Longitudinal Multi-Omic Profiles to Reveal Mechanisms of Obesity-Mediated Insulin Resistance

This 12-week controlled diet and weight intervention study seeks to define the molecular pathways that link excess body weight to the development of insulin resistance (IR). Blood, adipose and stool are sampled at three timepoints; baseline, peak weight (4 weeks) and post weight loss to monitor changes in cellular processes. Additionally, direct insulin sensitivity testing, and radiological measurement of visceral fat and intrahepatic fat content is measured at three timepoints to correlate clinical indices with cellular changes.

Study Overview

• Status: Recruiting
• Conditions: Obesity; Diabetes Mellitus, Type 2; Insulin Resistance; PreDiabetes; Diet Modification; Nonalcoholic Steatohepatitis; Nonalcoholic Fatty Liver
• Intervention / Treatment: Behavioral: Dietary Intervention Mediterranean Low Carbohydrate Diet; Behavioral: Dietary Intervention Standard Low Carbohydrate Diet; Behavioral: Dietary Intervention Standard Low Fat Diet

Detailed Description

Obesity has become an epidemic worldwide. Metabolic/cardiovascular complications of obesity are likely related to the fact that obese individuals tend to be insulin resistant (IR). While insulin- mediated glucose uptake (IMGU) correlates with adipose tissue mass, not all obese individuals are IR, and metabolic and cardiovascular profiles of those who are IR vs insulin sensitive (IS) differ significantly. Why one individual who reaches a BMI of 30 kg/m2 will develop IR and another with similar BMI and activity level remains IS is unclear. Furthermore, while insulin sensitivity improves with weight loss, this response varies as well. Given that fat mass per se does not fully explain the obesity contribution to IMGU, itis likely that differential adipocyte function plays a role. With this study, our purpose is to employ an integrated omics strategy to identify analyte/pathway signatures in blood and adipose tissue that characterize IR versus IS states and expand our biological knowledge of the mechanisms underlying IR.

• Study Type: Interventional
• Enrollment (Estimated): 110
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Ekrem M Ayhan, BS; Phone Number: 908-619-5381; Email: ayhane@stanford.edu
• Study Contact Backup: Name: Dalia Perelman, MS, RD; Email: daliap@stanford.edu

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Recruiting
      • Stanford University
      • Contact: Ekrem M Ayhan, BS; Phone Number: 908-619-5381; Email: ayhane@stanford.edu
      • Contact: Dalia Perelman, MS, RD; Email: daliap@stanford.edu
      • Principal Investigator: Tracey L McLaughlin, MD, MS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Age 35-65
• BMI 25-35 kg/m2
• Stable body weight
• Nondiabetic

Exclusion Criteria:

Patients with;

• diabetes
• major organ disease
• history of liposuction or bariatric surgery
• active eating or psychiatric disorder
• pregnancy or lactation, heavy alcohol use
• recent change in weight (over the past 12 weeks)
• use of weight loss medication, statins, or oral steroids

Clinical screening exclusions;

• hematocrit < 33%
• fasting glucose >/= 126 mg/dL
• blood pressure >160/100 mmHg

