Gonadal Dysfunction, Insulin Resistance, Obesity, Type 2 Diabetes
Conditions
Keywords
Insulin resistance, Puberty, Obesity, Hypogonadism, Gonadal dysfunction, Metformin
Brief summary
The Health Influences of Puberty (HIP) Study is designed to explore the relationships between puberty and the onset of type 2 diabetes in adolescents. The results of this study will help us better understand how to prevent type 2 diabetes in these youth. Children go through many changes during puberty, including important hormonal and behavioral alterations. Among these changes, it has long been known that, during puberty, insulin does not work as well as it does before and after puberty. This is called physiologic insulin resistance. In healthy children, this does not cause diabetes or affect blood sugar in any way because the body is able to compensate by making more insulin. Indeed, this is thought to be an important part of the adolescent growth spurt. However, in some children with increased risk for developing type 2 diabetes due to obesity and genetics, the worsening insulin resistance of puberty cannot be compensated for and these youth get diabetes early. The investigators believe this is because type 2 diabetes is rarely, if ever, seen before puberty begins, and the peak of diabetes onset in adolescents occurs at the time of the worst insulin resistance. This specific research project has two goals: 1. To examine effects of obesity on how well the body's insulin works during puberty, and 2. To see if treatment of obese children during this critical period of puberty with a medication that improves insulin resistance (metformin) will help prevent early onset type 2 diabetes.
Detailed description
Specific Aims: Pediatric insulin resistance and related disorders, such as type 2 diabetes mellitus (T2DM), are increasing in prevalence, and portend significant end-organ and cardiovascular morbidity and mortality. Thus, measures aimed at understanding its causes and preventing its onset are critical. The physiologic decrease in insulin sensitivity in all adolescents during puberty is well-established. It is also known that obese adolescents start out less insulin sensitive at the onset of puberty than lean adolescents, and that their insulin sensitivity worsens as puberty progresses. While there are both longitudinal and cross-sectional data confirming the natural recovery of pre-pubertal insulin sensitivity in normal weight adolescents after puberty is completed, it is unknown whether obese adolescents recover their pre-pubertal insulin sensitivity. Failure to regain pre-pubertal insulin sensitivity at the end of puberty, and failure of compensatory insulin secretion, may accelerate progression from obesity to insulin resistance to T2DM in at-risk youth and contribute to long-term cardiovascular risk. In addition, obesity and insulin resistance are associated with earlier onset of puberty and premature adrenarche in females. Insulin resistance also contributes to the gonadal dysfunction of polycystic ovarian disease in fully pubertal females and is associated with hypogonadism in older adult males. Little is known about effects of obesity and insulin resistance on gonadal function in young males. However, persistent metabolic changes at the end of puberty may contribute to gonadal dysfunction in obese youth. Currently, there are few longitudinal studies in either sex that evaluate the interactions among obesity, insulin resistance and gonadal function during puberty. The investigators' long-term goal is to better understand the metabolic changes that occur during puberty, their underlying mechanisms, and their potential contribution to adult disease. The overall aim is to evaluate the effects of obesity on the evolution of insulin sensitivity and gonadal function during puberty. In addition, because improvement in insulin action during puberty may slow β-cell deterioration, the investigators will evaluate whether compensatory insulin secretion is also affected in obese adolescents and whether treatment with metformin improves β-cell response. HYPOTHESES: 1. Obese adolescents will show decreased improvement in insulin sensitivity from Tanner stage 2/3 to Tanner 5 when compared with lean counterparts. 2. Obese adolescents treated with metformin will have greater improvement in insulin sensitivity from Tanner stage 2/3 to Tanner 5 vs. those treated with placebo. (See hypothesis schematics below) To test these hypotheses, we propose to address the following Specific Aims: SPECIFIC AIM 1 (Observational Arm): 1. To compare longitudinal changes in insulin sensitivity and secretion and their correlates in obese and normal weight adolescents during puberty. 1. Primary outcome: Change in insulin sensitivity (Si), as measured by frequently sampled intravenous glucose tolerance test (IVGTT), from early puberty to puberty completion in obese and normal weight adolescents. 2. Secondary outcomes: Change in insulin secretion (AIR) and disposition index (DI) as measured by IVGTT, body composition, fat distribution, markers of gonadal function, and inflammatory markers over time in these groups. SPECIFIC AIM 2 (Treatment Arm): 2. To compare longitudinal changes in insulin sensitivity and secretion and their correlates in obese adolescents treated with metformin or placebo during puberty. 1. Primary outcome: Change in Si from early puberty to puberty completion in obese controls and obese adolescents treated with metformin. 2. Secondary outcome: Change in AIR and DI, body composition, fat distribution, markers of gonadal function, and inflammatory markers over time in these groups.
Interventions
DRUGMetformin
After randomization, the study drug (metformin or placebo) is gradually titrated to full dose of 1000 mg BID (or to maximum tolerated, at least 500 mg BID) over a period of 4 weeks to minimize adverse gastrointestinal effects. Participants are seen every three months to measure compliance and dispense new study drug. Every 6 months, they also have a physical examination in order to determine puberty staging. Study measurements (IVGTT, bloodwork, DXA) are performed at Tanner 4 puberty and Tanner 5 (puberty completion), at which time the study drug is stopped. Study measurements will be performed again 6 months after study drug is completed to assess if effects are persistent after study drug is stopped. During the treatment period, all participants receive standard lifestyle counseling.
