Insulin Resistance, Obesity
Conditions
Brief summary
The purpose of this research study is to 1) understand how some, but not all people with obesity develop obesity related conditions such as type 2 diabetes and cardiovascular disease, and 2) compare the effects of 3 popular weight loss diets (Mediterranean, low-carbohydrate, or a very-low-fat plant-based diet) in people with obesity.
Detailed description
Obesity is associated with a constellation of cardiometabolic abnormalities (including insulin resistance, elevated blood pressure and dyslipidemia) that are risk factors for diabetes and cardiovascular disease. However, not all people experience the typical "complications" associated with obesity. Approximately 25% of obese people are protected from the adverse metabolic effects of excess fat accumulation and are considered metabolically-normal, based on their normal response to insulin. The mechanisms responsible for the development of insulin resistance and cardiometabolic complications in some, but not all, obese persons are unknown. In people that do develop the typical "complications" associated with obesity weight loss has profound therapeutic effects. Currently, there are three distinctly different types of diets that have demonstrated considerable benefits in improving cardiometabolic health in both lean and obese people: 1) a Mediterranean diet, 2) a low-carbohydrate, ketogenic diet, and 3) a plant-based, very-low-fat diet. However, there is considerable inter-individual variability in body weight loss among people in response to any given diet, and it is not known why some people lose more weight with one diet than another. The mechanisms responsible for the different weight and metabolic responses to specific types of diets and the independent effects of weight loss and dietary macronutrient composition on cardiometabolic health are unclear. The overarching goal of this project is therefore to fill these gaps in knowledge by conducting a careful cross-sectional characterization of metabolically normal lean, metabolically normal obese and metabolically abnormal obese individuals to compare body composition, body fat distribution, the plasma metabolome, systemic and adipose tissue inflammation and immune system function, adipose tissue and muscle biological function, the gut microbiome, the brain's structure, cognitive function and central reward mechanisms, and taste sensation between groups. . Metabolically abnormal obese participants will then be randomized to follow a Mediterranean, a low-carbohydrate ketogenic or a plant-based, very-low-fat diet to examine the different effects of these diets on the above outcomes with the purpose to determine the beneficial or potentially harmful effects of these different diets.
Interventions
OTHERMetabolically abnormal obese - Mediterranean diet
The effect of consuming a Mediterranean diet will be examined over 3 different phases: (i) weight maintenance for 4 to 8 weeks, with all meals provided; (ii) controlled 7-10% weight loss with caloric intake reduced by 25% to achieve the desired amount of weight loss in about 4 to 5 months with all meals provided; and (iii) Independent weight loss for about 4 months. During the independent weight loss phase of the study subjects will be asked to continue to consume a Mediterranean diet but will prepare all their food at home. No food will be provided during this portion of the study.
OTHERMetabolically abnormal obese - Low carbohydrate ketogenic diet
The effect of consuming a low-carbohydrate, ketogenic diet will be examined over 3 different phases: (i) weight maintenance for 4 to 8 weeks, with all meals provided; (ii) controlled 7-10% weight loss with caloric intake reduced by 25% to achieve the desired amount of weight loss in about 4 to 5 months with all meals provided; and (iii) Independent weight loss for about 4 months. During the independent weight loss phase of the study subjects will be asked to continue to consume a low carbohydrate ketogenic diet but will prepare all their food at home. No food will be provided during this portion of the study.
OTHERMetabolically abnormal obese - Plant-based, very-low-fat diet
The effect of consuming a plant-based, very-low-fat diet will be examined over 3 different phases: (i) weight maintenance for 4 to 8 weeks, with all meals provided; (ii) controlled 7-10% weight loss with caloric intake reduced by 25% to achieve the desired amount of weight loss in about 4 to 5 months with all meals provided; and (iii) Independent weight loss for about 4 months. During the independent weight loss phase of the study subjects will be asked to continue to consume a plant-based, very-low-fat diet but will prepare all their food at home. No food will be provided during this portion of the study.
BEHAVIORALAnnual Follow-up Visits
Metabolic health will be assessed 1 and 2-years after competing the diet intervention study. No intervention will be performed during the time.
