Metabolic Effect of Metformin in Obese Insulin Resistant Adolescents With Normal Glucose Tolerance
Metabolic Effect of Metformin in Obese Insulin Resistant Adolescents With Normal Glucose Tolerance
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.
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.
Inclusion Criteria:

 -  Attending weight management clinic at Yale New Haven Hospital

 -  Good general health, taking no other medication on a chronic basis

 -  Age 13 to 17 yrs in puberty (girls: breast Tanner stage II to IV, and boys: testes
 size > 6 ml)

 -  The presence of insulin resistance, defined by fasting insulin levels greater than 30
 µU/ml, and HOMA insulin resistance index > 6

 -  Normal glucose tolerance based on a 2-hr plasma glucose (<140 mg/dl) after the OGTT.

 -  All female subjects must have a negative urine pregnancy test during the study visits
 and must use an effective method of contraception if they are sexually active. Without
 their parent(s) present, all potential female subjects will be asked about their
 sexual activity and the specific form of contraception they are using.

 Exclusion Criteria:

 -  Baseline creatinine > 1.0 mg/dl

 -  Hepatic disease with elevated liver function test (ALT or AST) ≥ 2 X the upper limits
 of normal

 -  Pregnancy

 -  Presence of other endocrinopathies; except treated hypothyroidism on stable
 replacement doses of thyroid hormone

 -  Presence of cardiac, pulmonary or other significant chronic illness

 -  Adolescents with psychiatric disorder, claustrophobia or with substance abuse

 -  Recent use (within six months) of anorexic agents

 -  Presence of anemia (hematocrit < 35)

 -  Mixed ethnic background (defined as two parents of different ethnicity)

 -  Adolescents with metal implants (i.e. cardiac pace maker, metal prostheses, bullet
 remnants)