Insulin Resistance and Intramyocellular Lipid Content in Glucose Intolerant Subjects Receiving Rosiglitazone

This study will include subjects with an abnormal glucose tolerance test. Using a crossover design, we will evaluate the insulin sensitivity and intracellular lipid content of the heart, liver and skeletal muscle of subjects before and after therapy with Rosiglitazone and placebo. We hypothesize that Rosiglitazone will improve insulin sensitivity in association with reduced muscle lipid content that may arise either from increased lipid oxidation or enhanced storage of fat in adipose tissue.

Study Overview

• Status: Completed
• Conditions: Insulin Sensitivity
• Intervention / Treatment: Drug: Rosiglitazone; Drug: Placebo

Detailed Description

This protocol is a crossover study that will include subjects with an abnormal glucose tolerance test. Participants will be treated in a community-based practice setting and will receive detailed instruction on diet and glucose self-monitoring. The patients will be randomly assigned to treatment with 4 mg daily of Rosiglitazone or placebo. They will return to the clinic after 4 weeks to monitor changes in glucose levels, HbA1c and liver enzymes. The drug dose will be increased as indicated to 8 mg daily and the patients will be reevaluated every 4 weeks. The participants will all be admitted to the General Clinical Research Center at UT-Southwestern Medical Center at the end of 16 weeks to measure changes in the following primary endpoints: 1) insulin sensitivity, 2) lipid content of heart, liver, and skeletal muscle, 3) lipid oxidation. Additional noninvasive HMRS measurements will be made to quantify the muscle lipid content and respiratory gas exchange will be used to assess lipid oxidation. Following the GCRC admission, patients will switch to the alternative therapy for 16 additional weeks before the studies are repeated. We expect Rosiglitazone to improve insulin sensitivity in association with reduced muscle lipid content that may arise either from increased lipid oxidation or enhanced storage of fat in adipose tissue.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center at Dallas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 30-65
• Fasting plasma glucose < 126 mg/dL or plasma glucose > 140 mg/dL and <200 mg/dL two hours after a challenge with 75 gm of glucose

Exclusion Criteria:

• Taking drugs known or suspected to affect intermediary metabolism (e.g. thyroid supplements, oral glucocorticoids, anabolic steroids or androgens, antidepressants, anorexic drugs, xanthine derivatives, sympathomimetics, beta-agonists)
• Taking any other investigational drugs within 30 days of starting the study
• Alcohol consumption more than 7 drinks per week
• Recreational drugs or IV drug abuse
• Acute or chronic liver diseases (SGOT >42 U/L, SGPT >48 U/L, GGT >45 U/L)
• Chronic renal insufficiency (serum creatinine >1.5 mg/dL)
• Uncontrolled hypertension (systolic/diastolic blood pressure >160/95mmHg)
• Anemia (hematocrit <35%)
• Congestive heart failure
• Metallic prostheses precluding the use of magnetic resonance imaging
• Premenopausal women without definitive measures to prevent pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Rosiglitazone; Subjects in this arm will be randomly assigned to treatment with Rosiglitazone 4mg daily. After 4 weeks, we will assess changes in glucose levels and liver enzymes. The dose will then be increased to Rosiglitazone 8mg daily (if indicated). The patients will be reevaluated every 4 weeks, and at the end of 16 weeks, the participants will all be admitted to the research center at UTSW to measure changes in the following: 1) insulin sensitivity; 2) lipid content of heart, liver, & skeletal muscle; and 3) lipid oxidation using respiratory gas exchange. The patients will then switch to the alternative therapy for 16 additional weeks before the studies are repeated.	Drug: Rosiglitazone; Rosiglitazone 8mg PO daily for 16 weeks; Other Names: Avandia
Placebo Comparator: Placebo; Subjects in this arm will be randomly assigned to treatment with placebo. After 4 weeks, we will assess changes in glucose levels and liver enzymes. The patients will be reevaluated every 4 weeks, and at the end of 16 weeks, the participants will all be admitted to the research center at UTSW to measure changes in the following: 1) insulin sensitivity; 2) lipid content of heart, liver, & skeletal muscle; and 3) lipid oxidation using respiratory gas exchange. The patients will then switch to the alternative therapy for 16 additional weeks before the studies are repeated.	Drug: Placebo; Placebo 1 tablet PO daily for 16 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Insulin sensitivity	16 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Intracellular lipid content in myocardium, liver and skeletal muscle	16 weeks
Lipid oxidation	16 weeks

Collaborators and Investigators

• Sponsor: University of Texas Southwestern Medical Center
• Collaborators: GlaxoSmithKline
• Investigators: Principal Investigator: Lidia S Szczepaniak, PhD, University of Texas, Southwestern Medical Center at Dallas

Study record dates

Study Major Dates

• Study Start: February 1, 2004
• Primary Completion (Actual): March 1, 2007
• Study Completion (Actual): February 1, 2008

Study Registration Dates

• First Submitted: August 29, 2008
• First Submitted That Met QC Criteria: September 2, 2008
• First Posted (Estimate): September 3, 2008

Study Record Updates

• Last Update Posted (Estimate): September 3, 2008
• Last Update Submitted That Met QC Criteria: September 2, 2008
• Last Verified: September 1, 2008

More Information

Terms related to this study

• Keywords: insulin sensitivity; intracellular; lipotoxicity; triglyceride; magnetic resonance spectroscopy (MRS); thiazolidinediones; lipid oxidation; content
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Hyperinsulinism; Hypersensitivity; Insulin Resistance; Hypoglycemic Agents; Physiological Effects of Drugs; Rosiglitazone
• Other Study ID Numbers: GSK CRT49653/250