Clinical trial NCT02706262: Complex Effects of Dietary Manipulation on Metabolic Function, Inflammation and Health
Official title: Complex Effects of Dietary Manipulation on Metabolic Function, Inflammation and Health
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Obesity
Insulin Resistance
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
First posted: 2016-03-11
Enrollment: 180
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 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.

Eligibility criteria: 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

Primary outcomes:
measure: Insulin sensitivity
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: Change in insulin sensitivity
timeFrame: Before and after 4 to 8-weeks of weight maintenance and after 7-10% weight loss (~6-7 months)
Secondary outcomes:
measure: 24-hour glucose concentrations
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: Change in 24-hour glucose concentrations
timeFrame: Before and after 4 to 8-weeks of weight maintenance and after 7-10% weight loss (~6-7 months)
measure: 24-hour hormone concentrations
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: Change in 24-hour hormone concentrations
timeFrame: Before and after 4 to 8-weeks of weight maintenance and after 7-10% weight loss (~6-7 months)
measure: 24-hour cytokine concentrations
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: β-cell function
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: Change in β-cell function
timeFrame: Before and after 7-10% weight loss (~6-7 months) and independent weight loss (12 months) in metabolically abnormal obese individuals only.
measure: Insulin clearance
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: Insulin clearance
timeFrame: Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only.
measure: Fat mass and fat free mass
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: Change in fat mass and fat free mass
timeFrame: 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)
measure: Exosome-mediated intercellular signaling
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: Change in exosome-mediated intercellular signaling
timeFrame: 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)
measure: Abdominal adipose tissue volumes
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: Change in abdominal adipose tissue volumes
timeFrame: 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)
measure: Leg adipose tissue volumes
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: Change in leg adipose tissue volumes
timeFrame: 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)
measure: Intra-hepatic triglyceride content
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: Change in intra-hepatic triglyceride content
timeFrame: 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)
measure: Gut microbiome
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: Change in gut microbiome
timeFrame: Before and during 4 to 8-weeks of weight maintenance, 7-10% weight loss (~6-7 months) and independent weight loss (12 months)
measure: Plasma lipid profile
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: Change in plasma lipid profile
timeFrame: 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)
measure: Aerobic fitness
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: Change in aerobic fitness
timeFrame: 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
measure: Carotid artery intima media thickness
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: Change in carotid artery intima media thickness
timeFrame: Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
measure: Cardiac structure and function
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: Change in cardiac structure and function
timeFrame: Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
measure: Endothelial function
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: Change in endothelial function
timeFrame: Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
measure: Arterial stiffness
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: Change in arterial stiffness
timeFrame: Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
measure: Physical activity
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: Change in physical activity
timeFrame: Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
measure: Sleep efficiency
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: Change in sleep efficiency
timeFrame: Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
measure: Rate of incorporation of 2H2O into lipids
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: Change in the rate of incorporation of 2H2O into lipids
timeFrame: Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
measure: Rate of incorporation of 2H2O into proteins
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: Change in the rate of incorporation of 2H2O into proteins
timeFrame: Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
measure: Taste intensity
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: Change in taste intensity
timeFrame: Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
measure: Sweet taste palatability
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: Change in sweet taste palatability
timeFrame: Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
measure: Immune function
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: Change in immune function
timeFrame: Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
measure: Food consumption-induced changes in brain blood flow
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: Change in food consumption-induced changes in brain blood flow
timeFrame: Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
measure: Transcriptome in blood, muscle and adipose tissue
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: Change in transcriptome in blood, muscle and adipose tissue
timeFrame: Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
measure: Epigenome in blood, muscle and adipose tissue
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
measure: Change in epigenome in blood, muscle and adipose tissue
timeFrame: Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
measure: Dopamine receptor binding potential
timeFrame: Baseline in fasted and fed states in metabolically abnormal obese participants only.
measure: Subcutaneous abdominal adipose tissue oxygen tension
timeFrame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
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: Petersen MC, Smith GI, Palacios HH, Farabi SS, Yoshino M, Yoshino J, Cho K, Davila-Roman VG, Shankaran M, Barve RA, Yu J, Stern JH, Patterson BW, Hellerstein MK, Shulman GI, Patti GJ, Klein S. Cardiometabolic characteristics of people with metabolically healthy and unhealthy obesity. Cell Metab. 2024 Apr 2;36(4):745-761.e5. doi: 10.1016/j.cmet.2024.03.002.
citation: Mittendorfer B, van Vliet S, Smith GI, Petersen MC, Patterson BW, Klein S. Impaired plasma glucose clearance is a key determinant of fasting hyperglycemia in people with obesity. Obesity (Silver Spring). 2024 Mar;32(3):540-546. doi: 10.1002/oby.23963. Epub 2024 Jan 16.
