Precision Nutrition and Metabolic Function

Not Applicable

Recruiting

Conditions: Obesity
Insulin Resistance

Interventions: Other: Annual follow-up testing for 5 years
Behavioral: Mediterranean diet
Behavioral: Low-fat diet
Behavioral: Low-carbohydrate, ketogenic diet

Registration Number: NCT04131166

Lead Sponsor: Washington University School of Medicine

Brief Summary: 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.

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.

Recruitment & Eligibility

Status: RECRUITING

Sex: All

Target Recruitment: 300

Inclusion Criteria

Metabolically healthy 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 healthy 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 unhealthy 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

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Metabolically healthy lean	Annual follow-up testing for 5 years	Metabolically normal lean - Lean individuals that have good glucose (sugar) control, normal plasma triglyceride (fat) levels and a low liver fat content.
Metabolically normal obese - Low-fat diet	Annual follow-up testing for 5 years	Metabolically normal obese - Persons with obesity that have good glucose (sugar) control, normal plasma triglyceride (fat) levels and a low liver fat content randomized to the low-fat diet group.
Metabolically healthy obese - Mediterranean diet	Mediterranean diet	Metabolically normal obese - Persons with obesity that have good glucose (sugar) control, normal plasma triglyceride (fat) levels and a low liver fat content randomized to the Mediterranean diet group.
Metabolically healthy obese - Mediterranean diet	Annual follow-up testing for 5 years	Metabolically normal obese - Persons with obesity that have good glucose (sugar) control, normal plasma triglyceride (fat) levels and a low liver fat content randomized to the Mediterranean diet group.
Metabolically unhealthy obese - Mediterranean diet	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.
Metabolically unhealthy obese - Low-fat diet	Annual follow-up testing for 5 years	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.
Metabolically unhealthy obese - Low-carbohydrate ketogenic diet	Annual follow-up testing for 5 years	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.
Metabolically unhealthy obese - Low-fat diet	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.
Metabolically normal obese - Low-fat diet	Low-fat diet	Metabolically normal obese - Persons with obesity that have good glucose (sugar) control, normal plasma triglyceride (fat) levels and a low liver fat content randomized to the low-fat diet group.
Metabolically unhealthy obese - Mediterranean diet	Annual follow-up testing for 5 years	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.
Metabolically unhealthy obese - Low-carbohydrate ketogenic diet	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.
Metabolically healthy obese - Low-carbohydrate ketogenic diet	Low-carbohydrate, ketogenic diet	Metabolically normal obese - Persons with obesity that have good glucose (sugar) control, normal plasma triglyceride (fat) levels and a low liver fat content randomized to the low-carbohydrate ketogenic diet group.
Metabolically healthy obese - Low-carbohydrate ketogenic diet	Annual follow-up testing for 5 years	Metabolically normal obese - Persons with obesity that have good glucose (sugar) control, normal plasma triglyceride (fat) levels and a low liver fat content randomized to the low-carbohydrate ketogenic diet group.

Primary Outcome Measures

Name	Time	Method
Change in insulin sensitivity	Performed annually for 5 years	Whole-body insulin sensitivity will be assessed by using the hyperinsulinemic-euglycemic clamp procedure
Insulin sensitivity	Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).	Whole-body insulin sensitivity will be assessed by using the hyperinsulinemic-euglycemic clamp procedure

Secondary Outcome Measures

Name	Time	Method
Change in 24-hour hormone concentrations	Performed annually for 5 years	Plasma hormone concentrations will be evaluated from frequent blood samples over a 24 h period
Change in fat mass and fat free mass	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	Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy 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	Performed annually for 5 years	Signaling between cells and organs will be examined by isolating exosomes (small extracellular vesicles) from blood and adipose tissue
Intrahepatic triglyceride content	Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).	Intrahepatic triglyceride content will be assessed by magnetic resonance imagining (MRI)
Change in intra-hepatic triglyceride content	Performed annually for 5 years	Intra-hepatic triglyceride content will be assessed by magnetic resonance imagining (MRI)
Abdominal adipose tissue volumes	Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).	Abdominal subcutaneous and intra-abdominal adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)
Change in carotid artery intima media thickness	Performed annually for 5 years	Carotid artery intima media thickness will be assessed by ultrasound imaging
Change in transcriptome in blood, muscle and adipose tissue	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
Change in abdominal adipose tissue volumes	Performed annually for 5 years	Abdominal subcutaneous and intra-abdominal adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)
Cardiac structure and function	Baseline only (cross-sectional comparison of metabolically healthy obese and metabolically unhealthy obese subjects).	Ultrasound techniques will be used to assess cardiac structure and function
Change in endothelial function	Performed annually for 5 years	Endothelial function will be assessed using a non-invasive device (EndoPat 2000) in response to reactive hyperemia.
Transcriptome in blood, muscle and adipose tissue	Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).	The transcriptome (all RNA that are responsible for making proteins from DNA templates) will be evaluated by using RNA sequencing techniques
Arterial stiffness	Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).	Arterial stiffness will be assessed using a non-invasive device (SphygmoCor)
Change in 24-hour glucose concentrations	Performed annually for 5 years	Plasma glucose concentrations will be evaluated from frequent blood sampling over a 24 h period
24-hour hormone concentrations	Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).	Plasma hormone concentrations will be evaluated from frequent blood sampling over a 24 h period
Change in Insulin clearance	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	Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).	Fat mass and fat free mass will be assessed using dual-energy x-ray absorptiometry (DXA)
Change in gut microbiome	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
Change in arterial stiffness	Performed annually for 5 years	Arterial stiffness will be assessed using a non-invasive device (SphygmoCor)
24-hour glucose concentrations	Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).	Plasma glucose concentrations will be evaluated from frequent blood samples over a 24 h period
β-cell function	Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).	β-cell function will be assessed from a modified oral glucose tolerance test
Insulin clearance	Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).	Insulin clearance will be assessed from a modified oral glucose tolerance test and hyperinsulinemic-euglycemic clamp procedure
Leg adipose tissue volumes	Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).	Thigh and calf adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)
Change in leg adipose tissue volumes	Performed annually for 5 years	Thigh and calf adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)
Gut microbiome	Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy 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
Carotid artery intima media thickness	Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).	Carotid artery intima media thickness will be assessed by ultrasound imaging
Change in β-cell function	Performed annually for 5 years	β-cell function will be assessed from a modified oral glucose tolerance test
Change in cardiac structure and function	Performed annually for 5 years in metabolically healthy obese and metabolically unhealthy obese subjects.	Ultrasound techniques will be used to assess cardiac structure and function
Endothelial function	Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).	Endothelial function will be assessed using a non-invasive device (EndoPat 2000) in response to reactive hyperemia.

Trial Locations

Locations (1): Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States

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