Trial Information

Metabolic Effect of Metformin in Obese Insulin Resistant Adolescents With Normal Glucose Tolerance

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.