Mechanisms Underlying Metabolic Syndrome in Obesity

• Sponsor: Philip Kern (Other)
• Overall Status: Completed
• CT.gov ID: NCT00579813
• Collaborator: National Institutes of Health (NIH) (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Enrollment: 70
• Locations: 2
• Arms: 2
• Duration (Months): 69
• Patients Per Site: 35
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Metabolic Syndrome; Insulin Resistance; Prediabetes	Drug: Pioglitazone	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 70 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Mechanisms Underlying Metabolic Syndrome in Obesity
• Study Start Date: Apr 1, 2005
• Actual Primary Completion Date: Jan 1, 2009
• Actual Study Completion Date: Jan 1, 2011

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Change in Insulin Sensitivity Using FSIGT [Baseline and 10 weeks]

   The frequently sampled intravenous glucose tolerance test (FSIGT) involves the injection of IV glucose and the frequent measurement of glucose and insulin.

2. Effects of Pioglitazone on Changes in BMI [Baseline and 10 weeks]

   Body Mass Index (BMI) is measured at baseline, in lean and obese subjects, and after pioglitazone in obese subjects

3. Changes in Muscle Lipid After Pioglitazone [At baseline and 10 weeks]

   Muscle lipid following biopsy using oil red-O staining.

4. Changes in Fat Inflammation Following Pioglitazone [Baseline and 10 weeks]

   macrophages in fat at baseline, in lean and obese participants, and obese after pioglitazone (in obese)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Locations

	Site	City	State	Country	Postal Code
1	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
2	University of Kentucky	Lexington	Kentucky	United States	40536

Sponsors and Collaborators

• Philip Kern
• National Institutes of Health (NIH)
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Philip Kern, MD, University of Kentucky

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Philip Kern, Principal Investigator, University of Kentucky
• ClinicalTrials.gov Identifier: NCT00579813
• Other Study ID Numbers: 32677; R01DK071277
• First Posted: Dec 24, 2007
• Last Update Posted: Jun 15, 2017
• Last Verified: May 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• 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
• Keywords provided by Philip Kern, Principal Investigator, University of Kentucky: obesity; inflammation; diabetes
• Additional relevant MeSH terms: Obesity; Metabolic Syndrome; Insulin Resistance; Syndrome; Pioglitazone

Study Results

Participant Flow

Arm/Group Title	Lean Subjects	Obese Subjects
Arm/Group Description	Arm 1 was normal subjects on which baseline studies were performed to determine insulin sensitivity, intramyocellular lipid and resting metabolic rate.	Baseline studies (Oral glucose tolerance test, Dual energy x-ray absorbiometry, Resting metabolic rate, Frequently sampled intravenous glucose tolerance test, biopsies), then 10 weeks treatment on Pioglitazone. Baseline tests are repeated at the end of medication treatment.
Period Title: Overall Study
STARTED	60	10
COMPLETED	60	10
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Lean Subjects	Obese Subjects	Total
Arm/Group Description	Arm 1 was normal subjects on which baseline studies were performed to determine insulin sensitivity, intramyocellular lipid and resting metabolic rate.	Baseline studies (Oral glucose tolerance test, Dual energy x-ray absorbiometry, Resting metabolic rate, Frequently sampled intravenous glucose tolerance test, biopsies), then 10 weeks treatment on Pioglitazone. Baseline tests are repeated at the end of medication treatment.	Total of all reporting groups
Overall Participants	60	10	70
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	60 100%	10 100%	70 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53 (6)	57 (2)	55 (5)
Sex: Female, Male (Count of Participants)
Female	45 75%	7 70%	52 74.3%
Male	15 25%	3 30%	18 25.7%
Region of Enrollment (participants) [Number]
United States	60 100%	10 100%	70 100%

Outcome Measures

1. Primary Outcome

Title	Change in Insulin Sensitivity Using FSIGT
Description	The frequently sampled intravenous glucose tolerance test (FSIGT) involves the injection of IV glucose and the frequent measurement of glucose and insulin.
Time Frame	Baseline and 10 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Obese Subjects, Baseline	After Pioiglitazone	Lean Subjects, Baseline
Arm/Group Description	Baseline studies, obese	10 weeks of treatment	lean subjects, baseline
Measure Participants	10	10	60
Mean (Standard Deviation) [FSIGT units (x10^-4/min/uU/ml)]	1.7 (0.53)	2.4 (1.01)	7.02 (3.7)

2. Primary Outcome

Title	Effects of Pioglitazone on Changes in BMI
Description	Body Mass Index (BMI) is measured at baseline, in lean and obese subjects, and after pioglitazone in obese subjects
Time Frame	Baseline and 10 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Obese Subjects, Baseline	After Pioiglitazone	Lean Subjects, Baseline
Arm/Group Description	Baseline studies, obese	10 weeks of treatment	lean subjects, baseline
Measure Participants	10	10	60
Mean (Standard Deviation) [kg/m2]	32.4 (3.89)	33.4 (4.36)	22.6 (1.9)

3. Primary Outcome

Title	Changes in Muscle Lipid After Pioglitazone
Description	Muscle lipid following biopsy using oil red-O staining.
Time Frame	At baseline and 10 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Obese Subjects, Baseline	After Pioiglitazone	Lean Subjects, Baseline
Arm/Group Description	Baseline studies, obese	10 weeks of treatment	lean subjects, baseline
Measure Participants	10	10	60
Mean (Standard Deviation) [arbitrary units of oil red O staining]	7.0 (5.9)	4.6 (5.9)	2.7 (0.84)

4. Primary Outcome

Title	Changes in Fat Inflammation Following Pioglitazone
Description	macrophages in fat at baseline, in lean and obese participants, and obese after pioglitazone (in obese)
Time Frame	Baseline and 10 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Obese Subjects, Baseline	After Pioiglitazone	Lean Subjects, Baseline
Arm/Group Description	Baseline studies, obese	10 weeks of treatment	lean subjects, baseline
Measure Participants	10	10	60
Mean (Standard Deviation) [macrophages per mm2 by CD68 staining]	27 (6.3)	19 (9.5)	17 (6.2)

Adverse Events

Time Frame	3 years
Arm/Group Title	Lean Subjects		Obese Subjects
Arm/Group Description	Arm 1 was normal subjects on which baseline studies were performed to determine insulin sensitivity, intramyocellular lipid and resting metabolic rate.		Baseline studies (Oral glucose tolerance test, Dual energy x-ray absorbiometry, Resting metabolic rate, Frequently sampled intravenous glucose tolerance test, biopsies), then 10 weeks treatment on Pioglitazone. Baseline tests are repeated at the end of medication treatment.
All Cause Mortality
	Lean Subjects		Obese Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Lean Subjects		Obese Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/60 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Lean Subjects		Obese Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/60 (0%)		0/10 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.