Sponsors
Washington University School of Medicine
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 normal lean subjects must have a BMI ≥18.5 and ≤24.9 kg/m2; Obese subjects must have a BMI ≥30.0 and ≤50.0 kg/m2 * Metabolically normal lean and obese subjects must have intrahepatic triglyceride (IHTG) content ≤5%; plasma triglyceride (TG) concentration \<150 mg/dl; fasting plasma glucose concentration \<100 mg/dl, 2-hr oral glucose tolerance plasma glucose concentration \<140 mg/dl, and hemoglobin A1C ≤5.6% * Metabolically abnormal obese subjects must have intrahepatic triglyceride (IHTG) content ≥5.6%; HbA1C ≥5.7%, or fasting plasma glucose concentration ≥100 mg/dl, or 2-hr oral glucose tolerance test (OGTT) plasma glucose concentration ≥140 mg/dl.
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) * Polycystic ovary syndrome * Cancer or cancer that has been in remission for \<5 years * 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) * 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 * Smoke cigarettes \> 10 cigarettes/week * Use marijuana \>2 x/week, or use of illegal drugs * Men who consume \>21 units (e.g. glass of wine or bottle of beer) of alcohol per week and women who consume \>14 units of alcohol per week * 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 * Persons who are unable or unwilling to follow the study protocol or who, for any reason, the research team considers not an appropriate candidate for this study, including non-compliance with screening appointments or study visits
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin sensitivity | 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 | Before and after 4 to 8-weeks of weight maintenance and after 7-10% weight loss (~6-7 months) | 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 normal lean, metabolically normal obese and metabolically abnormal obese subjects). | Glucose concentrations will be evaluated from frequent blood samples over a 24 h period |
| Change in 24-hour glucose concentrations | Before and after 4 to 8-weeks of weight maintenance and after 7-10% weight loss (~6-7 months) | Glucose concentrations will be evaluated from frequent blood samples over a 24 h period |
| 24-hour hormone concentrations | 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 | Before and after 4 to 8-weeks of weight maintenance and after 7-10% weight loss (~6-7 months) | Plasma hormone concentrations will be evaluated from frequent blood sampling over a 24 h period |
| 24-hour cytokine concentrations | Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects). | Plasma cytokine concentrations will be evaluated from frequent blood sampling over a 24 h period |
| β-cell function | 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 | Before and after 7-10% weight loss (~6-7 months) and independent weight loss (12 months) in metabolically abnormal obese individuals only. | β-cell function will be assessed from a modified oral glucose tolerance test |
| Insulin clearance | 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 |
| Fat mass and fat free mass | 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 | Before and after 4 to 8-weeks of weight maintenance, after 7-10% weight loss (~6-7 months) and after independent weight loss (12 months) | 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 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 | Before and after 4 to 8-weeks of weight maintenance, after 7-10% weight loss (~6-7 months) and after independent weight loss (12 months) | Signaling between cells and organs will be examined by isolating exosomes (small extracellular vesicles) from blood and adipose tissue |
| Abdominal adipose tissue volumes | 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 | Before and after 4 to 8-weeks of weight maintenance, after 7-10% weight loss (~6-7 months) and after independent weight loss (12 months) | 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 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 | Before and after 4 to 8-weeks of weight maintenance, after 7-10% weight loss (~6-7 months) and after independent weight loss (12 months) | Thigh and calf adipose tissue volumes will be assessed by magnetic resonance imagining (MRI) |
| Intra-hepatic triglyceride content | 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 techniques |
| Change in intra-hepatic triglyceride content | Before and after 4 to 8-weeks of weight maintenance, after 7-10% weight loss (~6-7 months) and after independent weight loss (12 months) | Intra-hepatic triglyceride content will be assessed by magnetic resonance techniques |
| Gut microbiome | 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 | Before and during 4 to 8-weeks of weight maintenance, 7-10% weight loss (~6-7 months) and independent weight loss (12 months) | 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 |
| Plasma lipid profile | Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects). | Fasting plasma lipid profile will be assessed by nuclear magnetic resonance (NMR) techniques |
| Change in plasma lipid profile | Before and after 4 to 8-weeks of weight maintenance, after 7-10% weight loss (~6-7 months) and after independent weight loss (12 months) | Fasting plasma lipid profile will be assessed by nuclear magnetic resonance (NMR) techniques |
| Aerobic fitness | Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects). | Maximal oxygen consumption will be assessed using indirect calorimetry during a graded exercise test to volitional fatigue |
| Change in aerobic fitness | Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals randomized to the plant-based very-low-fat diet only | Maximal oxygen consumption will be assessed using indirect calorimetry during a graded exercise test to volitional fatigue |
| Carotid artery intima media thickness | 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 | Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only | Carotid artery intima media thickness will be assessed by ultrasound imaging |
