Longitudinal Multi-Omic Profiles to Reveal Mechanisms of Obesity-Mediated Insulin Resistance
Overview
- Phase
- Not Applicable
- Intervention
- Not specified
- Conditions
- Diabetes Mellitus, Type 2
- Sponsor
- Stanford University
- Enrollment
- 110
- Locations
- 1
- Primary Endpoint
- Change from baseline on the magnetic-resonance based measurement of intrahepatic lipid deposition
- Status
- Recruiting
- Last Updated
- last year
Overview
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.
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.
Investigators
Tracey McLaughlin
Professor of Medicine
Stanford University
Eligibility Criteria
Inclusion Criteria
- •Age 35-65
- •BMI 25-35 kg/m2
- •Stable body weight
- •Nondiabetic
Exclusion Criteria
- •Patients with;
- •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
Outcomes
Primary Outcomes
Change from baseline on the magnetic-resonance based measurement of intrahepatic lipid deposition
Time Frame: Post-weight loss (8 weeks)
Compare measurement of liver fat content via magnetic resonance spectroscopy (MRS) after 8 week diet and weight intervention
Change from baseline in plasma inflammatory cytokine levels in serum samples as measured by Luminex immunoassay
Time Frame: Peak Weight (4 weeks)
Compare intra-personal levels of plasma inflammatory cytokines as measured by Luminex immunoassay after 4 week diet and weight intervention
Change from baseline on the 2-stage Steady State Plasma Glucose test
Time Frame: 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
Time Frame: Post-weight loss (8 weeks)
Compare measurement of abdominal V:S fat volume via computed tomography (CT) after 8 week diet and weight intervention
Measurement of markers of lipid and carbohydrate metabolism and inflammation from adipose mRNA
Time Frame: Baseline
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.
Quantification of plasma inflammatory cytokine levels in serum samples by Luminex immunoassay
Time Frame: 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 peak weight on the 2-stage Steady State Plasma Glucose test
Time Frame: Post-weight loss (8 weeks)
Compare direct measurement of insulin sensitivity after 8 week diet and weight intervention