The Health Influences of Puberty (HIP) Study

Phase 4

Completed

• Conditions: Type 2 Diabetes; Gonadal Dysfunction; Obesity; Insulin Resistance
• Interventions: Drug: Placebo; Drug: Metformin

• Registration Number: NCT01775813
• Lead Sponsor: University of Colorado, Denver

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.

Study Timeline

• Study Start: 2011-06
• Study First Submitted: 2012-10-05
• Study First Submitted QC: 2013-01-22
• Study First Posted: 2013-01-25
• Primary Completion: 2018-05-31
• Study Completion: 2018-05-31
• Results First Submitted: 2021-04-27
• Status Verified: 2022-01
• Results First Submitted QC: 2022-01-03
• Last Update Submitted: 2022-01-03
• Results First Posted: 2022-02-01
• Last Update Posted: 2022-02-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 104

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)

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Obese placebo arm	Placebo	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
Obese metformin arm	Metformin	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

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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
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
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
Alanine Transaminase (ALT)	Baseline (Tanner 2-3), Tanner 4, Tanner 5	ALT measured in serum at each time point
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.
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
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
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
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
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
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
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
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
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.

Trial Locations

Locations (1)

Children's Hospital Colorado; 🇺🇸 Aurora, Colorado, United States