Composition & Function of Sarcoplasmic Reticulum in Persons With the Metabolic Syndrome

Study Overview
=================
Brief Summary
-----------------
The investigators previous research has suggested that lipid (fatty) composition in the muscle cells of mice plays a key role in their insulin sensitivity. The purpose of this study is to determine whether these specific fat signatures translate to humans by comparing the muscle of healthy patients to those with pre-diabetes, or the metabolic syndrome.

Detailed Description
-----------------
The Comp-SR study explores the role of lipid metabolism in key metabolic pathways in skeletal muscle. It is a translation of previous research done in mice studying the effects and functions of certain key enzymes involved in lipid metabolism found to be associated with insulin resistance. These enzymes are fatty acid synthase (FAS), choline/ethanolamine phosphotransferase 1 (CEPT1) and sarcoplasmic-endoplasmic reticulum ATPase (SERCA). Based on the investigators research, it appears that the activity and function of these enzymes determines the ratio of certain phospholipids in the sarcoplasmic reticulum (SR), namely phosphatidylethanolamine (PE) and phosphatidylcholine (PC). Furthermore, the investigators have found that the ratio of these phospholipids correlates with the mouse's sensitivity to insulin. Based on the muscle biopsies of four healthy persons, it was found that human muscle contains similar phospholipids and phospholipid ratios to mice. It is hypothesized that these phospholipid signatures may be predictive of the metabolic status of humans as well. The specific aims of this study are to determine if the composition and function of the sarcoplasmic reticulum is altered in persons with the metabolic syndrome compared to lean controls. This knowledge could provide new understanding of impediments to effective therapy, novel biomarkers of disease progression, and innovative treatment targets for diabetes.

Official Title
-----------------
Modulating Physiologic Effects Of Phospholipid Metabolism In Obesity And Diabetes; AIM 4: Composition and Function of Sarcoplasmic Reticulum in Persons With the Metabolic Syndrome

Conditions
-----------------
Metabolic Syndrome

Intervention / Treatment
-----------------
* Procedure: muscle biopsy


Participation Criteria
=================
Eligibility Criteria
-----------------
Control subjects Inclusion: Sedentary: No routine exercise, walking <10,000 steps per day Age >18 and <65 Body Mass Index (BMI) <32 Healthy by physical exam (patient is devoid of major acute or chronic illness) No significant abnormality in screening labs Exclusion: Currently on any significant prescription medications other than oral contraceptives in women Currently Pregnant Current Tobacco Use Subjects with the Metabolic Syndrome Inclusion: Sedentary: No routine exercise, walking <10,000 steps per day Age >18 and <65 Body Mass Index (BMI) >30 Meet at least three of the following Adult Treatment Panel (ATP) III criteria for the metabolic syndrome: waist circumference > or = 40 inches in men, > or = 35 inches in women blood triglycerides > or = 150 mg/dL blood HDL cholesterol <40 mg/dL in men, <50 in women blood pressure > or = 130 mmHg systolic, or > or = 85 mmHg diastolic fasting blood sugar > or = 100 mg/dL Exclusion: Diagnosed with Type 2 diabetes, coronary artery disease, cancer, liver, lung, or kidney disease or any other major illness Currently on any significant prescription medications other than: oral contraceptives in women More than two standard medication for stage 1 hypertension in men or women (blood pressure 140-159/90-99) Currently Pregnant Current Tobacco Use

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Metabolic Syndrome<br>Muscle biopsy to determine sarcoplasmic reticulum composition and function, Oral Glucose tolerance test with insulin levels at time points to determine Insulin sensitivity, DEXA scan to determine lean muscle and fat mass | Procedure: muscle biopsy<br>* A member of the study team will obtain a small sample of muscle tissue from the patient's thigh (vastus lateralis muscle).<br>|
| Control<br>Muscle biopsy to determine sarcoplasmic reticulum composition and function, Oral Glucose tolerance test with insulin levels at time points to determine Insulin sensitivity, DEXA scan to determine lean muscle and fat mass | Procedure: muscle biopsy<br>* A member of the study team will obtain a small sample of muscle tissue from the patient's thigh (vastus lateralis muscle).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sarcoplasmic Reticulum Composition | We will take a muscle tissue sample from the subject's thigh (vastus lateralis) to quantify phosphatidylcholine to phosphatidylethanolamine ratio of the sarcoplasmic reticulum, as well as SERCA activity and FAS and CEPT1 quantity in the sample. | Study Visit Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin Sensitivity | We will perform an oral glucose tolerance test with insulin levels obtained at each time point to determine the Matsuda index, an estimation of insulin sensitivity. | Study visit week 4 | 
| Lean and Fat Body Mass | We will perform a Duel Energy X-ray absorptiometry (DEXA) scan to approximate lean and fat body mass of study subjects. | Study Visit week 4 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Pre-diabetes, Metabolic Syndrome, impaired glucose tolerance, Phospholipids