DRUGPlacebo
Stamped placebo pill to look like the 1000 mg metformin pill Dosage: 1 pill taken orally twice daily Duration: From early puberty (Tanner 3-4) until puberty completion (Tanner 5), approximately 3 years
Sponsors
American Diabetes Association
National Institutes of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Children's Hospital Colorado
University of Colorado, Denver
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
9 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* BMI ≥ 95th percentile * At least Tanner 2, but no more than Tanner 3 * Age ≥ 9 years * Absence of impaired glucose tolerance (IGT), impaired fasting glucose (IFG) or Type 2 diabetes mellitus (T2DM)
Exclusion criteria
* Presence of T2DM, IGT or IFG * Any disorder or medication known to effect glucose tolerance; * Hypertension or hyperlipidemia requiring pharmacological intervention; * Weight \>300lbs. due to limits of imaging tables. * Chronic illness
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Sensitivity | Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline, 6 mos post-treatment-average 3 yrs from baseline | As measured by in intravenous glucose tolerance test (IVGTT) as calculated by Bergman's minimal model. Higher numbers indicate a better outcome. Patients are randomized to receive metformin or placebo at Tanner stage 2-3 of puberty. They are reassessed at Tanner 4 and again at Tanner 5. At that point, the treatment is stopped and they are reassessed 6 months after stopping treatment to see if effects of treatment persist. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Secretion (Acute Insulin Response to Glucose, AIRg) | Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline, 6 mos post-treatment-average 3 yrs from baseline | As measured by IVGTT as calculated by Bergman's minimal model. Higher numbers indicate a better outcome. Please see primary outcome for more detail about timing of measurement. |
| Disposition Index | Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline, 6 mos post-treatment-average 3 yrs from baseline | Please see primary outcome for more detail about timing of measurement. Disposition index is measured via (IVGTT) as calculated by Bergman's minimal model. Higher numbers indicate a better outcome. It reflects the product of outcome measures 1 and 2 (Si x AIRg). |
| Low Density Lipoprotein | Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline, 6 mos post-treatment-average 3 yrs from baseline | Please see primary outcome for more detail about timing of measurement. |
| Insulin-like Growth Factor 1 | Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline | IGF-1 measured in serum at each time point |
| Total Testosterone | Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline | Testosterone measured in serum at each time point |
| Estradiol | Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline | Estradiol measured in serum at each time point |
| Sex Hormone Binding Globulin | Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline | SHBG measured in serum at each time point |
| Dehydroepiandrosterone Sulfate | Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline | DHEA-S measured in serum at each time point |
| High Sensitivity C-reactive Protein | Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline | hsCRP measured in serum at each time point |
| Alanine Transaminase (ALT) | Baseline (Tanner 2-3), Tanner 4, Tanner 5 | ALT measured in serum at each time point |
| Change in Urinary Luteinizing Hormone | Baseline, every 6 months during the trial, Final visit (average 3 yrs after baseline) | LH measured in an overnight urine sample at time points below |
| Change in Urinary Follicle-stimulating Hormone | Baseline, every 6 months during the trial, Final visit-average 3 yrs after baseline | FSH measured in overnight urine sample at time points below |
| Change in Urinary Estradiol Metabolites | Baseline, every 6 months during the trial, Final visit-average 3 yrs after baseline | estradiol metabolite (E1c) measured in an overnight urine sample at each time point |
| Hemoglobin A1c | Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline | HbA1c measured by HPLC at time points below |
| Leptin | Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline | Leptin measured in serum at time points below |
| Percent Body Fat | Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline | % body fat measured by DXA at time points below |
| Visceral Adipose | Baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline | Percent Visceral Fat, Measured in a subset (10 per group) by single slice MRI |
| Liver Adipose | Baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline | Liver fat percent. Measured in a subset (10 per group) by fast MRI technique |
| High Density Lipoprotein | Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline, 6 mos post-treatment-average 3 yrs from baseline | Please see primary outcome for more detail about timing of measurement. |
| Aspartate Aminotransferase (AST) | Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline | AST measured in serum at each time point |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Normal Weight Normal Weight by BMI. No treatment. | 47 |
| Obese - NT Obese by BMI. Participants were not taking metformin or placebo | 13 |
| Obese - Placebo Dosage form: Stamped placebo pill to look like the 1000 mg metformin pill Dosage: 1 pill taken orally twice daily Duration: From early puberty (Tanner 3-4) until puberty completion (Tanner 5), approximately 3 years | 24 |
| Obese - Metformin Dosage form: Metformin 1000 mg tablets Dosage: 1000 mg by mouth twice daily Duration: From early puberty (Tanner 3-4) until puberty completion (Tanner 5), approximately 3 years | 20 |
| Total | 104 |
Baseline characteristics
| Characteristic | Normal Weight | Obese - NT | Obese - Placebo | Obese - Metformin | Total |
|---|---|---|---|---|---|
| Age, Continuous | 12.070 years STANDARD_DEVIATION 1.513 | 11.274 years STANDARD_DEVIATION 1.138 | 11.146 years STANDARD_DEVIATION 1.088 | 11.863 years STANDARD_DEVIATION 1.562 | 11.754 years STANDARD_DEVIATION 1.437 |
| Race/Ethnicity, Customized Asian | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Black | 8 Participants | 1 Participants | 2 Participants | 2 Participants | 13 Participants |
| Race/Ethnicity, Customized Hispanic | 12 Participants | 7 Participants | 19 Participants | 16 Participants | 54 Participants |
| Race/Ethnicity, Customized Native American | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Non-Hispanic White | 23 Participants | 4 Participants | 2 Participants | 1 Participants | 30 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants |
| Region of Enrollment United States | 47 participants | 13 participants | 24 participants | 20 participants | 104 participants |
| Sex: Female, Male Female | 22 Participants | 6 Participants | 17 Participants | 9 Participants | 54 Participants |
| Sex: Female, Male Male | 25 Participants | 7 Participants | 7 Participants | 11 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 24 | 0 / 47 | 0 / 13 |
| other Total, other adverse events | 11 / 20 | 14 / 24 | 0 / 47 | 0 / 13 |
| serious Total, serious adverse events | 0 / 20 | 0 / 24 | 0 / 47 | 0 / 13 |
Outcome results
Primary
Insulin Sensitivity
As measured by in intravenous glucose tolerance test (IVGTT) as calculated by Bergman's minimal model. Higher numbers indicate a better outcome. Patients are randomized to receive metformin or placebo at Tanner stage 2-3 of puberty. They are reassessed at Tanner 4 and again at Tanner 5. At that point, the treatment is stopped and they are reassessed 6 months after stopping treatment to see if effects of treatment persist.
Time frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline, 6 mos post-treatment-average 3 yrs from baseline
Population: 24 participants analyzed in the Obese NT Placebo group are also analyzed in the Obese Placebo group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Weight | Insulin Sensitivity | Baseline | 8.559 x10-4/min-1/mIU/mL | Standard Deviation 5.755 |
