Metabolic Effect of Metformin in Obese Insulin Resistant Adolescents With Normal Glucose Tolerance
Condition: Pediatric Obesity; Insulin Resistance; Hyperinsulinemia
MeSH terms: Insulin Resistance; Pediatric Obesity; Hyperinsulinism
Study type: Interventional
Phase: Phase 4

Summary: 
      The primary objective of this randomized, parallel group, double-blind, placebo-controlled
      study is to determine whether treatment with metformin enhances insulin sensitivity in a
      group of ethnically diverse obese insulin-resistant adolescents with normal glucose
      tolerance.
    

Detailed description: 
      First Visit

      Patients who agree to participate in this research study, will have an initial screening
      where the subject will be asked about his/her health, a sample of blood will be drawn, the
      subject will be examined, and an oral glucose tolerance (OGTT) test will be done.

        -  OGTT: The study takes about four hours and will begin on an "empty stomach." A small
           I.V. will be placed in a vein in the subject's arm. The I.V. will allow a member of the
           research team to take small amounts of blood for measuring glucose and other substances
           that circulate in the blood. About 7 tablespoons of blood will be drawn in total during
           the OGTT. The I.V. will remain in place all during the study. At the beginning of the
           study, the subject will be asked to drink about 8 ounces (one cup) of a high sugar cola-
           or orange-flavored drink.

      If the subject meets all the requirements to be in the study and has a normal glucose
      tolerance test, he/she will be randomized to either the intensely (Euglycemic
      hyperinsulinemic clamp) or standard studied group and have the following six or seven tests
      performed: DEXA scan and Tanita, exercise step test, PAT test, MRI (Abdominal scan), MRS (leg
      scan), and Euglycemic hyperinsulinemic clamp (intensely studied group only). All of the tests
      are described below. Females will have a urine pregnancy test before each of these tests. If
      positive, the subject will not be allowed to participate/continue with the study.

        -  DEXA / Tanita: The DEXA scan will measure how much muscle and fat is in the subject's
           body and how dense the subject's bones are using an x-ray technique. Directly after the
           DEXA Scan, the subject's percentage of body fat will be measured using a Tanita scale.

        -  Exercise Step Test: The subject will be asked to step up and down two steps 20 times at
           their own pace. We will measure the subject's heart rate directly before and for three
           minutes after this exercise. After a ten minute break, the test will be repeated.

        -  Peripheral Arterial Tonometry (PAT): This test will allow us to evaluate the response of
           the small blood vessels in the subject's arm to changes in nerve signals to them. During
           this test, we will put a probe (similar to a tight-fitting glove) on one finger of each
           of the subject's hands and take some measurements for about five minutes. The probes
           contain latex, so this test will not be performed on subjects who are allergic to latex.
           Following these measurements, we will block blood flow to one of the hands for five
           minutes by putting a blood pressure cuff on one of the arms and inflating the cuff.
           After the pressure in the cuff is released, we will take more measurements for about
           five minutes.

        -  MRI (Belly Scan): Magnetic Resonance Imaging (MRI) will be used to take pictures of the
           subject's belly. These pictures will allow us to calculate how much fat the subject has
           just below the skin and how much fat is deeper inside the belly. We will also be able to
           estimate the percentage of fat in the subject's liver.

        -  MRS (Leg scan): We will measure how much fat is in the subject's calf muscle using
           magnetic resonance spectroscopy (MRS).

        -  Insulin, Glucose and Glycerol Infusion Study (Euglycemic hyperinsulinemic clamp): A
           small I.V. will be placed into a vein in each arm. One I.V. will be used to take out
           small amounts of blood for measuring the blood sugar and other substances that circulate
           in the blood. The other I.V. will be used to infuse insulin, glucose, and glycerol into
           the subject's blood. Insulin is a hormone that helps bring blood sugar into the cells.
           Glycerol is a component of fat that is normally present in a person's body.

      This infusion will not affect the subject's blood sugar in a harmful manner. It will allow us
      to follow the release of glucose from the liver and glycerol from fat tissue.

