The Health Influences of Puberty (HIP) Study

Study Overview
=================
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: Obese adolescents will show decreased improvement in insulin sensitivity from Tanner stage 2/3 to Tanner 5 when compared with lean counterparts. 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): To compare longitudinal changes in insulin sensitivity and secretion and their correlates in obese and normal weight adolescents during puberty. 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. 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): To compare longitudinal changes in insulin sensitivity and secretion and their correlates in obese adolescents treated with metformin or placebo during puberty. Primary outcome: Change in Si from early puberty to puberty completion in obese controls and obese adolescents treated with metformin. Secondary outcome: Change in AIR and DI, body composition, fat distribution, markers of gonadal function, and inflammatory markers over time in these groups.

Official Title
-----------------
Combined Influence of Puberty and Obesity on Insulin Resistance in Adolescents

Conditions
-----------------
Obesity, Insulin Resistance, Gonadal Dysfunction, Type 2 Diabetes

Intervention / Treatment
-----------------
* Drug: Metformin
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 9 Years
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Obese metformin arm<br>Double-blinded placebo-controlled trial of metformin during puberty, treatment arm Dosage form: Metformin 1000 mg tablets Dosage: 1000 mg by mouth twice daily Duration: From early puberty (Tanner 2-3) until puberty completion (Tanner 5), approximately 3 years | Drug: Metformin<br>* 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.<br>* Other names: Riomet;|
| Placebo Comparator: Obese placebo arm<br>Double-blinded placebo-controlled trial of metformin during puberty, placebo arm Dosage form: Placebo stamped to match 1000 mg metformin tablets Placebo comparator: Stamped placebo pill matching metformin dose Dosage: 1000 mg by mouth twice daily Duration: From early puberty (Tanner 2-3) until puberty completion (Tanner 5), approximately 3 years | Drug: Placebo<br>* 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<br>|
| No Intervention: Obese - NT<br>Comparator group for the observational comparison of metabolic changes in youth with normal weight and obesity as they progress through puberty. Duration: From early puberty (Tanner 2-3) until puberty completion (Tanner 5), approximately 3 years | |
| No Intervention: Normal weight<br>Comparator group for the observational comparison of metabolic changes in youth with normal weight and obesity as they progress through puberty. Duration: From early puberty (Tanner 2-3) until puberty completion (Tanner 5), approximately 3 years | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 
| 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). | 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 | 
| Low Density Lipoprotein | Please see primary outcome for more detail about timing of measurement. | 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 | 
| Insulin-like Growth Factor 1 | IGF-1 measured in serum at each time point | Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline | 
| Total Testosterone | Testosterone measured in serum at each time point | Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline | 
| Estradiol | Estradiol measured in serum at each time point | Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline | 
| Sex Hormone Binding Globulin | SHBG measured in serum at each time point | Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline | 
| Dehydroepiandrosterone Sulfate | DHEA-S measured in serum at each time point | Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline | 
| High Sensitivity C-reactive Protein | hsCRP measured in serum at each time point | Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline | 
| Aspartate Aminotransferase (AST) | AST measured in serum at each time point | Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline | 
| Alanine Transaminase (ALT) | ALT measured in serum at each time point | Baseline (Tanner 2-3), Tanner 4, Tanner 5 | 
| Change in Urinary Luteinizing Hormone | LH measured in an overnight urine sample at time points below | Baseline, every 6 months during the trial, Final visit (average 3 yrs after baseline) | 
| Change in Urinary Follicle-stimulating Hormone | FSH measured in overnight urine sample at time points below | Baseline, every 6 months during the trial, Final visit-average 3 yrs after baseline | 
| Change in Urinary Estradiol Metabolites | estradiol metabolite (E1c) measured in an overnight urine sample at each time point | Baseline, every 6 months during the trial, Final visit-average 3 yrs after baseline | 
| Hemoglobin A1c | HbA1c measured by HPLC at time points below | Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline | 
| Leptin | Leptin measured in serum at time points below | Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline | 
| Percent Body Fat | % body fat measured by DXA at time points below | Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline | 
| Visceral Adipose | Percent Visceral Fat, Measured in a subset (10 per group) by single slice MRI | Baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline | 
| Liver Adipose | Liver fat percent. Measured in a subset (10 per group) by fast MRI technique | Baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline | 
| High Density Lipoprotein | Please see primary outcome for more detail about timing of measurement. | 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Insulin resistance, Puberty, Obesity, Hypogonadism, Gonadal dysfunction, Metformin