabolically abnormal obese subjects randomized to follow a Mediterranean, low-carbohydrate or low-fat diet
    • Plasma hormone concentrations will be evaluated from frequent blood samples over a 24 h period
  • Change in 24-hour hormone concentrations
    • Time Frame: Performed annually for 5 years
    • Plasma hormone concentrations will be evaluated from frequent blood samples over a 24 h period
  • β-cell function
    • Time Frame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
    • β-cell function will be assessed from a modified oral glucose tolerance test
  • Change in β-cell function
    • Time Frame: Performed annually for 5 years
    • β-cell function will be assessed from a modified oral glucose tolerance test
  • Insulin clearance
    • Time Frame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
    • Insulin clearance will be assessed from a modified oral glucose tolerance test and hyperinsulinemic-euglycemic clamp procedure
  • Change in Insulin clearance
    • Time Frame: Performed annually for 5 years
    • Insulin clearance will be assessed from a modified oral glucose tolerance test and hyperinsulinemic-euglycemic clamp procedure
  • Fat mass and fat free mass
    • Time Frame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
    • Fat mass and fat free mass will be assessed using dual-energy x-ray absorptiometry (DXA)
  • Change in fat mass and fat free mass
    • Time Frame: Before and after 4-8 weeks of weight maintenance in metabolically abnormal obese subjects randomized to follow a Mediterranean, low-carbohydrate or low-fat diet
    • Fat mass and fat free mass will be assessed using dual-energy x-ray absorptiometry (DXA)
  • Change in fat mass and fat free mass
    • Time Frame: Performed annually for 5 years
    • Fat mass and fat free mass will be assessed using dual-energy x-ray absorptiometry (DXA)
  • Exosome-mediated intercellular signaling
    • Time Frame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
    • Signaling between cells and organs will be examined by isolating exosomes (small extracellular vesicles) from blood and adipose tissue
  • Change in exosome-mediated intercellular signaling
    • Time Frame: Before and after 4-8 weeks of weight maintenance in metabolically abnormal obese subjects randomized to follow a Mediterranean, low-carbohydrate or low-fat diet
    • Signaling between cells and organs will be examined by isolating exosomes (small extracellular vesicles) from blood and adipose tissue
  • Change in exosome-mediated intercellular signaling
    • Time Frame: Performed annually for 5 years
    • Signaling between cells and organs will be examined by isolating exosomes (small extracellular vesicles) from blood and adipose tissue
  • Intra-hepatic triglyceride content
    • Time Frame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
    • Intra-hepatic triglyceride content will be assessed by magnetic resonance imagining (MRI)
  • Change in intra-hepatic triglyceride content
    • Time Frame: Before and after 4-8 weeks of weight maintenance in metabolically abnormal obese subjects randomized to follow a Mediterranean, low-carbohydrate or low-fat diet
    • Intra-hepatic triglyceride content will be assessed by magnetic resonance imagining (MRI)
  • Change in intra-hepatic triglyceride content
    • Time Frame: Performed annually for 5 years
    • Intra-hepatic triglyceride content will be assessed by magnetic resonance imagining (MRI)
  • Abdominal adipose tissue volumes
    • Time Frame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
    • Abdominal subcutaneous and intra-abdominal adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)
  • Change in abdominal adipose tissue volumes
    • Time Frame: Before and after 4-8 weeks of weight maintenance in metabolically abnormal obese subjects randomized to follow a Mediterranean, low-carbohydrate or low-fat diet
    • Abdominal subcutaneous and intra-abdominal adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)
  • Change in abdominal adipose tissue volumes
    • Time Frame: Performed annually for 5 years
    • Abdominal subcutaneous and intra-abdominal adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)
  • Leg adipose tissue volumes
    • Time Frame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
    • Thigh and calf adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)
  • Change in leg adipose tissue volumes
    • Time Frame: Before and after 4-8 weeks of weight maintenance in metabolically abnormal obese subjects randomized to follow a Mediterranean, low-carbohydrate or low-fat diet
    • Thigh and calf adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)
  • Change in leg adipose tissue volumes
    • Time Frame: Performed annually for 5 years
    • Thigh and calf adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)
  • Gut microbiome
    • Time Frame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
    • Gut microbiota, meta-transcriptome (bacterial RNA sequencing to determine what proteins can be made by the microbiota) and the meta-metabolome (metabolites made by the microbiota) will be assessed
  • Change in gut microbiome
    • Time Frame: Before and after 4-8 weeks of weight maintenance in metabolically abnormal obese subjects randomized to follow a Mediterranean, low-carbohydrate or low-fat diet
    • Gut microbiota, meta-transcriptome (bacterial RNA sequencing to determine what proteins can be made by the microbiota) and the meta-metabolome (metabolites made by the microbiota) will be assessed
  • Change in gut microbiome
    • Time Frame: Performed annually for 5 years
    • Gut microbiota, meta-transcriptome (bacterial RNA sequencing to determine what proteins can be made by the microbiota) and the meta-metabolome (metabolites made by the microbiota) will be assessed
  • Carotid artery intima media thickness
    • Time Frame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
    • Carotid artery intima media thickness will be assessed by ultrasound imaging
  • Change in carotid artery intima media thickness
    • Time Frame: Performed annually for 5 years
    • Carotid artery intima media thickness will be assessed by ultrasound imaging
  • Cardiac structure and function
    • Time Frame: Baseline only (cross-sectional comparison of metabolically normal obese and metabolically abnormal obese subjects).
    • Ultrasound techniques will be used to assess cardiac structure and function
  • Change in cardiac structure and function
    • Time Frame: Performed annually for 5 years in metabolically normal obese and metabolically abnormal obese subjects.
    • Ultrasound techniques will be used to assess cardiac structure and function
  • Endothelial function
    • Time Frame: Baseline only (cross-sectional comparison of metabolically normal obese and metabolically abnormal obese subjects).
    • Endothelial function will be assessed using a non-invasive device (EndoPat 2000) in response to reactive hyperemia.
  • Change in endothelial function
    • Time Frame: Performed annually for 5 years
    • Endothelial function will be assessed using a non-invasive device (EndoPat 2000) in response to reactive hyperemia.
  • Arterial stiffness
    • Time Frame: Baseline only (cross-sectional comparison of metabolically normal obese and metabolically abnormal obese subjects).
    • Arterial stiffness will be assessed using a non-invasive device (SphygmoCor)
  • Change in arterial stiffness
    • Time Frame: Performed annually for 5 years
    • Arterial stiffness will be assessed using a non-invasive device (SphygmoCor)
  • Brain structure and blood flow
    • Time Frame: Baseline only (cross-sectional comparison of metabolically normal obese and metabolically abnormal obese subjects).
    • Brain structure and blood flow will be assessed by magnetic resonance imagining (MRI)
  • Change in brain structure and blood flow
    • Time Frame: Performed annually for 5 years
    • Brain structure and blood flow will be assessed by magnetic resonance imagining (MRI)
  • Transcriptome in blood, muscle and adipose tissue
    • Time Frame: Baseline only (cross-sectional comparison of metabolically normal obese and metabolically abnormal obese subjects).
    • The transcriptome (all RNA that are responsible for making proteins from DNA templates) will be evaluated by using RNA sequencing techniques
  • Change in transcriptome in blood, muscle and adipose tissue
    • Time Frame: Performed annually for 5 years
    • The transcriptome (all RNA that are responsible for making proteins from DNA templates) will be evaluated by using RNA sequencing techniques