| Normal Weight | Insulin Sensitivity | Tanner 4 | 6.661 x10-4/min-1/mIU/mL | Standard Deviation 4.418 |
| Normal Weight | Insulin Sensitivity | Tanner 5 | 6.438 x10-4/min-1/mIU/mL | Standard Deviation 3.835 |
| Normal Weight | Insulin Sensitivity | Post-Puberty | NA x10-4/min-1/mIU/mL | — |
| Obese - NT | Insulin Sensitivity | Tanner 4 | 1.995 x10-4/min-1/mIU/mL | Standard Deviation 0.959 |
| Obese - NT | Insulin Sensitivity | Tanner 5 | 2.082 x10-4/min-1/mIU/mL | Standard Deviation 1.764 |
| Obese - NT | Insulin Sensitivity | Post-Puberty | NA x10-4/min-1/mIU/mL | — |
| Obese - NT | Insulin Sensitivity | Baseline | 3.425 x10-4/min-1/mIU/mL | Standard Deviation 4.197 |
| Obese - Placebo | Insulin Sensitivity | Tanner 5 | 2.383 x10-4/min-1/mIU/mL | Standard Deviation 2.056 |
| Obese - Placebo | Insulin Sensitivity | Tanner 4 | 1.868 x10-4/min-1/mIU/mL | Standard Deviation 1.102 |
| Obese - Placebo | Insulin Sensitivity | Post-Puberty | 3.017 x10-4/min-1/mIU/mL | Standard Deviation 3.449 |
| Obese - Placebo | Insulin Sensitivity | Baseline | 3.756 x10-4/min-1/mIU/mL | Standard Deviation 4.97 |
| Obese - Metformin | Insulin Sensitivity | Post-Puberty | 2.182 x10-4/min-1/mIU/mL | Standard Deviation 2.353 |
| Obese - Metformin | Insulin Sensitivity | Tanner 4 | 2.873 x10-4/min-1/mIU/mL | Standard Deviation 2.155 |
| Obese - Metformin | Insulin Sensitivity | Baseline | 2.985 x10-4/min-1/mIU/mL | Standard Deviation 2.656 |
| Obese - Metformin | Insulin Sensitivity | Tanner 5 | 2.990 x10-4/min-1/mIU/mL | Standard Deviation 3.038 |
Secondary
Alanine Transaminase (ALT)
ALT measured in serum at each time point
Time frame: Baseline (Tanner 2-3), Tanner 4, Tanner 5
Population: 24 participants analyzed in the Obese NT Placebo group are also analyzed in the Obese Placebo group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Weight | Alanine Transaminase (ALT) | Baseline | 25.022 international units per liter | Standard Deviation 9.556 |
| Normal Weight | Alanine Transaminase (ALT) | Tanner 4 | 27.059 international units per liter | Standard Deviation 7.671 |
| Normal Weight | Alanine Transaminase (ALT) | Tanner 5 | 26.121 international units per liter | Standard Deviation 6.859 |
| Normal Weight | Alanine Transaminase (ALT) | Post-Puberty | NA international units per liter | — |
| Obese - NT | Alanine Transaminase (ALT) | Tanner 4 | 44.571 international units per liter | Standard Deviation 40.839 |
| Obese - NT | Alanine Transaminase (ALT) | Tanner 5 | 38.650 international units per liter | Standard Deviation 23.089 |
| Obese - NT | Alanine Transaminase (ALT) | Post-Puberty | NA international units per liter | — |
| Obese - NT | Alanine Transaminase (ALT) | Baseline | 35.194 international units per liter | Standard Deviation 22.132 |
| Obese - Placebo | Alanine Transaminase (ALT) | Tanner 5 | 47.500 international units per liter | Standard Deviation 25.995 |
| Obese - Placebo | Alanine Transaminase (ALT) | Tanner 4 | 51.182 international units per liter | Standard Deviation 43.829 |
| Obese - Placebo | Alanine Transaminase (ALT) | Post-Puberty | 50.231 international units per liter | Standard Deviation 36.967 |
| Obese - Placebo | Alanine Transaminase (ALT) | Baseline | 41.125 international units per liter | Standard Deviation 24.552 |
| Obese - Metformin | Alanine Transaminase (ALT) | Post-Puberty | 45.000 international units per liter | Standard Deviation 30.864 |
| Obese - Metformin | Alanine Transaminase (ALT) | Tanner 4 | 42.545 international units per liter | Standard Deviation 18.753 |
| Obese - Metformin | Alanine Transaminase (ALT) | Baseline | 52.400 international units per liter | Standard Deviation 50.296 |
| Obese - Metformin | Alanine Transaminase (ALT) | Tanner 5 | 39.636 international units per liter | Standard Deviation 17.328 |
Secondary
Aspartate Aminotransferase (AST)
AST measured in serum at each time point
Time frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Population: 24 participants analyzed in the Obese NT Placebo group are also analyzed in the Obese Placebo group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Weight | Aspartate Aminotransferase (AST) | Baseline | 42.174 international units per liter | Standard Deviation 14.685 |
| Normal Weight | Aspartate Aminotransferase (AST) | Tanner 4 | 35.706 international units per liter | Standard Deviation 11.202 |
| Normal Weight | Aspartate Aminotransferase (AST) | Tanner 5 | 33.364 international units per liter | Standard Deviation 11.811 |
| Normal Weight | Aspartate Aminotransferase (AST) | Post-Puberty | NA international units per liter | — |
| Obese - NT | Aspartate Aminotransferase (AST) | Tanner 4 | 44.429 international units per liter | Standard Deviation 25.621 |
| Obese - NT | Aspartate Aminotransferase (AST) | Tanner 5 | 36.650 international units per liter | Standard Deviation 17.458 |
| Obese - NT | Aspartate Aminotransferase (AST) | Post-Puberty | NA international units per liter | — |
| Obese - NT | Aspartate Aminotransferase (AST) | Baseline | 41.250 international units per liter | Standard Deviation 18.13 |
| Obese - Placebo | Aspartate Aminotransferase (AST) | Tanner 5 | 42.333 international units per liter | Standard Deviation 20.331 |
| Obese - Placebo | Aspartate Aminotransferase (AST) | Tanner 4 | 43.636 international units per liter | Standard Deviation 26.07 |
| Obese - Placebo | Aspartate Aminotransferase (AST) | Post-Puberty | 39.077 international units per liter | Standard Deviation 21.278 |
| Obese - Placebo | Aspartate Aminotransferase (AST) | Baseline | 43.542 international units per liter | Standard Deviation 20.156 |
| Obese - Metformin | Aspartate Aminotransferase (AST) | Post-Puberty | 36.273 international units per liter | Standard Deviation 17.396 |
| Obese - Metformin | Aspartate Aminotransferase (AST) | Tanner 4 | 40.273 international units per liter | Standard Deviation 14.065 |
| Obese - Metformin | Aspartate Aminotransferase (AST) | Baseline | 54.150 international units per liter | Standard Deviation 28.117 |
| Obese - Metformin | Aspartate Aminotransferase (AST) | Tanner 5 | 34.091 international units per liter | Standard Deviation 11.122 |
Secondary
Change in Urinary Estradiol Metabolites
estradiol metabolite (E1c) measured in an overnight urine sample at each time point
Time frame: Baseline, every 6 months during the trial, Final visit-average 3 yrs after baseline
Population: 24 participants analyzed in the Obese NT Placebo group are also analyzed in the Obese Placebo group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Weight | Change in Urinary Estradiol Metabolites | Tanner 2/3 | 7.711 ng/mgCr | Standard Deviation 22.531 |
| Normal Weight | Change in Urinary Estradiol Metabolites | Tanner 4 | 22.919 ng/mgCr | Standard Deviation 37.835 |
| Normal Weight | Change in Urinary Estradiol Metabolites | Tanner 5 | 41.036 ng/mgCr | Standard Deviation 78.16 |
| Normal Weight | Change in Urinary Estradiol Metabolites | Post-Puberty | NA ng/mgCr | — |
| Obese - NT | Change in Urinary Estradiol Metabolites | Tanner 4 | 8.584 ng/mgCr | Standard Deviation 9.932 |
| Obese - NT | Change in Urinary Estradiol Metabolites | Tanner 5 | 7.825 ng/mgCr | Standard Deviation 2.586 |
| Obese - NT | Change in Urinary Estradiol Metabolites | Post-Puberty | 26.402 ng/mgCr | Standard Deviation 38.299 |
| Obese - NT | Change in Urinary Estradiol Metabolites | Tanner 2/3 | 17.353 ng/mgCr | Standard Deviation 17.214 |
| Obese - Placebo | Change in Urinary Estradiol Metabolites | Tanner 5 | 7.825 ng/mgCr | Standard Deviation 2.586 |
| Obese - Placebo | Change in Urinary Estradiol Metabolites | Tanner 4 | 8.584 ng/mgCr | Standard Deviation 9.932 |
| Obese - Placebo | Change in Urinary Estradiol Metabolites | Post-Puberty | 26.402 ng/mgCr | Standard Deviation 38.299 |
| Obese - Placebo | Change in Urinary Estradiol Metabolites | Tanner 2/3 | 17.353 ng/mgCr | Standard Deviation 17.214 |
