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

Sponsor

Stanford University (Other)

Overall Status

Recruiting

CT.gov ID

NCT05165706

Collaborator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)

110

Enrollment

Location

Arms

Anticipated Duration (Months)

2.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2 PreDiabetes Insulin Resistance Obesity Nonalcoholic Steatohepatitis Nonalcoholic Fatty Liver Diet Modification	Behavioral: Dietary Intervention Behavioral: Dietary Intervention Behavioral: Dietary Intervention	N/A

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 Design

Study Type:

Interventional

Anticipated Enrollment :

110 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

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

Actual Study Start Date :

Jan 31, 2019

Anticipated Primary Completion Date :

Sep 30, 2022

Anticipated Study Completion Date :

Sep 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Mediterranean Low Carbohydrate Diet	Behavioral: Dietary Intervention 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	Behavioral: Dietary Intervention 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	Behavioral: Dietary Intervention 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.

Arm

Intervention/Treatment

Experimental: Mediterranean Low Carbohydrate Diet

Behavioral: Dietary Intervention

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

Behavioral: Dietary Intervention

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

Behavioral: Dietary Intervention

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.

Outcome Measures

Primary Outcome Measures

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