Complex Effects of Dietary Manipulation on Metabolic Function, Inflammation and Health

NCT02706262 | Active Not Recruiting DMC

• 1 other identifier: PSQ-201512086
• Study Type: interventional
• Target: 180
• Locations: 1 country
• Sites: 1

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.

Conditions

Obesity; Insulin Resistance

Outcome Measures

Primary Outcomes (2)

• Insulin sensitivity

  Whole-body insulin sensitivity will be assessed by using the hyperinsulinemic-euglycemic clamp procedure

  Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).

• Change in insulin sensitivity

  Whole-body insulin sensitivity will be assessed by using the hyperinsulinemic-euglycemic clamp procedure

  Before and after 4 to 8-weeks of weight maintenance and after 7-10% weight loss (~6-7 months)

Secondary Outcomes (59)

• 24-hour glucose concentrations

  Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).

• 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)

• 24-hour hormone concentrations

  Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).

• 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)

• 24-hour cytokine concentrations

  Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).

Study Arms (5)

Metabolically normal lean - Baseline testing only

NO INTERVENTION

Metabolically normal lean - Lean individuals that have good glucose (sugar) control, normal plasma triglyceride (fat) levels and a low liver fat content. Dietary intervention - None.

Metabolically normal obese - Baseline testing only

NO INTERVENTION

Metabolically normal obese - Persons with obesity that have good glucose (sugar) control, normal plasma triglyceride (fat) levels and a low liver fat content. Dietary intervention - None.

Metabolically abnormal obese - Mediterranean diet

EXPERIMENTAL

Metabolically abnormal obese - Persons with obesity with glucose levels higher than recommended and a moderate to high amount of fat in the liver. Dietary intervention - A nutritionally balanced diet that includes fruits, vegetables, fish, beans, whole grains, and olive oil with approximately 50% of daily calories coming from complex carbohydrates, 30% of calories from fat, and 20% of calories from protein.

Other: Metabolically abnormal obese - Mediterranean diet; Behavioral: Annual Follow-up Visits

Metabolically abnormal obese - Low carbohydrate ketogenic diet

EXPERIMENTAL

Metabolically abnormal obese - Persons with obesity with glucose levels higher than recommended and a moderate to high amount of fat in the liver. Dietary intervention - A very-low-carbohydrate, adequate protein, high-fat diet containing 20 grams of carbohydrate or less per day (about 5% of calories), derived mainly from vegetables.

Other: Metabolically abnormal obese - Low carbohydrate ketogenic diet; Behavioral: Annual Follow-up Visits

Metabolically abnormal obese - Plant-based very-low-fat diet

EXPERIMENTAL

Metabolically abnormal obese - Persons with obesity with glucose levels higher than recommended and a moderate to high amount of fat in the liver. Dietary intervention - A plant-based diet high in complex carbohydrates and low in fat, protein, and sodium, with approximately 70% of daily calories from carbohydrates, 15% from fat, and 15% from protein.

Other: Metabolically abnormal obese - Plant-based, very-low-fat diet; Behavioral: Annual Follow-up Visits

Interventions

Metabolically abnormal obese - Mediterranean diet OTHER

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.

Metabolically abnormal obese - Mediterranean diet

Metabolically abnormal obese - Low carbohydrate ketogenic diet OTHER

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.

Metabolically abnormal obese - Low carbohydrate ketogenic diet

Metabolically abnormal obese - Plant-based, very-low-fat diet OTHER

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.

Metabolically abnormal obese - Plant-based very-low-fat diet

Annual Follow-up Visits BEHAVIORAL

Metabolic health will be assessed 1 and 2-years after competing the diet intervention study. No intervention will be performed during the time.

Metabolically abnormal obese - Low carbohydrate ketogenic diet; Metabolically abnormal obese - Mediterranean diet; Metabolically abnormal obese - Plant-based very-low-fat diet

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Publications (15)

• 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.

  PMID: 38569471 BACKGROUND

• 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.

  PMID: 38228469 BACKGROUND

• 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.

  PMID: 31528845 RESULT

• 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.

  PMID: 31454790 RESULT

• 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.

  PMID: 32086877 RESULT

• 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.

  PMID: 32099031 RESULT

• 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.

  PMID: 32191646 RESULT

• 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.

  PMID: 31805015 RESULT

• 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.

  PMID: 33164985 RESULT

• 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.

  PMID: 33743554 RESULT

• 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.

  PMID: 34004161 RESULT

• 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.

  PMID: 35817849 RESULT

• 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.

  PMID: 34905513 RESULT

• 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.

  PMID: 37475685 RESULT

• 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.

  PMID: 37365374 RESULT

MeSH Terms

Conditions

Obesity; Insulin Resistance

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases

Study Officials

• Samuel Klein, MD

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 24, 2016
• First Posted: March 11, 2016
• Study Start: February 1, 2016
• Primary Completion: April 1, 2025
• Study Completion (Estimated): December 1, 2027
• Last Updated: January 27, 2026

Record last verified: 2026-01

Locations

US (1)