Metabolic Syndrome, Obesity
Conditions
Keywords
Obesity, Fat distribution, Adipogenesis, Adipocyte, Preadipocyte, Ectopic fat
Brief summary
The body shape of obese women varies between having the majority of fat either above the waist (apple shape) or below the waist (pear shape). The study will investigate what restricts: apple-shaped women from being pear-shaped at the cellular level. Since pear shaped women tend to have better health, this study will open the door to future research in regulating body shape and thus improving health.
Detailed description
Adipose tissue expandability and the distribution of stored fat in the body are stronger predictors of health risk. A better understanding of the factors that determine regional fat mass growth may lead to developing new strategies for prevention or treatment of metabolic complications of obesity. The objective of this proposal is to study the responsiveness of different fat depots to adipogenic stimulation in upper-body and lower-body obese women.
Interventions
DRUGPioglitazone
30mg per day for four months
DRUGPlacebo
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Pennington Biomedical Research Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
* You are a pre-menopausal woman between 18-40 years of age * Your Body Mass Index (BMI, weight-to-height2 ratio) is 27 - 38 kg/m2, inclusive * The ratio of your waist-to-hip circumferences is either \>0.84 (apple-type body shape) or \<0.77 (pear-type body shape) * You are willing to undergo a drug intervention for 16 weeks * You are willing to drink heavy water \[similar to the ordinary water that is highly enriched in the naturally occurring stable (non-radioactive) form of hydrogen, deuterium; also called deuterium-labeled water\] for 8 weeks before the beginning and during the second half of the drug intervention; you will need 24-hours access to a refrigerator for storage of the water. * You agree to use a double barrier method as a form of birth control to prevent pregnancy. Oral contraceptives (birth control pills) are not allowed in the study. Acceptable methods of birth control are condoms, spermicide, IUD (intrauterine device, must be hormone free - see list in clinic), diaphragm and abstinence. An example of a double barrier method would be condoms plus spermicide, etc.
Exclusion criteria
* You have gained or lost more than 4.5 lb (2 kg) in the last 3 months * You have had significant changes in the diet or level of physical activity within the past month * You have a blood sugar of greater than 100 or a diagnosis of diabetes. * You have abnormal liver enzyme values from your blood work * You have a history of heart, kidney, lung, liver, and thyroid disease * You have an average blood pressure \>140/90 at your screening visit * Have you had a positive test for human immunodeficiency virus (HIV), hepatitis B or hepatitis C? * You require chronic use of medications including diuretics, steroids, thyroid hormones, and adrenergic-stimulating agents (bronchodilators, nasal decongestants)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| In Vivo Adipose Cell Formation (Adipogenesis) | Change from baseline in adipogenesis at 16 weeks | Following the consumption of water labeled with the stable isotope deuterium (2H2O; heavy water), adipose tissue biopsies from the subcutaneous abdominal and femoral (thigh) depots will be collected. The 2H from the heavy water is enriched into the DNA of newly synthesized cells. Measures of DNA synthesis (obtained via gas chromatography and mass spectrometry analysis of 2H-enrichment) denote new adipose cell formation, or adipogenesis. The primary outcome is to assess the change (from baseline) in adipose cell formation rates (i.e. adipogenesis) in response to 16-weeks of pioglitazone versus the control group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Visceral Adipose Tissue (Percentage of Total Abdominal Adipose Tissue) | Change from baseline in visceral fat at 16 weeks | The volume of fat tissue around the internal organs in the abdomen (visceral adipose tissue; VAT) and underneath the skin (subcutaneous abdominal adipose tissue; scABD) will be determined by Magnetic Resonance Imaging (MRI) of the abdominal region. VAT:total abdominal AT (TAT) reflects the percentage of abdominal fat that is VAT and is calculated as VAT/(scABD AT + VAT). |
| Lipid Accretion in the Liver (Intra-hepatic Lipid; IHL) | Change from Baseline in intra-hepato-cellular lipid at 16 weeks | Lipid accretion in the liver cells will be measured using 1H-MRS of the liver. |
| Matsuda Index (Measure of Insulin Sensitivity) | Change from Baseline in Matsuda Index at 16 weeks | Insulin sensitivity (glucose tolerance) will be assessed using an oral 75 g oral glucose tolerance test (OGTT) after an overnight fast. Blood samples will be collected at 0, 30, 60, 90, and 120 min after glucose administration to measure serum glucose and insulin. Insulin sensitivity was calculated using the Matsuda insulin sensitivity index \[10,000/ √(glucose 0' x insulin 0') X (mean glucose OGTT x mean insulin OGTT)\]. A higher value denotes increased insulin sensitivity. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Administration of placebo to upper- and lower-body obese women
Placebo | 20 |
| Drug Administration of pioglitazone to upper- and lower-body obese women
Pioglitazone: 30mg per day for four months | 21 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 8 | 6 |
Baseline characteristics
| Characteristic | Placebo | Drug | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants | 21 Participants | 41 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 21 Participants | 41 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 10 Participants | 20 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 11 Participants | 21 Participants |
| Region of Enrollment United States | 20 participants | 21 participants | 41 participants |
| Sex: Female, Male Female | 20 Participants | 21 Participants | 41 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 15 / 31 | 15 / 32 |
| serious Total, serious adverse events | 0 / 31 | 0 / 32 |
Outcome results
Primary
In Vivo Adipose Cell Formation (Adipogenesis)
Following the consumption of water labeled with the stable isotope deuterium (2H2O; heavy water), adipose tissue biopsies from the subcutaneous abdominal and femoral (thigh) depots will be collected. The 2H from the heavy water is enriched into the DNA of newly synthesized cells. Measures of DNA synthesis (obtained via gas chromatography and mass spectrometry analysis of 2H-enrichment) denote new adipose cell formation, or adipogenesis. The primary outcome is to assess the change (from baseline) in adipose cell formation rates (i.e. adipogenesis) in response to 16-weeks of pioglitazone versus the control group.
