Mechanisms Underlying Metabolic Syndrome in Obesity

Phase 4

Completed

Conditions: Metabolic Syndrome
Insulin Resistance
Prediabetes

Interventions: Drug: Pioglitazone

Registration Number: NCT00579813

Lead Sponsor: Philip Kern

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 70

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
2	Pioglitazone	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.

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method

Trial Locations

Locations (2): University of Arkansas for Medical Sciences
🇺🇸
Little Rock, Arkansas, United States
University of Kentucky
🇺🇸
Lexington, Kentucky, United States