Mechanisms Underlying Metabolic Syndrome in Obesity
|Study Design:||Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
|Official Title:||Mechanisms Underlying Metabolic Syndrome in Obesity|
- Particpants [ Time Frame: December 2009 ]
|Study Start Date:||April 2005|
|Study Completion Date:||January 2011|
|Primary Completion Date:||January 2009 (Final data collection date for primary outcome measure)|
No Intervention: 1
Baseline studies (OGTT, DXA, RMR, FSIGT, and biopsies) on normal control subjects.
Active Comparator: 2
Baseline studies (OGTT, DXA, RMR, FSIGT, biopsies), then 10 weeks treatment on Pioglitazone. Baseline tests are repeated at the end of medication treatment.
Pioglitazone 30mg for 2 weeks, then Pioglitazone 45mg for 8 weeks.
Other Name: Actos
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00579813
|United States, Arkansas|
|University of Arkansas for Medical Sciences|
|Little Rock, Arkansas, United States, 72205|
|Principal Investigator:||Robert E McGehee, Ph.D.||University of Arkansas|