Mechanisms Underlying Metabolic Syndrome in Obesity

Metabolic Syndrome Clinical Trial

Official title:

Mechanisms Underlying Metabolic Syndrome in Obesity

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00579813
• Other study ID #: 32677
• Secondary ID: R01DK071277
• Status: Completed
• Phase: Phase 4
• First received: December 20, 2007
• Last updated: May 8, 2017
• Start date: April 2005
• Est. completion date: January 2011

Study information

• Verified date: May 2017
• Source: University of Kentucky
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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 information / eligibility

• Status: Completed
• Enrollment: 70
• Est. completion date: January 2011
• Est. primary completion date: January 2009
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Insulin Resistance
• Metabolic Syndrome
• Metabolic Syndrome X
• Obesity
• Prediabetes
• Prediabetic State
• Syndrome

Intervention

Drug:
• Pioglitazone
Pioglitazone 30mg for 2 weeks, then Pioglitazone 45mg for 8 weeks.

Locations

Country	Name	City	State
United States	University of Kentucky	Lexington	Kentucky
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas

Sponsors (3)

Lead Sponsor	Collaborator
Philip Kern	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Effects of Obesity and Pioglitazone on Muscle Lipid and Inflammation and Insulin Sensitivity (FSIGT)	Effects of obese (vs lean) on muscle lipid, inflammation and insulin sensitivity, and effects of pioglitazone on same in obese subjects	December 2009
Primary	Effects of Obesity and Pioglitazone on BMI	Effects of obese (vs lean) and pioglitazone on BMI	December 2009
Primary	Effects of Obesity and Pioglitazone on Muscle Lipid	Effects of obese (vs lean) on muscle lipid	December 2009
Primary	Effects of Obesity and Pioglitazone on Inflammation	Effects of obese (vs lean) and pioglitazone (in obese) on adipose tissue macrophages	December 2009