      The subject's blood sugar will be checked closely during the study by taking blood samples
      from the second I.V. Readings of the blood sugar on each sample will be made at the bedside.
      If the blood sugar starts to fall, it can be fixed right away. At the end of another three
      hours, the infusion will be stopped and the subject will eat a meal that will be provided for
      him/her. The infusion of glucose will be reduced while the subject is eating until the
      subject's blood sugar is stable. This test takes about 6 hours. The total amount of blood
      drawn during this test will be less than 8 tablespoons or about half a cup.

      Indirect calorimetry is a way to measure how much sugar and fat a person is burning when we
      give insulin. Testing how much fat and sugar a subject burns is an important part of the
      insulin, glucose, and glycerol infusion study. Therefore we will ask the subject to wear a
      plastic hood (like an astronaut space helmet) before starting the infusion of insulin and at
      two other times during the study.

      Taking Metformin or Placebo

      Once the subject has completed the six (standard studied group) or seven (intensely studied
      group only) tests described above, as well as two urine tests for protein, he/she will be
      randomized to either:

        -  Take Metformin; or

        -  Take a placebo pill

      The subject will begin by taking one pill (either Metformin or placebo) every day, just
      before supper. The dose will be slowly increased as follows:

      Week 1: Before breakfast = 0 and Before supper = 1 (500mg); Week 2: Before breakfast = 1
      (500mg) and Before supper = 1 (500mg); Week 3-14: Before breakfast = 1 (500mg) and Before
      supper = 2 (500mg)

      The subject will be taking the pills for 3 1/2 months, during which time we will ask that
      he/she keep a diary of any complaints, problems, or symptoms. Neither the subject, the
      subject's doctor, nor any of the members of the research team will find out which pill the
      subject was taking until the end of the study.

      Monthly Follow-up

      Subjects will be asked to come back every month for a physical exam. We will measure their
      height, weight, and blood pressure each time. A urine pregnancy test will be done on all
      female participants at every visit. At the subject's first follow up visit we will draw a
      small amount of blood and run tests to make sure the subject is healthy. We will ask the
      subject and his/her parent about any symptoms that the subject has had, any pills that he/she
      might have missed taking, and the use of other medications. We will measure the subject's
      vitamin B12 level on his/her third follow up visit.

      End of Study

      About three months after the subject begins taking the Metformin or placebo pills, he/she
      will repeat the tests described above (oral glucose tolerance test, DEXA and Tanita, exercise
      step test, PAT test, MRI, and MRS). In the sub-group of participants who had the glucose,
      insulin, and glycerol infusion test, this will also be repeated at the end of the study.

      Open Label Phase (Taking Metformin)

      After the tests described above are completed, all participants (even if they had been
      assigned a placebo pill) will be given the choice of taking Metformin for the next six
      months. If the subject does choose to continue, we will continue to monitor him/her monthly,
      as described in the section above on monthly follow-up. At the end of the additional six
      months, we will repeat all the tests that the subject had at the beginning of the study. For
      the intensely studied group, this includes the insulin, glucose and glycerol infusion.
    

Intervention name(s): Metformin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): The subject will receive either metformin or placebo drug, given as 500mg tablets (or corresponding placebos) necessary to increase the dose incrementally over a three week period.
The time it takes to incrementally increase the dose to the desired dose of 500mg in am and 1000mg in pm will count as intervention time. Both the metformin and placebo group will also be given a multivitamin with vitamin B12 to avoid potential anemia.; The subject will receive either metformin or placebo drug, given as 500mg tablets (or corresponding placebos) necessary to increase the dose incrementally over a three week period.
The time it takes to incrementally increase the dose to the desired dose of 500mg in am and 1000mg in pm will count as intervention time. Both the metformin and placebo group will also be given a multivitamin with vitamin B12 to avoid potential anemia.
Other intervention name(s): Glucophage, Glucophage XR, Glumetza, Fortamet, Riomet
Intervention MeSH terms: Metformin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Pediatric Obesity; Insulin Resistance; Hyperinsulinemia; Metformin; Glucose Tolerance; Microalbuminuria; Adolescents; Visceral Fat