| Obese - Metformin | Change in Urinary Estradiol Metabolites | Post-Puberty | 30.883 ng/mgCr | Standard Deviation 33.674 |
| Obese - Metformin | Change in Urinary Estradiol Metabolites | Tanner 4 | 37.722 ng/mgCr | Standard Deviation 34.648 |
| Obese - Metformin | Change in Urinary Estradiol Metabolites | Tanner 2/3 | 28.451 ng/mgCr | Standard Deviation 26.082 |
| Obese - Metformin | Change in Urinary Estradiol Metabolites | Tanner 5 | 71.546 ng/mgCr | Standard Deviation 77.343 |
Secondary
Change in Urinary Follicle-stimulating Hormone
FSH measured in overnight urine sample at time points below
Time frame: Baseline, every 6 months during the trial, Final visit-average 3 yrs after baseline
Population: 24 participants analyzed in the Obese NT Placebo group are also analyzed in the Obese Placebo group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Weight | Change in Urinary Follicle-stimulating Hormone | Tanner 2/3 | 3.911 international units per milliliter (IU/m | Standard Deviation 5.59 |
| Normal Weight | Change in Urinary Follicle-stimulating Hormone | Tanner 4 | 2.555 international units per milliliter (IU/m | Standard Deviation 2.541 |
| Normal Weight | Change in Urinary Follicle-stimulating Hormone | Tanner 5 | 6.540 international units per milliliter (IU/m | Standard Deviation 9.36 |
| Normal Weight | Change in Urinary Follicle-stimulating Hormone | Post-Puberty | NA international units per milliliter (IU/m | — |
| Obese - NT | Change in Urinary Follicle-stimulating Hormone | Tanner 4 | 4.874 international units per milliliter (IU/m | Standard Deviation 3.586 |
| Obese - NT | Change in Urinary Follicle-stimulating Hormone | Tanner 5 | 4.093 international units per milliliter (IU/m | Standard Deviation 3.962 |
| Obese - NT | Change in Urinary Follicle-stimulating Hormone | Post-Puberty | 5.993 international units per milliliter (IU/m | Standard Deviation 6.429 |
| Obese - NT | Change in Urinary Follicle-stimulating Hormone | Tanner 2/3 | 3.837 international units per milliliter (IU/m | Standard Deviation 4.264 |
| Obese - Placebo | Change in Urinary Follicle-stimulating Hormone | Tanner 5 | 4.093 international units per milliliter (IU/m | Standard Deviation 3.962 |
| Obese - Placebo | Change in Urinary Follicle-stimulating Hormone | Tanner 4 | 4.874 international units per milliliter (IU/m | Standard Deviation 3.586 |
| Obese - Placebo | Change in Urinary Follicle-stimulating Hormone | Post-Puberty | 5.993 international units per milliliter (IU/m | Standard Deviation 6.429 |
| Obese - Placebo | Change in Urinary Follicle-stimulating Hormone | Tanner 2/3 | 3.837 international units per milliliter (IU/m | Standard Deviation 4.264 |
| Obese - Metformin | Change in Urinary Follicle-stimulating Hormone | Post-Puberty | 3.911 international units per milliliter (IU/m | Standard Deviation 2.689 |
| Obese - Metformin | Change in Urinary Follicle-stimulating Hormone | Tanner 4 | 3.162 international units per milliliter (IU/m | Standard Deviation 2.686 |
| Obese - Metformin | Change in Urinary Follicle-stimulating Hormone | Tanner 2/3 | 3.615 international units per milliliter (IU/m | Standard Deviation 4.356 |
| Obese - Metformin | Change in Urinary Follicle-stimulating Hormone | Tanner 5 | 3.213 international units per milliliter (IU/m | Standard Deviation 3.323 |
Secondary
Change in Urinary Luteinizing Hormone
LH measured in an overnight urine sample at time points below
Time frame: Baseline, every 6 months during the trial, Final visit (average 3 yrs after baseline)
Population: 24 participants analyzed in the Obese NT Placebo group are also analyzed in the Obese Placebo group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Weight | Change in Urinary Luteinizing Hormone | Tanner 2/3 | 3.849 international units per liter | Standard Deviation 4.53 |
| Normal Weight | Change in Urinary Luteinizing Hormone | Tanner 4 | 4.518 international units per liter | Standard Deviation 8.496 |
| Normal Weight | Change in Urinary Luteinizing Hormone | Tanner 5 | 4.494 international units per liter | Standard Deviation 7.616 |
| Normal Weight | Change in Urinary Luteinizing Hormone | Post-Puberty | NA international units per liter | — |
| Obese - NT | Change in Urinary Luteinizing Hormone | Tanner 4 | 3.310 international units per liter | Standard Deviation 3.793 |
| Obese - NT | Change in Urinary Luteinizing Hormone | Tanner 5 | 2.014 international units per liter | Standard Deviation 1.442 |
| Obese - NT | Change in Urinary Luteinizing Hormone | Post-Puberty | 5.373 international units per liter | Standard Deviation 11.363 |
| Obese - NT | Change in Urinary Luteinizing Hormone | Tanner 2/3 | 2.257 international units per liter | Standard Deviation 2.186 |
| Obese - Placebo | Change in Urinary Luteinizing Hormone | Tanner 5 | 2.014 international units per liter | Standard Deviation 1.442 |
| Obese - Placebo | Change in Urinary Luteinizing Hormone | Tanner 4 | 3.310 international units per liter | Standard Deviation 3.793 |
| Obese - Placebo | Change in Urinary Luteinizing Hormone | Post-Puberty | 5.373 international units per liter | Standard Deviation 11.363 |
| Obese - Placebo | Change in Urinary Luteinizing Hormone | Tanner 2/3 | 2.257 international units per liter | Standard Deviation 2.186 |
| Obese - Metformin | Change in Urinary Luteinizing Hormone | Post-Puberty | 30.861 international units per liter | Standard Deviation 62.387 |
| Obese - Metformin | Change in Urinary Luteinizing Hormone | Tanner 4 | 3.729 international units per liter | Standard Deviation 4.036 |
| Obese - Metformin | Change in Urinary Luteinizing Hormone | Tanner 2/3 | 3.809 international units per liter | Standard Deviation 3.667 |
| Obese - Metformin | Change in Urinary Luteinizing Hormone | Tanner 5 | 8.993 international units per liter | Standard Deviation 14.725 |
Secondary
Dehydroepiandrosterone Sulfate
DHEA-S measured in serum at each time point
Time frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Weight | Dehydroepiandrosterone Sulfate | Tanner 5 | 130.206 mcg/dl | Standard Deviation 69.229 |
| Normal Weight | Dehydroepiandrosterone Sulfate | Baseline | 90.146 mcg/dl | Standard Deviation 60.522 |
| Normal Weight | Dehydroepiandrosterone Sulfate | Tanner 4 | 101.889 mcg/dl | Standard Deviation 62.016 |
| Normal Weight | Dehydroepiandrosterone Sulfate | Post-Puberty | NA mcg/dl | — |
| Obese - NT | Dehydroepiandrosterone Sulfate | Post-Puberty | NA mcg/dl | — |
| Obese - NT | Dehydroepiandrosterone Sulfate | Tanner 5 | 137.250 mcg/dl | Standard Deviation 74.248 |
| Obese - NT | Dehydroepiandrosterone Sulfate | Baseline | 96.750 mcg/dl | Standard Deviation 63.592 |
| Obese - NT | Dehydroepiandrosterone Sulfate | Tanner 4 | 101.533 mcg/dl | Standard Deviation 67.038 |
| Obese - Placebo | Dehydroepiandrosterone Sulfate | Tanner 4 | 116.182 mcg/dl | Standard Deviation 71.822 |
| Obese - Placebo | Dehydroepiandrosterone Sulfate | Baseline | 91.167 mcg/dl | Standard Deviation 60.501 |
| Obese - Placebo | Dehydroepiandrosterone Sulfate | Tanner 5 | 137.083 mcg/dl | Standard Deviation 86.885 |
| Obese - Placebo | Dehydroepiandrosterone Sulfate | Post-Puberty | 132.154 mcg/dl | Standard Deviation 68.295 |
| Obese - Metformin | Dehydroepiandrosterone Sulfate | Tanner 4 | 129.545 mcg/dl | Standard Deviation 69.398 |
| Obese - Metformin | Dehydroepiandrosterone Sulfate | Baseline | 107.600 mcg/dl | Standard Deviation 64.722 |
| Obese - Metformin | Dehydroepiandrosterone Sulfate | Post-Puberty | 176.818 mcg/dl | Standard Deviation 110.84 |
| Obese - Metformin | Dehydroepiandrosterone Sulfate | Tanner 5 | 145.818 mcg/dl | Standard Deviation 66.535 |
Secondary
Disposition Index
Please see primary outcome for more detail about timing of measurement. Disposition index is measured via (IVGTT) as calculated by Bergman's minimal model. Higher numbers indicate a better outcome. It reflects the product of outcome measures 1 and 2 (Si x AIRg).