citation: Seo JB, Riopel M, Cabrales P, Huh JY, Bandyopadhyay GK, Andreyev AY, Murphy AN, Beeman SC, Smith GI, Klein S, Lee YS, Olefsky JM. Knockdown of Ant2 Reduces Adipocyte Hypoxia And Improves Insulin Resistance in Obesity. Nat Metab. 2019 Jan;1(1):86-97. doi: 10.1038/s42255-018-0003-x. Epub 2018 Nov 19.
citation: Stern JH, Smith GI, Chen S, Unger RH, Klein S, Scherer PE. Obesity dysregulates fasting-induced changes in glucagon secretion. J Endocrinol. 2019 Nov;243(2):149-160. doi: 10.1530/JOE-19-0201.
citation: Eisenstein SA, Black KJ, Samara A, Koller JM, Dunn JP, Hershey T, Klein S, Smith GI. Striatal Dopamine Responses to Feeding are Altered in People with Obesity. Obesity (Silver Spring). 2020 Apr;28(4):765-771. doi: 10.1002/oby.22753. Epub 2020 Feb 21.
citation: Ding X, Iyer R, Novotny C, Metzger D, Zhou HH, Smith GI, Yoshino M, Yoshino J, Klein S, Swaminath G, Talukdar S, Zhou Y. Inhibition of Grb14, a negative modulator of insulin signaling, improves glucose homeostasis without causing cardiac dysfunction. Sci Rep. 2020 Feb 25;10(1):3417. doi: 10.1038/s41598-020-60290-1.
citation: Smith GI, Polidori DC, Yoshino M, Kearney ML, Patterson BW, Mittendorfer B, Klein S. Influence of adiposity, insulin resistance, and intrahepatic triglyceride content on insulin kinetics. J Clin Invest. 2020 Jun 1;130(6):3305-3314. doi: 10.1172/JCI136756.
citation: Smith GI, Shankaran M, Yoshino M, Schweitzer GG, Chondronikola M, Beals JW, Okunade AL, Patterson BW, Nyangau E, Field T, Sirlin CB, Talukdar S, Hellerstein MK, Klein S. Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease. J Clin Invest. 2020 Mar 2;130(3):1453-1460. doi: 10.1172/JCI134165.
citation: Cifarelli V, Beeman SC, Smith GI, Yoshino J, Morozov D, Beals JW, Kayser BD, Watrous JD, Jain M, Patterson BW, Klein S. Decreased adipose tissue oxygenation associates with insulin resistance in individuals with obesity. J Clin Invest. 2020 Dec 1;130(12):6688-6699. doi: 10.1172/JCI141828.
citation: Beals JW, Smith GI, Shankaran M, Fuchs A, Schweitzer GG, Yoshino J, Field T, Matthews M, Nyangau E, Morozov D, Mittendorfer B, Hellerstein MK, Klein S. Increased Adipose Tissue Fibrogenesis, Not Impaired Expandability, Is Associated With Nonalcoholic Fatty Liver Disease. Hepatology. 2021 Sep;74(3):1287-1299. doi: 10.1002/hep.31822. Epub 2021 Jun 22.
citation: Fuchs A, Samovski D, Smith GI, Cifarelli V, Farabi SS, Yoshino J, Pietka T, Chang SW, Ghosh S, Myckatyn TM, Klein S. Associations Among Adipose Tissue Immunology, Inflammation, Exosomes and Insulin Sensitivity in People With Obesity and Nonalcoholic Fatty Liver Disease. Gastroenterology. 2021 Sep;161(3):968-981.e12. doi: 10.1053/j.gastro.2021.05.008. Epub 2021 May 15.
citation: Farabi SS, Smith GI, Schweitzer GG, Stein RI, Klein S. Do lifestyle factors and quality of life differ in people with metabolically healthy and unhealthy obesity? Int J Obes (Lond). 2022 Oct;46(10):1778-1785. doi: 10.1038/s41366-022-01180-6. Epub 2022 Jul 11.
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.
citation: Dunn JP, Lamichhane B, Smith GI, Garner A, Wallendorf M, Hershey T, Klein S. Dorsal striatal response to taste is modified by obesity and insulin resistance. Obesity (Silver Spring). 2023 Aug;31(8):2065-2075. doi: 10.1002/oby.23799.
citation: Beals JW, Kayser BD, Smith GI, Schweitzer GG, Kirbach K, Kearney ML, Yoshino J, Rahman G, Knight R, Patterson BW, Klein S. Dietary weight loss-induced improvements in metabolic function are enhanced by exercise in people with obesity and prediabetes. Nat Metab. 2023 Jul;5(7):1221-1235. doi: 10.1038/s42255-023-00829-4. Epub 2023 Jun 26.