Precision Nutrition and Metabolic Function

Study Overview
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Brief Summary
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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
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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.

Official Title
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Precision Nutrition and Metabolic Function

Conditions
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Obesity, Insulin Resistance

Intervention / Treatment
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* Behavioral: Mediterranean diet
* Behavioral: Low-carbohydrate, ketogenic diet
* Behavioral: Low-fat diet
* Other: Annual follow-up testing for 5 years


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Metabolically healthy lean<br>Metabolically normal lean - Lean individuals that have good glucose (sugar) control, normal plasma triglyceride (fat) levels and a low liver fat content. | Other: Annual follow-up testing for 5 years<br>* Annual follow-up testing with no restrictions on dietary intake during periods between annual testing.<br>|
| Experimental: Metabolically healthy obese - Mediterranean diet<br>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. | Behavioral: Mediterranean diet<br>* A Mediterranean-type diet will be consumed for 4 to 8 weeks in the weight stable state with all meals provided.<br>Other: Annual follow-up testing for 5 years<br>* Annual follow-up testing with no restrictions on dietary intake during periods between annual testing.<br>|
| Experimental: Metabolically healthy obese - Low-carbohydrate ketogenic diet<br>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. | Behavioral: Low-carbohydrate, ketogenic diet<br>* A low-carbohydrate, ketogenic diet will be consumed for 4 to 8 weeks in the weight stable state with all meals provided.<br>Other: Annual follow-up testing for 5 years<br>* Annual follow-up testing with no restrictions on dietary intake during periods between annual testing.<br>|
| Experimental: Metabolically normal obese - Low-fat diet<br>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. | Behavioral: Low-fat diet<br>* A low-fat diet will be consumed for 4 to 8 weeks in the weight stable state with all meals provided.<br>Other: Annual follow-up testing for 5 years<br>* Annual follow-up testing with no restrictions on dietary intake during periods between annual testing.<br>|
| Experimental: Metabolically unhealthy obese - Mediterranean diet<br>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. | Behavioral: Mediterranean diet<br>* A Mediterranean-type diet will be consumed for 4 to 8 weeks in the weight stable state with all meals provided.<br>Other: Annual follow-up testing for 5 years<br>* Annual follow-up testing with no restrictions on dietary intake during periods between annual testing.<br>|
| Experimental: Metabolically unhealthy obese - Low-carbohydrate ketogenic diet<br>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. | Behavioral: Low-carbohydrate, ketogenic diet<br>* A low-carbohydrate, ketogenic diet will be consumed for 4 to 8 weeks in the weight stable state with all meals provided.<br>Other: Annual follow-up testing for 5 years<br>* Annual follow-up testing with no restrictions on dietary intake during periods between annual testing.<br>|
| Experimental: Metabolically unhealthy obese - Low-fat diet<br>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. | Behavioral: Low-fat diet<br>* A low-fat diet will be consumed for 4 to 8 weeks in the weight stable state with all meals provided.<br>Other: Annual follow-up testing for 5 years<br>* Annual follow-up testing with no restrictions on dietary intake during periods between annual testing.<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

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