Regional Fat Depots and Insulin Resistance

Study Overview
=================
Brief Summary
-----------------
The biological basis for insulin resistance associated with obesity is unknown. By studying equally-overweight/obese individuals who are either insulin resistant or insulin sensitive, the investigators will compare characteristics of fat tissue to test several hypotheses: 1) impaired differentiation and fat storage in the subcutaneous fat depot characterize insulin resistant individuals, who have, as a result, fat in other tissues like liver and muscle, as well as more fat circulating in the blood; 2) inflammation is greater in visceral and/or subcutaneous adipose tissue depots in insulin resistant individuals as compared with insulin sensitive individuals.

Detailed Description
-----------------
Insulin resistance (IR) is a major contributor to obesity-related morbidities such as diabetes and cardiovascular disease. While obesity is associated with IR, the biological basis for this association is unclear, and not all obese individuals are IR. The once-popular portal hypothesis, which states that lipolysis from VAT in particular accounts for IR, has been questioned because VAT contributes only 15% of the total systemic free fatty acid (FFA) flux. Other proposed mechanisms linking obesity to IR include inflammation, adiponectin, and ectopic fat. It is unclear whether VAT mass is more closely linked to IR than is subcutaneous adipose tissue (SAT) mass. Furthermore, evidence linking differential biological activity to IR in VAT or SAT is indirect, largely derived from studies comparing lean to obese or VAT to SAT without evaluation of IR. Thus, the purpose of this study is to investigate the biological mechanisms by which SAT and/or VAT contribute to IR. Specifically, the investigators will explore two related hypotheses- that impaired adipocyte differentiation in SAT is related to IR, ectopic fat deposition and expansion of VAT depot, and that inflammation in VAT is associated with IR. Utilizing adipose cell size/distribution obtained by Beckman Coulter Multisizer, gene expression via quantitative PCR, in-vivo quantification of IR via a modified insulin suppression test, and CT scans of abdomen/thigh, our specific aims are to: Confirm that impairment of adipocyte differentiation in SAT is associated with IR by comparing cell size characteristics and differentiation markers in IR and IS subjects undergoing elective surgery; Test the hypothesis that the same relationship will not be seen in VAT; Demonstrate that VAT mass is expanded in the presence of impaired differentiation of adipocytes in SAT; Demonstrate that intramuscular fat is related to both IR and impaired differentiation of adipocytes in SAT using cell size characteristics and differentiation markers; Demonstrate that increased inflammation in omental fat is associated with IR independent of obesity using inflammation markers (gene and protein).

Official Title
-----------------
Heterogeneity of Fat Depots

Conditions
-----------------
Diabetes Mellitus Type 2, Obesity, Insulin Resistance

Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: No major organ disease Fasting blood glucose < 126 mg/dL BMI 25-35 kg/m2 Nonpregnant/nonlactating Exclusion Criteria: pregnancy/lactation major organ disease drugs that influence insulin resistance unstable body weight or active weight loss program outside BMI range or age range diabetic by fasting glucose criteria 126 mg/dL or higher

Ages Eligible for Study
-----------------
Minimum Age: 39 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 |
| --- | --- |
| Insulin resistant group<br>there is no intervention | |
| Insulin sensitive group<br>There is no intervention | |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adipose Cell Size | Harvest adipose tissue from human biopsy. Prepare for cell size analysis using Beckman Multisizer Coulter Counter | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Macrophage density | Human adipose tissue will be formalin-fixed and paraffin-blocked for immunohistochemical analysis to identify macrophage number and pattern | 3 years | 
| Gene Expression | Adipose tissue from humans will be frozen and RNA prepared for measurement of relative expression of genes related to adipose cell differentiation, fat storage, and inflammation | 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
obesity, adipocyte differentiation, inflammation, insulin resistance, visceral fat, regional fat depots