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

Stanford University

Status: Enrolling

Conditions: Nonalcoholic Fatty Liver; Insulin Resistance; Obesity; Diabetes Mellitus, Type 2; Diet Modification; Nonalcoholic Steatohepatitis; PreDiabetes

Treatments: Behavioral: Dietary Intervention Standard Low Carbohydrate Diet; Behavioral: Dietary Intervention Standard Low Fat Diet; Behavioral: Dietary Intervention Mediterranean Low Carbohydrate Diet

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT05165706

5R01DK110186-02 (U.S. NIH Grant/Contract)

40195

Details and patient eligibility

About

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.

Full 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.

Enrollment: 110 estimated patients

Sex: All

Ages: 35 to 65 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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110 participants in 3 patient groups

Mediterranean Low Carbohydrate Diet

Experimental group

Description:

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.

Treatment:

Behavioral: Dietary Intervention Mediterranean Low Carbohydrate Diet

Standard Low Carbohydrate Diet

Experimental group

Description:

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.

Treatment:

Behavioral: Dietary Intervention Standard Low Carbohydrate Diet

Low Fat, Healthy Carbohydrate Diet

Experimental group

Description:

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.

Treatment:

Behavioral: Dietary Intervention Standard Low Fat Diet