Mechanisms Underlying Metabolic Syndrome in Obesity

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

Study Overview

• Status: Completed
• Conditions: Metabolic Syndrome; Insulin Resistance; Prediabetes
• Intervention / Treatment: Drug: Pioglitazone

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.

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: 1; Baseline studies (OGTT, DXA, RMR, FSIGT, and biopsies) on normal control subjects. Oral glucose tolerance tests, body composition assessment, resting metabolic rate, insulin sensitivity measurement with the frequently sampled method and Minimal Model. These studies will establish baseline data in lean subjects on adipose tissue gene expression, insulin sensitivity, glucose tolerance, metabolic rate and body composition. There is no intervention.
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. 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.	Drug: Pioglitazone; Pioglitazone 30mg for 2 weeks, then Pioglitazone 45mg for 8 weeks.; Other Names: Actos

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Philip Kern
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institutes of Health (NIH)
• Investigators: Principal Investigator: Philip Kern, MD, University of Kentucky

Study record dates

Study Major Dates

• Study Start: April 1, 2005
• Primary Completion (Actual): January 1, 2009
• Study Completion (Actual): January 1, 2011

Study Registration Dates

• First Submitted: December 20, 2007
• First Submitted That Met QC Criteria: December 20, 2007
• First Posted (Estimate): December 24, 2007

Study Record Updates

• Last Update Posted (Actual): June 15, 2017
• Last Update Submitted That Met QC Criteria: May 24, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: diabetes; obesity; inflammation
• Additional Relevant MeSH Terms: Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Disease; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Hyperinsulinism; Syndrome; Obesity; Metabolic Syndrome; Insulin Resistance; Hypoglycemic Agents; Physiological Effects of Drugs; Pioglitazone
• Other Study ID Numbers: 32677; R01DK071277 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data from this study has been published. Individual (deidentified) data will be shared with other investigators upon request to Dr Kern.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No