Time frame: Change from baseline in adipogenesis at 16 weeks
Population: Of the 23 participants in the Placebo group, N=3 did not have adipose tissue biopsy data, and of the 26 participants in the Drug group, N=5 did not have adipose tissue biopsy data. Therefore, the Primary Outcome Analysis only included N=20 and N=21, respectively.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | In Vivo Adipose Cell Formation (Adipogenesis) | Abdominal | -0.3 percent | Standard Error 1.5 |
| Placebo | In Vivo Adipose Cell Formation (Adipogenesis) | Femoral | -1.2 percent | Standard Error 1.1 |
| Drug | In Vivo Adipose Cell Formation (Adipogenesis) | Abdominal | 1.8 percent | Standard Error 1.4 |
| Drug | In Vivo Adipose Cell Formation (Adipogenesis) | Femoral | 2.1 percent | Standard Error 1.1 |
Secondary
Lipid Accretion in the Liver (Intra-hepatic Lipid; IHL)
Lipid accretion in the liver cells will be measured using 1H-MRS of the liver.
Time frame: Change from Baseline in intra-hepato-cellular lipid at 16 weeks
Population: Of the 23 participants in the Placebo group, N=3 did not have adipose tissue biopsy data, and of the 26 participants in the Drug group, N=5 did not have adipose tissue biopsy data. Therefore, the Secondary Outcome Analysis only included N=20 and N=21, respectively.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Lipid Accretion in the Liver (Intra-hepatic Lipid; IHL) | -0.7 percent | Standard Error 1.2 |
| Drug | Lipid Accretion in the Liver (Intra-hepatic Lipid; IHL) | -2.0 percent | Standard Error 1.2 |
Secondary
Matsuda Index (Measure of Insulin Sensitivity)
Insulin sensitivity (glucose tolerance) will be assessed using an oral 75 g oral glucose tolerance test (OGTT) after an overnight fast. Blood samples will be collected at 0, 30, 60, 90, and 120 min after glucose administration to measure serum glucose and insulin. Insulin sensitivity was calculated using the Matsuda insulin sensitivity index \[10,000/ √(glucose 0' x insulin 0') X (mean glucose OGTT x mean insulin OGTT)\]. A higher value denotes increased insulin sensitivity.
Time frame: Change from Baseline in Matsuda Index at 16 weeks
Population: Of the 23 participants in the Placebo group, N=3 did not have adipose tissue biopsy data, and of the 26 participants in the Drug group, N=5 did not have adipose tissue biopsy data. Therefore, the Secondary Outcome Analysis only included N=20 and N=21, respectively.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Matsuda Index (Measure of Insulin Sensitivity) | -0.39 index | Standard Error 0.41 |
| Drug | Matsuda Index (Measure of Insulin Sensitivity) | 0.80 index | Standard Error 0.4 |
Secondary
Visceral Adipose Tissue (Percentage of Total Abdominal Adipose Tissue)
The volume of fat tissue around the internal organs in the abdomen (visceral adipose tissue; VAT) and underneath the skin (subcutaneous abdominal adipose tissue; scABD) will be determined by Magnetic Resonance Imaging (MRI) of the abdominal region. VAT:total abdominal AT (TAT) reflects the percentage of abdominal fat that is VAT and is calculated as VAT/(scABD AT + VAT).
Time frame: Change from baseline in visceral fat at 16 weeks
Population: Of the 23 participants in the Placebo group, N=3 did not have adipose tissue biopsy data, and of the 26 participants in the Drug group, N=5 did not have adipose tissue biopsy data. Therefore, the Secondary Outcome Analysis only included N=20 and N=21, respectively.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Visceral Adipose Tissue (Percentage of Total Abdominal Adipose Tissue) | 0.5 percent | Standard Error 0.3 |
| Drug | Visceral Adipose Tissue (Percentage of Total Abdominal Adipose Tissue) | -0.8 percent | Standard Error 0.3 |