Participating in This Clinical Trial

Inclusion Criteria

  • Metabolically normal lean subjects must have a body mass index (BMI) 18.5-24.9 kg/m2, intrahepatic triglyceride (IHTG) content ≤5%, serum triglyceride (TG) concentration <150 mg/dl, fasting plasma glucose concentration <100 mg/dl, 2-hr oral glucose tolerance test (OGTT) plasma glucose concentration ≤140 mg/dl, and hemoglobin A1C (HbA1C) ≤5.6%.
  • Metabolically normal obese subjects must have a BMI 30-49.9 kg/m2; IHTG content ≤5%, serum TG concentration <150 mg/dl, fasting plasma glucose concentration <100 mg/dl, 2-hr OGTT plasma glucose concentration ≤140 mg/dl, and HbA1C ≤5.6%.
  • Metabolically abnormal obese subjects must have a BMI 30-49.9 kg/m2; IHTG content ≥5.6% and fasting plasma glucose concentration ≥100 mg/dl or 2-hr OGTT plasma glucose concentration ≥140 mg/dl or HbA1C ≥5.7%.

Exclusion Criteria

  • medical, surgical, or biological menopause;
  • previous bariatric surgery where the gastrointestinal tract is reconstructed such as Roux-en-Y, sleeve gastrectomy and biliopancreatic diversion surgeries;
  • laparoscopic adjustable gastric band (lab band) surgery within the last 3 years;
  • structured exercise ≥250 min per week (e.g., brisk walking);
  • unstable weight (>4% change during the last 2 months before entering the study);
  • significant organ system dysfunction (e.g., diabetes requiring medications, severe pulmonary, kidney or cardiovascular disease);
  • cancer or cancer that has been in remission for <5 years;
  • polycystic ovary syndrome;
  • major psychiatric illness;
  • conditions that render subject unable to complete all testing procedures (e.g., severe ambulatory impairments, limb amputations, or metal implants that interfere with imaging procedures; coagulation disorders);
  • severe anemia;
  • regular use of tobacco products;
  • excessive consumption of alcohol (≥3 drinks/day for men and ≥2 drinks/day for women);
  • use of medications that are known to affect the study outcome measures (e.g., steroids, non-statin lipid-lowering medications) or increase the risk of study procedures (e.g., anticoagulants) and that cannot be temporarily discontinued for this study;
  • use of antibiotics in last 60 days;
  • pregnant or lactating women;
  • vegans, vegetarians, those with lactose intolerance and/or severe aversions/sensitivities to eggs, fish, nuts, wheat and soy, and/or any individuals with food allergies that induce an anaphylactic response;
  • persons who are not able to grant voluntary informed consent

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 55 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Washington University School of Medicine
  • Collaborator
    • Centene Corporation
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Samuel Klein, MD, Principal Investigator, Washington University School of Medicine
  • Overall Contact(s)
    • Janet Winkelmann, 314-286-2099, janetwinkelmann@wustl.edu

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