Insulin Resistance, Obesity
Conditions
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.
Interventions
BEHAVIORALMediterranean diet
A Mediterranean-type diet will be consumed for 4 to 8 weeks in the weight stable state with all meals provided.
BEHAVIORALLow-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.
BEHAVIORALLow-fat diet
A low-fat diet will be consumed for 4 to 8 weeks in the weight stable state with all meals provided.
OTHERAnnual follow-up testing for 5 years
Annual follow-up testing with no restrictions on dietary intake during periods between annual testing.
Sponsors
Washington University School of Medicine
Centene Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| Change in insulin sensitivity | 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 | Whole-body insulin sensitivity will be assessed by using the hyperinsulinemic-euglycemic clamp procedure |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| Change in 24-hour glucose concentrations | 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 | 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 24-hour hormone concentrations | 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 | Plasma hormone 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 |
| Change in β-cell function | Performed annually for 5 years | 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 |
| 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 fat mass and fat free mass | 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 | 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 | 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 | 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 | 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 | 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 abdominal adipose tissue volumes | 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 | Abdominal subcutaneous and intra-abdominal adipose tissue volumes will be assessed by magnetic resonance imagining (MRI) |
| 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 | 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 | 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 |
| Change in gut microbiome | 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 | 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 carotid artery intima media thickness | Performed annually for 5 years | Carotid artery intima media thickness will be assessed by ultrasound imaging |
| 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 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. |
| 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. |
| 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 arterial stiffness | Performed annually for 5 years | Arterial stiffness will be assessed using a non-invasive device (SphygmoCor) |
| 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 |
| 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 |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORSamuel Klein, MD
Washington University School of Medicine
Outcome results
None listed