Time frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline, 6 mos post-treatment-average 3 yrs from baseline
Population: 24 participants analyzed in the Obese NT Placebo group are also analyzed in the Obese Placebo group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Weight | Disposition Index | Baseline | 3750.463 x10-4/min-1 | Standard Deviation 1625.015 |
| Normal Weight | Disposition Index | Tanner 4 | 3706.940 x10-4/min-1 | Standard Deviation 1972.563 |
| Normal Weight | Disposition Index | Tanner 5 | 3234.061 x10-4/min-1 | Standard Deviation 2474.754 |
| Normal Weight | Disposition Index | Post-Puberty | NA x10-4/min-1 | — |
| Obese - NT | Disposition Index | Tanner 4 | 3269.039 x10-4/min-1 | Standard Deviation 1500.261 |
| Obese - NT | Disposition Index | Tanner 5 | 2897.244 x10-4/min-1 | Standard Deviation 1547.515 |
| Obese - NT | Disposition Index | Post-Puberty | NA x10-4/min-1 | — |
| Obese - NT | Disposition Index | Baseline | 4195.921 x10-4/min-1 | Standard Deviation 1743.345 |
| Obese - Placebo | Disposition Index | Tanner 5 | 3194.773 x10-4/min-1 | Standard Deviation 1918.812 |
| Obese - Placebo | Disposition Index | Tanner 4 | 2897.689 x10-4/min-1 | Standard Deviation 1553.948 |
| Obese - Placebo | Disposition Index | Post-Puberty | 3627.762 x10-4/min-1 | Standard Deviation 2375.166 |
| Obese - Placebo | Disposition Index | Baseline | 4286.209 x10-4/min-1 | Standard Deviation 1966.92 |
| Obese - Metformin | Disposition Index | Post-Puberty | 2539.933 x10-4/min-1 | Standard Deviation 1393.267 |
| Obese - Metformin | Disposition Index | Tanner 4 | 5046.218 x10-4/min-1 | Standard Deviation 2858.784 |
| Obese - Metformin | Disposition Index | Baseline | 4438.821 x10-4/min-1 | Standard Deviation 2420.123 |
| Obese - Metformin | Disposition Index | Tanner 5 | 3537.273 x10-4/min-1 | Standard Deviation 768.858 |
Secondary
Estradiol
Estradiol measured in serum at each time point
Time frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Population: 24 participants analyzed in the Obese NT Placebo group are also analyzed in the Obese Placebo group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Weight | Estradiol | Baseline | 22.375 pg/mL | Standard Deviation 34.068 |
| Normal Weight | Estradiol | Tanner 4 | 50.583 pg/mL | Standard Deviation 70.888 |
| Normal Weight | Estradiol | Tanner 5 | 57.382 pg/mL | Standard Deviation 79.251 |
| Normal Weight | Estradiol | Post-Puberty | NA pg/mL | — |
| Obese - NT | Estradiol | Tanner 4 | 35.867 pg/mL | Standard Deviation 49.693 |
| Obese - NT | Estradiol | Tanner 5 | 42.800 pg/mL | Standard Deviation 38.324 |
| Obese - NT | Estradiol | Post-Puberty | NA pg/mL | — |
| Obese - NT | Estradiol | Baseline | 15.722 pg/mL | Standard Deviation 7.756 |
| Obese - Placebo | Estradiol | Tanner 5 | 48.833 pg/mL | Standard Deviation 47.61 |
| Obese - Placebo | Estradiol | Tanner 4 | 44.545 pg/mL | Standard Deviation 56.077 |
| Obese - Placebo | Estradiol | Post-Puberty | 70.923 pg/mL | Standard Deviation 91.316 |
| Obese - Placebo | Estradiol | Baseline | 15.833 pg/mL | Standard Deviation 7.738 |
| Obese - Metformin | Estradiol | Post-Puberty | 69.636 pg/mL | Standard Deviation 85.94 |
| Obese - Metformin | Estradiol | Tanner 4 | 23.364 pg/mL | Standard Deviation 14.123 |
| Obese - Metformin | Estradiol | Baseline | 14.750 pg/mL | Standard Deviation 6.695 |
| Obese - Metformin | Estradiol | Tanner 5 | 48.000 pg/mL | Standard Deviation 29.192 |
Secondary
Hemoglobin A1c
HbA1c measured by HPLC at time points below
Time frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Population: 24 participants analyzed in the Obese NT Placebo group are also analyzed in the Obese Placebo group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Weight | Hemoglobin A1c | Baseline | 5.139 mmol/mol | Standard Deviation 0.25 |
| Normal Weight | Hemoglobin A1c | Tanner 4 | 5.200 mmol/mol | Standard Deviation 0.26 |
| Normal Weight | Hemoglobin A1c | Tanner 5 | 5.233 mmol/mol | Standard Deviation 0.293 |
| Normal Weight | Hemoglobin A1c | Post-Puberty | NA mmol/mol | — |
| Obese - NT | Hemoglobin A1c | Tanner 4 | 5.627 mmol/mol | Standard Deviation 0.531 |
| Obese - NT | Hemoglobin A1c | Tanner 5 | 5.476 mmol/mol | Standard Deviation 0.36 |
| Obese - NT | Hemoglobin A1c | Post-Puberty | NA mmol/mol | — |
| Obese - NT | Hemoglobin A1c | Baseline | 5.336 mmol/mol | Standard Deviation 0.488 |
| Obese - Placebo | Hemoglobin A1c | Tanner 5 | 5.500 mmol/mol | Standard Deviation 0.398 |
| Obese - Placebo | Hemoglobin A1c | Tanner 4 | 5.627 mmol/mol | Standard Deviation 0.531 |
| Obese - Placebo | Hemoglobin A1c | Post-Puberty | 5.515 mmol/mol | Standard Deviation 0.519 |
| Obese - Placebo | Hemoglobin A1c | Baseline | 5.336 mmol/mol | Standard Deviation 0.488 |
| Obese - Metformin | Hemoglobin A1c | Post-Puberty | 5.691 mmol/mol | Standard Deviation 0.929 |
| Obese - Metformin | Hemoglobin A1c | Tanner 4 | 5.570 mmol/mol | Standard Deviation 0.25 |
| Obese - Metformin | Hemoglobin A1c | Baseline | 5.400 mmol/mol | Standard Deviation 0.286 |
| Obese - Metformin | Hemoglobin A1c | Tanner 5 | 5.473 mmol/mol | Standard Deviation 0.552 |
Secondary
High Density Lipoprotein
Please see primary outcome for more detail about timing of measurement.
