Study of Changes in Skeletal Muscle After Caloric Restriction

Study Overview
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Brief Summary
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Research has shown that fat stored within muscles affects the muscle's sensitivity to insulin and ability to handle blood glucose. The purpose of this study is to examine the effects of weight loss surgery-induced caloric restriction on the accumulation and types of fats within skeletal muscle, as well as the effects of such caloric restriction on insulin sensitivity and inflammatory responses in skeletal muscle. The investigator proposes that caloric restriction will result in decreases in diacylglycerols enriched with saturated fat and increases in diacylglycerols enriched with monounsaturated fats.

Detailed Description
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We hypothesize that in a setting of surgically-induced weight loss decrements in select DAGs result in improved glucose utilization, altered insulin signaling and decreased inflammatory responses. We propose to examine the impact of molecular DAG species accumulation on glucose utilization, insulin signaling and inflammation in skeletal muscle from morbidly obese subjects before/after 10% weight loss facilitated by Roux-en-Y Gastric Bypass (RYGB). We will compare these results to those from a control, normal weight cohort The detected differences in DAG molecular species, insulin action, inflammatory responses between normal and obese subjects (before/after weight loss) will emphasize pathways coordinately altered as a consequence of adiposity and RYGB surgery. The primary endpoints for this study will be: Insulin sensitivity (glucose Rd, insulin levels, DAG mass, DAG species amounts).Secondary endpoints will be: FFA levels, inflammatory cytokine production, and insulin signaling in skeletal muscle.

Official Title
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Diacylglycerols and Insulin Action in Skeletal Muscle Upon Caloric Restriction

Conditions
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Obesity

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For Normal Weight Subjects: Age 21-65 years BMI of 21 to 27 kg/m2 Normal glucose tolerance as determined by OGTT on day of screening No family history of diabetes For Morbidly Obese Subjects: Age 21-65 years BMI of 30 to 65 kg/m2 Scheduled for Roux-en-Y gastric bypass at Vanderbilt Medical Center Insulin resistant as determined by OGTT on day of screening Exclusion Criteria (for all subjects): Clinically significant heart disease Clinically significant hepatic or renal disease Pregnancy Breastfeeding Any abnormality that would preclude safe completion of study Use of statins Use of thiazide or furosemide diuretics, beta blockers, or other chronic medications with known adverse effects on glucose tolerance levels unless subject has been on stable dose of such medications for the past 3 months before entering the study

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Normal body weight<br>Female subjects, ages 21-65 yrs, with BMI of 21-27 kg/m2 with normal glucose tolerance. | |
| Roux-en-Y gastric bypass<br>Female subjects ages 21-65 with insulin resistance and scheduled for Roux-en-Y gastric bypass at Vanderbilt University Medical Center will be studied before and 4-6 weeks after surgery. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| UPLC-ESI MS/MS profiling of lipd extracts from muscle biopsies to evaluate effects of gastric bypass induced-caloric restriction on diacylglycerol molecular species accumulation. |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the effects of gastric bypass induced-caloric restriction on skeletal muscle insulin action via a hyperinsulinemic-euglycemic clamp and profiling markers of insulin signaling. |  | 1 year | 
| To evaluate the effects of gastric bypass induced-caloric restriction on lipid-mediated inflammatory responses by profiling cytokines and free fatty acids in blood and inflammation markers in skeletal muscle biopsies. |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Obesity, Insulin sensitivity, Inflammation