| Cardiac structure and function | Baseline only (cross-sectional comparison of metabolically normal lean, 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 | Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only | Ultrasound techniques will be used to assess cardiac structure and function |
| Endothelial function | Baseline only (cross-sectional comparison of metabolically normal lean, 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 | Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only | 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 normal lean, metabolically normal obese and metabolically abnormal obese subjects). | Arterial stiffness will be assessed using a non-invasive device (SphygmoCor) |
| Change in arterial stiffness | Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only | Arterial stiffness will be assessed using a non-invasive device (SphygmoCor) |
| Physical activity | Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects). | Physical activity will be assessed using tri-axial accelerometry |
| Change in physical activity | Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only | Physical activity will be assessed using tri-axial accelerometry |
| Sleep efficiency | Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects). | Sleep efficiency will be assessed using tri-axial accelerometry |
| Change in sleep efficiency | Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only | Sleep efficiency will be assessed using tri-axial accelerometry |
| Rate of incorporation of 2H2O into lipids | Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects). | Metabolic pathways relating to lipid (fat) synthesis in the liver and adipose tissue (fat) will be assessed by heavy water (2H2O) ingestion followed by fat biopsies and blood sampling |
| Change in the rate of incorporation of 2H2O into lipids | Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only | Metabolic pathways relating to lipid (fat) synthesis in the liver and adipose tissue (fat) will be assessed by heavy water (2H2O) ingestion followed by fat biopsies and blood sampling |
| Rate of incorporation of 2H2O into proteins | Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects). | Metabolic pathways relating to protein synthesis in the muscle and adipose tissue will be assessed by heavy water (2H2O) ingestion followed by skeletal muscle and and adipose tissue biopsies and blood sampling |
| Change in the rate of incorporation of 2H2O into proteins | Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only | Metabolic pathways relating to protein synthesis in the muscle and adipose tissue will be assessed by heavy water (2H2O) ingestion followed by skeletal muscle and and adipose tissue biopsies and blood sampling |
| Taste intensity | Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects). | Subjects will be evaluated by using the NIH toolbox Taste Intensity Test |
| Change in taste intensity | Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only | Subjects will be evaluated by using the NIH toolbox Taste Intensity Test |
| Sweet taste palatability | Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects). | Sweet palatability will be assessed using the general Labeled Magnitude Scale |
| Change in sweet taste palatability | Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only | Sweet palatability will be assessed using the general Labeled Magnitude Scale |
| Immune function | Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects). | Immune cell populations within plasma and adipose tissue will be profiled using multi-color fluorescence activated cell sorting (FACS) techniques. |
| Change in immune function | Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only | Immune cell populations within plasma and adipose tissue will be profiled using multi-color fluorescence activated cell sorting (FACS) techniques. |
| Food consumption-induced changes in brain blood flow | Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects). | Food consumption-induced changes in brain blood flow will be assessed by blood-oxygen dependent (BOLD) and arterial spin labeling using functional magnetic resonance imaging (fMRI) techniques |
| Change in food consumption-induced changes in brain blood flow | Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only | Food consumption-induced changes in brain blood flow will be assessed by blood-oxygen dependent (BOLD) and arterial spin labeling using functional magnetic resonance imaging (fMRI) techniques |
| Transcriptome in blood, muscle and adipose tissue | Baseline only (cross-sectional comparison of metabolically normal lean, 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 | Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only | The transcriptome (all RNA that are responsible for making proteins from DNA templates) will be evaluated by using RNA sequencing techniques |
| Epigenome in blood, muscle and adipose tissue | Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects). | The epigenome (chemical modifications of DNA that signal genes to be on or off) will be evaluated by using Illumina Infinium HumanMethylation450 BeadChip assays. |
| Change in epigenome in blood, muscle and adipose tissue | Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only | The epigenome (chemical modifications of DNA that signal genes to be on or off) will be evaluated by using Illumina Infinium HumanMethylation450 BeadChip assays. |
| Dopamine receptor binding potential | Baseline in fasted and fed states in metabolically abnormal obese participants only. | Dopamine receptor binding potential will be assessed by Positron Emission Tomography (PET) using \[11C\]raclopride in the fasted and fed states |
| Subcutaneous abdominal adipose tissue oxygen tension | Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects). | Oxygen tension will be assessed in subcutaneous abdominal adipose tissue in the abdomen using oxygen-sensitive fiber-optic probes (OxyLiteTM, Oxford Optronix, Ltd) |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORSamuel Klein, MD
Washington University School of Medicine
Outcome results
None listed