Time frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline, 6 mos post-treatment-average 3 yrs from baseline
Population: 24 participants analyzed in the Obese NT Placebo group are also analyzed in the Obese Placebo group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Weight | High Density Lipoprotein | Baseline | 51.442 mg/dL | Standard Deviation 8.921 |
| Normal Weight | High Density Lipoprotein | Tanner 4 | 51.667 mg/dL | Standard Deviation 11.734 |
| Normal Weight | High Density Lipoprotein | Tanner 5 | 46.909 mg/dL | Standard Deviation 8.498 |
| Normal Weight | High Density Lipoprotein | Post-Puberty | NA mg/dL | — |
| Obese - NT | High Density Lipoprotein | Tanner 4 | 39.455 mg/dL | Standard Deviation 9.533 |
| Obese - NT | High Density Lipoprotein | Tanner 5 | 38.944 mg/dL | Standard Deviation 8.755 |
| Obese - NT | High Density Lipoprotein | Post-Puberty | NA mg/dL | — |
| Obese - NT | High Density Lipoprotein | Baseline | 39.306 mg/dL | Standard Deviation 6.511 |
| Obese - Placebo | High Density Lipoprotein | Tanner 5 | 39.333 mg/dL | Standard Deviation 8.897 |
| Obese - Placebo | High Density Lipoprotein | Tanner 4 | 39.455 mg/dL | Standard Deviation 9.533 |
| Obese - Placebo | High Density Lipoprotein | Post-Puberty | 40.923 mg/dL | Standard Deviation 8.645 |
| Obese - Placebo | High Density Lipoprotein | Baseline | 38.917 mg/dL | Standard Deviation 7.003 |
| Obese - Metformin | High Density Lipoprotein | Post-Puberty | 41.818 mg/dL | Standard Deviation 8.171 |
| Obese - Metformin | High Density Lipoprotein | Tanner 4 | 42.273 mg/dL | Standard Deviation 4.735 |
| Obese - Metformin | High Density Lipoprotein | Baseline | 41.368 mg/dL | Standard Deviation 7.274 |
| Obese - Metformin | High Density Lipoprotein | Tanner 5 | 43.000 mg/dL | Standard Deviation 5.916 |
Secondary
High Sensitivity C-reactive Protein
hsCRP measured in serum at each time point
Time frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Population: 24 participants analyzed in the Obese NT Placebo group are also analyzed in the Obese Placebo group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Weight | High Sensitivity C-reactive Protein | Baseline | 1.001 units on a scale | Standard Deviation 2.604 |
| Normal Weight | High Sensitivity C-reactive Protein | Tanner 4 | 0.305 units on a scale | Standard Deviation 0.631 |
| Normal Weight | High Sensitivity C-reactive Protein | Tanner 5 | 1.015 units on a scale | Standard Deviation 3.265 |
| Normal Weight | High Sensitivity C-reactive Protein | Post-Puberty | NA units on a scale | — |
| Obese - NT | High Sensitivity C-reactive Protein | Tanner 4 | 4.530 units on a scale | Standard Deviation 5.034 |
| Obese - NT | High Sensitivity C-reactive Protein | Tanner 5 | 3.331 units on a scale | Standard Deviation 3.814 |
| Obese - NT | High Sensitivity C-reactive Protein | Post-Puberty | NA units on a scale | — |
| Obese - NT | High Sensitivity C-reactive Protein | Baseline | 2.523 units on a scale | Standard Deviation 2.644 |
| Obese - Placebo | High Sensitivity C-reactive Protein | Tanner 5 | 3.985 units on a scale | Standard Deviation 4.681 |
| Obese - Placebo | High Sensitivity C-reactive Protein | Tanner 4 | 4.357 units on a scale | Standard Deviation 5.661 |
| Obese - Placebo | High Sensitivity C-reactive Protein | Post-Puberty | 3.958 units on a scale | Standard Deviation 3.51 |
| Obese - Placebo | High Sensitivity C-reactive Protein | Baseline | 3.117 units on a scale | Standard Deviation 3.06 |
| Obese - Metformin | High Sensitivity C-reactive Protein | Post-Puberty | 2.667 units on a scale | Standard Deviation 4.647 |
| Obese - Metformin | High Sensitivity C-reactive Protein | Tanner 4 | 1.841 units on a scale | Standard Deviation 1.494 |
| Obese - Metformin | High Sensitivity C-reactive Protein | Baseline | 3.962 units on a scale | Standard Deviation 3.608 |
| Obese - Metformin | High Sensitivity C-reactive Protein | Tanner 5 | 0.961 units on a scale | Standard Deviation 0.915 |
Secondary
Insulin-like Growth Factor 1
IGF-1 measured in serum at each time point
Time frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Population: 24 participants analyzed in the Obese NT Placebo group are also analyzed in the Obese Placebo group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Weight | Insulin-like Growth Factor 1 | Baseline | 313.500 ng/ml | Standard Deviation 103.339 |
| Normal Weight | Insulin-like Growth Factor 1 | Tanner 4 | 405.389 ng/ml | Standard Deviation 116.845 |
| Normal Weight | Insulin-like Growth Factor 1 | Tanner 5 | 398.000 ng/ml | Standard Deviation 97.117 |
| Normal Weight | Insulin-like Growth Factor 1 | Post-Puberty | NA ng/ml | — |
| Obese - NT | Insulin-like Growth Factor 1 | Tanner 4 | 370.800 ng/ml | Standard Deviation 89.816 |
| Obese - NT | Insulin-like Growth Factor 1 | Tanner 5 | 389.800 ng/ml | Standard Deviation 116.087 |
| Obese - NT | Insulin-like Growth Factor 1 | Post-Puberty | NA ng/ml | — |
| Obese - NT | Insulin-like Growth Factor 1 | Baseline | 262.278 ng/ml | Standard Deviation 91.924 |
| Obese - Placebo | Insulin-like Growth Factor 1 | Tanner 5 | 351.833 ng/ml | Standard Deviation 74.909 |
| Obese - Placebo | Insulin-like Growth Factor 1 | Tanner 4 | 380.273 ng/ml | Standard Deviation 77.04 |
| Obese - Placebo | Insulin-like Growth Factor 1 | Post-Puberty | 319.692 ng/ml | Standard Deviation 93.694 |
| Obese - Placebo | Insulin-like Growth Factor 1 | Baseline | 243.042 ng/ml | Standard Deviation 85.04 |
| Obese - Metformin | Insulin-like Growth Factor 1 | Post-Puberty | 395.818 ng/ml | Standard Deviation 114.417 |
| Obese - Metformin | Insulin-like Growth Factor 1 | Tanner 4 | 410.300 ng/ml | Standard Deviation 116.467 |
| Obese - Metformin | Insulin-like Growth Factor 1 | Baseline | 281.700 ng/ml | Standard Deviation 86.014 |
| Obese - Metformin | Insulin-like Growth Factor 1 | Tanner 5 | 404.800 ng/ml | Standard Deviation 88.745 |
Secondary
Insulin Secretion (Acute Insulin Response to Glucose, AIRg)
As measured by IVGTT as calculated by Bergman's minimal model. Higher numbers indicate a better outcome. Please see primary outcome for more detail about timing of measurement.
