The Health Influences of Puberty (HIP) Study
Condition: Obesity; Insulin Resistance; Gonadal Dysfunction; Type 2 Diabetes
MeSH terms: Obesity; Insulin Resistance; Gonadal Disorders
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): Metformin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 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.; 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
Other intervention name(s): Glucophage; Glumetza; Fortamet; Riomet
Intervention MeSH terms: Metformin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Insulin resistance; Puberty; Obesity; Hypogonadism; Gonadal dysfunction; Metformin