Mechanisms Underlying Metabolic Syndrome in Obesity

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
University of Arkansas
ClinicalTrials.gov Identifier:
NCT00579813
First received: December 20, 2007
Last updated: August 22, 2011
Last verified: August 2011
  Purpose

The purpose of this study is to better understand the link between obesity and diabetes or pre-diabetes.


Condition Intervention Phase
Metabolic Syndrome
Insulin Resistance
Prediabetes
Drug: Pioglitazone
Phase 4

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Mechanisms Underlying Metabolic Syndrome in Obesity

Resource links provided by NLM:


Further study details as provided by University of Arkansas:

Primary Outcome Measures:
  • Particpants [ Time Frame: December 2009 ] [ Designated as safety issue: No ]

Enrollment: 70
Study Start Date: April 2005
Study Completion Date: January 2011
Primary Completion Date: January 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: Pioglitazone
Pioglitazone 30mg for 2 weeks, then Pioglitazone 45mg for 8 weeks.
Other Name: Actos

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.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00579813

Locations
United States, Arkansas
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States, 72205
Sponsors and Collaborators
University of Arkansas
Investigators
Principal Investigator: Robert E McGehee, Ph.D. University of Arkansas
  More Information

No publications provided

Responsible Party: University of Arkansas
ClinicalTrials.gov Identifier: NCT00579813     History of Changes
Other Study ID Numbers: 32677, NIH grant R01DK071277
Study First Received: December 20, 2007
Results First Received: February 22, 2011
Last Updated: August 22, 2011
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by University of Arkansas:
obesity
inflammation
diabetes

Additional relevant MeSH terms:
Obesity
Syndrome
Metabolic Syndrome X
Insulin Resistance
Overnutrition
Nutrition Disorders
Overweight
Body Weight
Signs and Symptoms
Disease
Pathologic Processes
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Pioglitazone
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 18, 2014