Time frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline, 6 mos post-treatment-average 3 yrs from baseline
Population: 24 participants analyzed in the Obese NT Placebo group are also analyzed in the Obese Placebo group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Weight | Insulin Secretion (Acute Insulin Response to Glucose, AIRg) | Baseline | 583.535 µIU/mL | Standard Deviation 432.753 |
| Normal Weight | Insulin Secretion (Acute Insulin Response to Glucose, AIRg) | Tanner 4 | 783.191 µIU/mL | Standard Deviation 623.946 |
| Normal Weight | Insulin Secretion (Acute Insulin Response to Glucose, AIRg) | Tanner 5 | 680.858 µIU/mL | Standard Deviation 572.884 |
| Normal Weight | Insulin Secretion (Acute Insulin Response to Glucose, AIRg) | Post-Puberty | NA µIU/mL | — |
| Obese - NT | Insulin Secretion (Acute Insulin Response to Glucose, AIRg) | Tanner 4 | 1951.323 µIU/mL | Standard Deviation 1035.697 |
| Obese - NT | Insulin Secretion (Acute Insulin Response to Glucose, AIRg) | Tanner 5 | 2103.309 µIU/mL | Standard Deviation 1505.04 |
| Obese - NT | Insulin Secretion (Acute Insulin Response to Glucose, AIRg) | Post-Puberty | NA µIU/mL | — |
| Obese - NT | Insulin Secretion (Acute Insulin Response to Glucose, AIRg) | Baseline | 1877.895 µIU/mL | Standard Deviation 1052.328 |
| Obese - Placebo | Insulin Secretion (Acute Insulin Response to Glucose, AIRg) | Tanner 5 | 2013.628 µIU/mL | Standard Deviation 1417.407 |
| Obese - Placebo | Insulin Secretion (Acute Insulin Response to Glucose, AIRg) | Tanner 4 | 1996.867 µIU/mL | Standard Deviation 1215.017 |
| Obese - Placebo | Insulin Secretion (Acute Insulin Response to Glucose, AIRg) | Post-Puberty | 1943.542 µIU/mL | Standard Deviation 1353.036 |
| Obese - Placebo | Insulin Secretion (Acute Insulin Response to Glucose, AIRg) | Baseline | 1858.16 µIU/mL | Standard Deviation 1079.128 |
| Obese - Metformin | Insulin Secretion (Acute Insulin Response to Glucose, AIRg) | Post-Puberty | 1667.713 µIU/mL | Standard Deviation 917.27 |
| Obese - Metformin | Insulin Secretion (Acute Insulin Response to Glucose, AIRg) | Tanner 4 | 2157.349 µIU/mL | Standard Deviation 1099.876 |
| Obese - Metformin | Insulin Secretion (Acute Insulin Response to Glucose, AIRg) | Baseline | 2368.931 µIU/mL | Standard Deviation 1616.348 |
| Obese - Metformin | Insulin Secretion (Acute Insulin Response to Glucose, AIRg) | Tanner 5 | 1804.026 µIU/mL | Standard Deviation 761.849 |
Secondary
Leptin
Leptin measured in serum at time points below
Time frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Population: 24 participants analyzed in the Obese NT Placebo group are also analyzed in the Obese Placebo group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Weight | Leptin | Post-Puberty | NA ng/mL | — |
| Normal Weight | Leptin | Baseline | 5.956 ng/mL | Standard Deviation 5.616 |
| Normal Weight | Leptin | Tanner 4 | 5.964 ng/mL | Standard Deviation 4.582 |
| Normal Weight | Leptin | Tanner 5 | 8.338 ng/mL | Standard Deviation 7.088 |
| Obese - NT | Leptin | Tanner 5 | 38.155 ng/mL | Standard Deviation 21.061 |
| Obese - NT | Leptin | Baseline | 32.097 ng/mL | Standard Deviation 13.624 |
| Obese - NT | Leptin | Post-Puberty | NA ng/mL | — |
| Obese - NT | Leptin | Tanner 4 | 36.867 ng/mL | Standard Deviation 20.519 |
| Obese - Placebo | Leptin | Tanner 4 | 44.036 ng/mL | Standard Deviation 19.121 |
| Obese - Placebo | Leptin | Tanner 5 | 47.642 ng/mL | Standard Deviation 21.269 |
| Obese - Placebo | Leptin | Post-Puberty | 53.200 ng/mL | Standard Deviation 41.323 |
| Obese - Placebo | Leptin | Baseline | 33.917 ng/mL | Standard Deviation 15.207 |
| Obese - Metformin | Leptin | Post-Puberty | 48.445 ng/mL | Standard Deviation 31.855 |
| Obese - Metformin | Leptin | Tanner 4 | 29.791 ng/mL | Standard Deviation 21.892 |
| Obese - Metformin | Leptin | Baseline | 32.215 ng/mL | Standard Deviation 17.027 |
| Obese - Metformin | Leptin | Tanner 5 | 31.182 ng/mL | Standard Deviation 20.982 |
Secondary
Liver Adipose
Liver fat percent. Measured in a subset (10 per group) by fast MRI technique
Time frame: Baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Population: Data was not collected for some participants at all visits.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Weight | Liver Adipose | Baseline | 1.376 percentage of liver mass | Standard Deviation 0.594 |
| Normal Weight | Liver Adipose | Tanner 5 | 2.208 percentage of liver mass | Standard Deviation 0.637 |
| Obese - NT | Liver Adipose | Tanner 5 | 8.219 percentage of liver mass | Standard Deviation 5.757 |
| Obese - NT | Liver Adipose | Baseline | 8.290 percentage of liver mass | Standard Deviation 7.177 |
| Obese - Placebo | Liver Adipose | Baseline | 13.765 percentage of liver mass | Standard Deviation 5.457 |
| Obese - Placebo | Liver Adipose | Tanner 5 | 10.327 percentage of liver mass | Standard Deviation 8.023 |
| Obese - Metformin | Liver Adipose | Baseline | 8.290 percentage of liver mass | Standard Deviation 7.177 |
| Obese - Metformin | Liver Adipose | Tanner 5 | 8.291 percentage of liver mass | Standard Deviation 5.757 |
Secondary
Low Density Lipoprotein
Please see primary outcome for more detail about timing of measurement.
Time frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline, 6 mos post-treatment-average 3 yrs from baseline
Population: 24 participants analyzed in the Obese NT Placebo group are also analyzed in the Obese Placebo group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Weight | Low Density Lipoprotein | Baseline | 79.488 mg/dl | Standard Deviation 22.691 |
| Normal Weight | Low Density Lipoprotein | Tanner 4 | 75.367 mg/dl | Standard Deviation 15.852 |
| Normal Weight | Low Density Lipoprotein | Tanner 5 | 78.485 mg/dl | Standard Deviation 20.52 |
| Normal Weight | Low Density Lipoprotein | Post-Puberty | NA mg/dl | — |
| Obese - NT | Low Density Lipoprotein | Tanner 4 | 96.636 mg/dl | Standard Deviation 19.464 |
| Obese - NT | Low Density Lipoprotein | Tanner 5 | 96.222 mg/dl | Standard Deviation 24.422 |
| Obese - NT | Low Density Lipoprotein | Post-Puberty | NA mg/dl | — |
| Obese - NT | Low Density Lipoprotein | Baseline | 86.533 mg/dl | Standard Deviation 22.543 |
| Obese - Placebo | Low Density Lipoprotein | Tanner 5 | 97.667 mg/dl | Standard Deviation 27.655 |
| Obese - Placebo | Low Density Lipoprotein | Tanner 4 | 96.636 mg/dl | Standard Deviation 19.464 |
| Obese - Placebo | Low Density Lipoprotein | Post-Puberty | 103.154 mg/dl | Standard Deviation 26.62 |
| Obese - Placebo | Low Density Lipoprotein | Baseline | 88.583 mg/dl | Standard Deviation 23.824 |
| Obese - Metformin | Low Density Lipoprotein | Post-Puberty | 86.545 mg/dl | Standard Deviation 28.507 |
| Obese - Metformin | Low Density Lipoprotein | Tanner 4 | 81.818 mg/dl | Standard Deviation 24.677 |