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Mediterranean Low Carbohydrate Diet; Assigned participants will receive instruction by a registered dietitian on a diet that is high in unsaturated fats and low in carbohydrates. Total caloric intake will be adjusted to induce a supervised metabolic challenge defined as weight gain of approximately 2.5 kg over 5 weeks followed by 3-5kg weight loss over 8 weeks.	Behavioral: Dietary Intervention Mediterranean Low Carbohydrate Diet; Assigned participants will receive instruction by a registered dietitian on a diet that is high in unsaturated fats and low in carbohydrates. Total caloric intake will be adjusted to induce a supervised metabolic challenge defined as weight gain of approximately 2.5 kg over 5 weeks followed by 3-5kg weight loss over 8 weeks.
Experimental: Standard Low Carbohydrate Diet; Assigned participants will receive instruction by a registered dietitian on a low carbohydrate diet that is high in fats found in the typical American diet. Total caloric intake will be adjusted to induce a supervised metabolic challenge defined as weight gain of approximately 2.5 kg over 5 weeks followed by 3-5kg weight loss over 8 weeks.	Behavioral: Dietary Intervention Standard Low Carbohydrate Diet; Assigned participants will receive instruction by a registered dietitian on a low carbohydrate diet that is high in fats found in the typical American diet. Total caloric intake will be adjusted to induce a supervised metabolic challenge defined as weight gain of approximately 2.5 kg over 5 weeks followed by 3-5kg weight loss over 8 weeks.
Experimental: Low Fat, Healthy Carbohydrate Diet; Assigned participants will receive instruction by a registered dietitian on a low fat diet that is high in complex carbohydrates. Total caloric intake will be adjusted to induce a supervised metabolic challenge defined as weight gain of approximately 2.5 kg over 5 weeks followed by 3-5kg weight loss over 8 weeks.	Behavioral: Dietary Intervention Standard Low Fat Diet; Assigned participants will receive instruction by a registered dietitian on a low fat diet that is high in complex carbohydrates. Total caloric intake will be adjusted to induce a supervised metabolic challenge defined as weight gain of approximately 2.5 kg over 5 weeks followed by 3-5kg weight loss over 8 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline on the 2-stage Steady State Plasma Glucose test	Compare direct measurement of insulin sensitivity after 4 week diet and weight intervention	Peak weight (4 weeks)
Change from baseline on the radiographic measurement of visceral to subcutaneous (V:S) fat ratio	Compare measurement of abdominal V:S fat volume via computed tomography (CT) after 4 week diet and weight intervention	Peak weight (4 weeks)
Change from baseline on the magnetic-resonance based measurement of intrahepatic lipid deposition	Compare measurement of liver fat content via magnetic resonance spectroscopy (MRS) after 4 week diet and weight intervention	Peak weight (4 weeks)
Change from peak weight on the 2-stage Steady State Plasma Glucose test	Compare direct measurement of insulin sensitivity after 8 week diet and weight intervention	Post-weight loss (8 weeks)
Change from baseline on the radiographic measurement of visceral to subcutaneous (V:S) fat ratio	Compare measurement of abdominal V:S fat volume via computed tomography (CT) after 8 week diet and weight intervention	Post-weight loss (8 weeks)
Change from baseline on the magnetic-resonance based measurement of intrahepatic lipid deposition	Compare measurement of liver fat content via magnetic resonance spectroscopy (MRS) after 8 week diet and weight intervention	Post-weight loss (8 weeks)
Quantification of plasma inflammatory cytokine levels in serum samples by Luminex immunoassay	Compare plasma inflammatory cytokine levels in serum samples as measured by Luminex immunoassay between participants identified as Insulin Sensitive (IS) and Insulin Resistant (IR) using the 2-stage Steady State Plasma Glucose test.	Baseline
Change from baseline in plasma inflammatory cytokine levels in serum samples as measured by Luminex immunoassay	Compare intra-personal levels of plasma inflammatory cytokines as measured by Luminex immunoassay after 4 week diet and weight intervention	Peak Weight (4 weeks)
Measurement of markers of lipid and carbohydrate metabolism and inflammation from adipose mRNA	Compare adipose tissue transcripts such as known MODY transcription factors, defensin chemokine receptors, and platelet activation factors measured by PCR between participants identified as Insulin sensitive (IS) and Insulin resistant (IR) using the 2-stage Steady State Plasma Glucose test.	Baseline

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Tracey McLaughlin, MD, Stanford University, Department of Medicine, Division of Endocrinology

Study record dates

Study Major Dates

• Study Start (Actual): January 31, 2019
• Primary Completion (Estimated): November 30, 2026
• Study Completion (Estimated): December 30, 2026

Study Registration Dates

• First Submitted: July 3, 2018
• First Submitted That Met QC Criteria: December 7, 2021
• First Posted (Actual): December 21, 2021

Study Record Updates

• Last Update Posted (Actual): December 4, 2024
• Last Update Submitted That Met QC Criteria: December 2, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Microbiome; Metabolomics; Low Fat Diet; Low Carbohydrate Diet
• Additional Relevant MeSH Terms: Endocrine System Diseases; Nutrition Disorders; Metabolic Diseases; Overnutrition; Body Weight; Digestive System Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Liver Diseases; Hyperinsulinism; Overweight; Obesity; Diabetes Mellitus, Type 2; Fatty Liver; Non-alcoholic Fatty Liver Disease; Insulin Resistance
• Other Study ID Numbers: 40195; 5R01DK110186-02 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No