Metabolic SyndromePhase 4NCT00579813
Mechanisms Underlying Metabolic Syndrome in Obesity
A Phase 4 study testing Pioglitazone in people with Metabolic Syndrome and Insulin Resistance, run by Philip Kern at 2 sites in United States.
Trial summary
The purpose of this study is to better understand the link between obesity and diabetes or pre-diabetes. Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Metabolic Syndrome, Insulin Resistance, Prediabetes
- What is being tested?
- Pioglitazone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 70 participants
- Where
- 2 sitesUnited States
- Study dates
- Apr 2005to Jan 2011
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 18-65 years of age
- BMI 28+
- diabetes, impaired glucose tolerance or normal glucose tolerance
Who cannot join
- 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
Trial locations and contacts
2 sites in 1 country.
United States2 sites
University of Kentucky
Lexington, Kentucky, 40536
University of Arkansas for Medical Sciences
Little Rock, Arkansas, 72205
About this study
The purpose of this study is to better understand the link between obesity and diabetes or pre-diabetes.
Read the 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.
- Conditions
- Metabolic Syndrome, Insulin Resistance, Prediabetes
- Being tested
- Pioglitazone
- Keywords
- obesity, inflammation, diabetes
- Medical subject headings
- Metabolic Syndrome, Insulin Resistance, Prediabetic State, Obesity, Inflammation, Diabetes Mellitus
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PioglitazoneDrug
Also called Actos
Pioglitazone 30mg for 2 weeks, then Pioglitazone 45mg for 8 weeks.
| Study group | Role | What they receive |
|---|---|---|
| 1 | No intervention | 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. |
| 2 | Active comparator | 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. Receives: Drug: Pioglitazone |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
Measured: Baseline and 10 weeks
Changes in Muscle Lipid After Pioglitazone
Muscle lipid following biopsy using oil red-O staining.
Measured: 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)
Measured: Baseline and 10 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Dec 2007 (estimated)
- Study startApr 2005
- Primary completionJan 2009
- Study completionJan 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Metabolic SyndromeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 70 participants (actual)
Sponsor and investigators
- Lead sponsor
- Philip Kern
- Sponsor type
- University, hospital or other
- Collaborators
- National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Responsible party
- Sponsor-investigator, Philip Kern, University of Kentucky
- Investigators
- Philip Kern, MD, Principal investigator, University of Kentucky
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00579813
- Sponsor's protocol ID
- 32677
- Other IDs
- R01DK071277
- Status last verified
- May 2017
- First submitted
- 20 Dec 2007
- Last updated
- 15 Jun 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Data from this study has been published. Individual (deidentified) data will be shared with other investigators upon request to Dr Kern.
Study at a glance
From the registry record, last updated by the sponsor on 15 Jun 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Mechanisms Underlying Metabolic Syndrome in Obesity
- ClinicalTrials.gov ID
- NCT00579813
- Acronym / sponsor ID
- 32677
- Conditions
- Metabolic Syndrome, Insulin Resistance, Prediabetes
- Keywords
- obesity, inflammation, diabetes
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 70 participants (actual)
- Lead sponsor
- Philip KernUniversity, hospital or other
- Collaborators
- National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Study start
- Apr 2005
- Primary completion
- Jan 2009 (actual)
- Study completion
- Jan 2011 (actual)
- First posted
- 24 Dec 2007 (estimated)
- Results
- Posted 12 Jul 2011
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to better understand the link between obesity and diabetes or pre-diabetes.
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
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 1 | No intervention | –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. |
| 2 | Active comparator | Drug: PioglitazoneBaseline 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. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 18-65 years of age
- BMI 28+
- diabetes, impaired glucose tolerance or normal glucose tolerance
Key exclusion criteria (5 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PioglitazoneAlso: ActosPioglitazone 30mg for 2 weeks, then Pioglitazone 45mg for 8 weeks. | Drug | 2 |
Primary outcome
Change in Insulin Sensitivity Using FSIGT
Time frame: 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.
Effects of Pioglitazone on Changes in BMI
Time frame: Baseline and 10 weeks
Body Mass Index (BMI) is measured at baseline, in lean and obese subjects, and after pioglitazone in obese subjects
Changes in Muscle Lipid After Pioglitazone
Time frame: At baseline and 10 weeks
Muscle lipid following biopsy using oil red-O staining.
Changes in Fat Inflammation Following Pioglitazone
Time frame: Baseline and 10 weeks
macrophages in fat at baseline, in lean and obese participants, and obese after pioglitazone (in obese)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Jun 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: Yes. Data from this study has been published. Individual (deidentified) data will be shared with other investigators upon request to Dr Kern.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Philip Kern, MD principal investigator
University of Kentucky
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Pioglitazone in people with Metabolic Syndrome and Insulin Resistance, run by Philip Kern at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 15 Jun 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 12 Jul 2011). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Insulin Sensitivity Using FSIGT (time frame: Baseline and 10 weeks). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Jun 2017.