| Obese - Metformin | Low Density Lipoprotein | Baseline | 83.779 mg/dl | Standard Deviation 25.029 |
| Obese - Metformin | Low Density Lipoprotein | Tanner 5 | 75.000 mg/dl | Standard Deviation 27.799 |
Secondary
Percent Body Fat
% body fat measured by DXA at time points below
Time frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Population: 24 participants analyzed in the Obese NT Placebo group are also analyzed in the Obese Placebo group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Weight | Percent Body Fat | Baseline | 24.883 percentage of body fat | Standard Deviation 6.452 |
| Normal Weight | Percent Body Fat | Tanner 4 | 25.054 percentage of body fat | Standard Deviation 6.159 |
| Normal Weight | Percent Body Fat | Tanner 5 | 25.500 percentage of body fat | Standard Deviation 7.478 |
| Normal Weight | Percent Body Fat | Post-Puberty | NA percentage of body fat | — |
| Obese - NT | Percent Body Fat | Tanner 4 | 43.380 percentage of body fat | Standard Deviation 3.649 |
| Obese - NT | Percent Body Fat | Tanner 5 | 42.889 percentage of body fat | Standard Deviation 4.688 |
| Obese - NT | Percent Body Fat | Post-Puberty | NA percentage of body fat | — |
| Obese - NT | Percent Body Fat | Baseline | 42.126 percentage of body fat | Standard Deviation 5.259 |
| Obese - Placebo | Percent Body Fat | Tanner 5 | 44.555 percentage of body fat | Standard Deviation 3.692 |
| Obese - Placebo | Percent Body Fat | Tanner 4 | 44.264 percentage of body fat | Standard Deviation 3.489 |
| Obese - Placebo | Percent Body Fat | Post-Puberty | 43.962 percentage of body fat | Standard Deviation 5.701 |
| Obese - Placebo | Percent Body Fat | Baseline | 44.700 percentage of body fat | Standard Deviation 3.304 |
| Obese - Metformin | Percent Body Fat | Post-Puberty | 41.418 percentage of body fat | Standard Deviation 5.669 |
| Obese - Metformin | Percent Body Fat | Tanner 4 | 40.610 percentage of body fat | Standard Deviation 7.906 |
| Obese - Metformin | Percent Body Fat | Baseline | 43.826 percentage of body fat | Standard Deviation 5.412 |
| Obese - Metformin | Percent Body Fat | Tanner 5 | 39.964 percentage of body fat | Standard Deviation 6.49 |
Secondary
Sex Hormone Binding Globulin
SHBG measured in serum at each time point
Time frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Population: 24 participants analyzed in the Obese NT Placebo group are also analyzed in the Obese Placebo group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Weight | Sex Hormone Binding Globulin | Baseline | 61.958 nmol/l | Standard Deviation 21.68 |
| Normal Weight | Sex Hormone Binding Globulin | Tanner 4 | 50.417 nmol/l | Standard Deviation 24.098 |
| Normal Weight | Sex Hormone Binding Globulin | Tanner 5 | 43.500 nmol/l | Standard Deviation 15.498 |
| Normal Weight | Sex Hormone Binding Globulin | Post-Puberty | NA nmol/l | — |
| Obese - NT | Sex Hormone Binding Globulin | Tanner 4 | 17.200 nmol/l | Standard Deviation 7.58 |
| Obese - NT | Sex Hormone Binding Globulin | Tanner 5 | 16.250 nmol/l | Standard Deviation 5.581 |
| Obese - NT | Sex Hormone Binding Globulin | Post-Puberty | NA nmol/l | — |
| Obese - NT | Sex Hormone Binding Globulin | Baseline | 20.417 nmol/l | Standard Deviation 8.31 |
| Obese - Placebo | Sex Hormone Binding Globulin | Tanner 5 | 15.750 nmol/l | Standard Deviation 6.468 |
| Obese - Placebo | Sex Hormone Binding Globulin | Tanner 4 | 16.364 nmol/l | Standard Deviation 6.742 |
| Obese - Placebo | Sex Hormone Binding Globulin | Post-Puberty | 15.538 nmol/l | Standard Deviation 4.409 |
| Obese - Placebo | Sex Hormone Binding Globulin | Baseline | 18.958 nmol/l | Standard Deviation 6.805 |
| Obese - Metformin | Sex Hormone Binding Globulin | Post-Puberty | 17.273 nmol/l | Standard Deviation 10.64 |
| Obese - Metformin | Sex Hormone Binding Globulin | Tanner 4 | 19.545 nmol/l | Standard Deviation 14.348 |
| Obese - Metformin | Sex Hormone Binding Globulin | Baseline | 17.550 nmol/l | Standard Deviation 8.451 |
| Obese - Metformin | Sex Hormone Binding Globulin | Tanner 5 | 16.455 nmol/l | Standard Deviation 8.825 |
Secondary
Total Testosterone
Testosterone measured in serum at each time point
Time frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Population: 24 participants analyzed in the Obese NT Placebo group are also analyzed in the Obese Placebo group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Weight | Total Testosterone | Baseline | 108.625 ng/dl | Standard Deviation 135.377 |
| Normal Weight | Total Testosterone | Tanner 4 | 145.972 ng/dl | Standard Deviation 159.866 |
| Normal Weight | Total Testosterone | Tanner 5 | 235.559 ng/dl | Standard Deviation 235.224 |
| Normal Weight | Total Testosterone | Post-Puberty | NA ng/dl | — |
| Obese - NT | Total Testosterone | Tanner 4 | 87.933 ng/dl | Standard Deviation 103.902 |
| Obese - NT | Total Testosterone | Tanner 5 | 158.300 ng/dl | Standard Deviation 234.056 |
| Obese - NT | Total Testosterone | Post-Puberty | NA ng/dl | — |
| Obese - NT | Total Testosterone | Baseline | 35.278 ng/dl | Standard Deviation 28.375 |
| Obese - Placebo | Total Testosterone | Tanner 5 | 165.750 ng/dl | Standard Deviation 282.171 |
| Obese - Placebo | Total Testosterone | Tanner 4 | 89.364 ng/dl | Standard Deviation 105.331 |
| Obese - Placebo | Total Testosterone | Post-Puberty | 152.692 ng/dl | Standard Deviation 168.109 |
| Obese - Placebo | Total Testosterone | Baseline | 30.125 ng/dl | Standard Deviation 20.422 |
| Obese - Metformin | Total Testosterone | Post-Puberty | 150.727 ng/dl | Standard Deviation 161.357 |
| Obese - Metformin | Total Testosterone | Tanner 4 | 121.727 ng/dl | Standard Deviation 113.418 |
| Obese - Metformin | Total Testosterone | Baseline | 41.050 ng/dl | Standard Deviation 32.705 |
| Obese - Metformin | Total Testosterone | Tanner 5 | 117.909 ng/dl | Standard Deviation 132.301 |
Secondary
Visceral Adipose
Percent Visceral Fat, Measured in a subset (10 per group) by single slice MRI
Time frame: Baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Population: Data was not collected for some participants at all visits.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Weight | Visceral Adipose | Baseline | 7.647 Percent | Standard Deviation 3.702 |
| Normal Weight | Visceral Adipose | Tanner 5 | 6.322 Percent | Standard Deviation 2.676 |
| Obese - NT | Visceral Adipose | Tanner 5 | 12.236 Percent | Standard Deviation 1.564 |
| Obese - NT | Visceral Adipose | Baseline | 12.007 Percent | Standard Deviation 2.263 |
| Obese - Placebo | Visceral Adipose | Baseline | 12.076 Percent | Standard Deviation 3.968 |
| Obese - Placebo | Visceral Adipose | Tanner 5 | 10.079 Percent | Standard Deviation 1.886 |
| Obese - Metformin | Visceral Adipose | Baseline | 12.007 Percent | Standard Deviation 2.263 |
| Obese - Metformin | Visceral Adipose | Tanner 5 | 12.236 Percent | Standard Deviation 1.564 |