Clinical trial NCT04131166: Precision Nutrition and Metabolic Function
Official title: Precision Nutrition and Metabolic Function
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Obesity
Insulin Resistance
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: Centene Corporation
First posted: 2019-10-18
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.

Eligibility criteria: 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

Primary outcomes:
measure: Insulin sensitivity
timeFrame: Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).
measure: Change in insulin sensitivity
timeFrame: 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
measure: Change in insulin sensitivity
timeFrame: Performed annually for 5 years
Secondary outcomes:
measure: 24-hour glucose concentrations
timeFrame: Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).
measure: Change in 24-hour glucose concentrations
timeFrame: 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
measure: Change in 24-hour glucose concentrations
timeFrame: Performed annually for 5 years
measure: 24-hour hormone concentrations
timeFrame: Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).
measure: Change in 24-hour hormone concentrations
timeFrame: 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
measure: Change in 24-hour hormone concentrations
timeFrame: Performed annually for 5 years
measure: β-cell function
timeFrame: Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).
measure: Change in β-cell function
timeFrame: Performed annually for 5 years
measure: Insulin clearance
timeFrame: Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).
measure: Change in Insulin clearance
timeFrame: Performed annually for 5 years
measure: Fat mass and fat free mass
timeFrame: Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).
measure: Change in fat mass and fat free mass
timeFrame: 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
measure: Change in fat mass and fat free mass
timeFrame: Performed annually for 5 years
measure: Exosome-mediated intercellular signaling
timeFrame: Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).
measure: Change in exosome-mediated intercellular signaling
timeFrame: 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
measure: Change in exosome-mediated intercellular signaling
timeFrame: Performed annually for 5 years
measure: Intrahepatic triglyceride content
timeFrame: Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).
measure: Change in intra-hepatic triglyceride content
timeFrame: 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
measure: Change in intra-hepatic triglyceride content
timeFrame: Performed annually for 5 years
measure: Abdominal adipose tissue volumes
timeFrame: Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).
measure: Change in abdominal adipose tissue volumes
timeFrame: 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
measure: Change in abdominal adipose tissue volumes
timeFrame: Performed annually for 5 years
measure: Leg adipose tissue volumes
timeFrame: Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).
measure: Change in leg adipose tissue volumes
timeFrame: 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
measure: Change in leg adipose tissue volumes
timeFrame: Performed annually for 5 years
measure: Gut microbiome
timeFrame: Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).
measure: Change in gut microbiome
timeFrame: 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
measure: Change in gut microbiome
timeFrame: Performed annually for 5 years
measure: Carotid artery intima media thickness
timeFrame: Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).
measure: Change in carotid artery intima media thickness
timeFrame: Performed annually for 5 years
measure: Cardiac structure and function
timeFrame: Baseline only (cross-sectional comparison of metabolically healthy obese and metabolically unhealthy obese subjects).
measure: Change in cardiac structure and function
timeFrame: Performed annually for 5 years in metabolically healthy obese and metabolically unhealthy obese subjects.
measure: Endothelial function
timeFrame: Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).
measure: Change in endothelial function
timeFrame: Performed annually for 5 years
measure: Arterial stiffness
timeFrame: Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).
measure: Change in arterial stiffness
timeFrame: Performed annually for 5 years
measure: Transcriptome in blood, muscle and adipose tissue
timeFrame: Baseline only (cross-sectional comparison of metabolically healthy lean, metabolically healthy obese and metabolically unhealthy obese subjects).
measure: Change in transcriptome in blood, muscle and adipose tissue
timeFrame: Performed annually for 5 years
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Samuel Klein, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mittendorfer B, Patterson BW, Smith GI, Yoshino M, Klein S. beta Cell function and plasma insulin clearance in people with obesity and different glycemic status. J Clin Invest. 2022 Feb 1;132(3):e154068. doi: 10.1172/JCI154068.