Mechanisms Underlying Metabolic Syndrome in Obesity

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to better understand the link between obesity and diabetes or pre-diabetes.

Detailed Description
-----------------
Obesity is the most common and powerful force for creating insulin resistance and metabolic syndrome, however, the molecular basis of this association is not well understood. In this proposal, three independently funded researchers-Philip Kern, MD a clinical investigator, and Charlotte Peterson, PhD and Robert McGehee, PhD, with significant experience in muscle and adipocyte biology, respectively-will formalize a collaborative effort as a natural extension of previous work and shared interests in the fields of obesity, insulin resistance, and tissue lipid accumulation. Our overall hypothesis is that insulin resistance in humans stems largely from ectopic accumulation of intramyocellular lipid (IMCL) during the development of obesity. Further, we hypothesize that excess IMCL accumulation is dependent on secretory proteins derived from a complex interplay between adipocytes and macrophages in adipose tissue. To test these hypotheses, we will examine the interactions among adipocytes, macrophages, and muscle cells isolated and cultured from subjects that are obese with insulin resistance and impaired glucose tolerance (IGT), and from some with Type 2 Diabetes. This study population has elevated IMCL and is at high risk for obesity complications, but avoids the pathophysiologic complications of glucotoxicity. These subjects will be compared to obese subjects with normal glucose tolerance (NGT). Aim 1 will explore mechanisms that contribute to IMCL and elucidate its role in the development of IGT. Cultured muscle cells will be used to determine whether obese subjects with IGT versus NGT demonstrate intrinsic differences in muscle gene expression and metabolic activity under differing extracellular fatty acid concentrations. Lipid accumulation and oxidation, and insulin-mediated glycogen synthesis and signaling will be assessed. Aim 2 will determine if the IMCL accumulation is dependent on adipose tissue secretory proteins. We will use co-cultures of adipocytes, myoblasts, and adipose stromal vascular cells to examine IMCL and the development of insulin resistance. Aim 3 will determine whether the stromal fraction from IGT subjects promotes IMCL more effectively than that from NGT subjects in co-cultures with muscle cells. We will compare the stromal vascular fractions with regard to monocyte/macrophage accumulation and cytokine expression. Aim 4 will determine if improved glucose tolerance in response to a 10-week treatment with pioglitazone results in decreased IMCL and identify cellular mechanisms involved. Co-culture studies will also be used with muscle and stromal cells, before and after pioglitazone treatment. These experiments will provide mechanistic insight into the link between obesity and muscle function leading to metabolic syndrome.

Official Title
-----------------
Mechanisms Underlying Metabolic Syndrome in Obesity

Conditions
-----------------
Metabolic Syndrome, Insulin Resistance, Prediabetes

Intervention / Treatment
-----------------
* Drug: Pioglitazone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 18-65 years of age BMI 28+ diabetes, impaired glucose tolerance or normal glucose tolerance Exclusion Criteria: AST >2x normal congestive heart failure history of coronary artery disease chronic renal insufficiency (creatinine > 1.4mg/dl) use of gemfibrozil, ACE inhibitors, and angiotensin receptor II blockers, or anticoagulants

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?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: 1<br>Baseline studies (OGTT, DXA, RMR, FSIGT, and biopsies) on normal control subjects. Oral glucose tolerance tests, body composition assessment, resting metabolic rate, insulin sensitivity measurement with the frequently sampled method and Minimal Model. These studies will establish baseline data in lean subjects on adipose tissue gene expression, insulin sensitivity, glucose tolerance, metabolic rate and body composition. There is no intervention. | |
| Active Comparator: 2<br>Baseline studies (OGTT, DXA, RMR, FSIGT, biopsies), then 10 weeks treatment on Pioglitazone. Baseline tests are repeated at the end of medication treatment. All of the studies described in arm 1 are repeated after treatment. The subjects in this group have impaired glucose tolerance. After the measurement of adipose tissue gene expression, insulin sensitivity, glucose tolerance, metabolic rate and body composition, subjects are treated with pioglitazone, working up to 45 mg/day, for 10 weeks. After this time, adipose tissue gene expression, insulin sensitivity, glucose tolerance, metabolic rate and body composition are repeated. | Drug: Pioglitazone<br>* Pioglitazone 30mg for 2 weeks, then Pioglitazone 45mg for 8 weeks.<br>* Other names: Actos;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Insulin Sensitivity Using FSIGT | The frequently sampled intravenous glucose tolerance test (FSIGT) involves the injection of IV glucose and the frequent measurement of glucose and insulin. | Baseline and 10 weeks | 
| Effects of Pioglitazone on Changes in BMI | Body Mass Index (BMI) is measured at baseline, in lean and obese subjects, and after pioglitazone in obese subjects | Baseline and 10 weeks | 
| Changes in Muscle Lipid After Pioglitazone | Muscle lipid following biopsy using oil red-O staining. | At baseline and 10 weeks | 
| Changes in Fat Inflammation Following Pioglitazone | macrophages in fat at baseline, in lean and obese participants, and obese after pioglitazone (in obese) | Baseline and 10 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
obesity, inflammation, diabetes