Pharmacogenomics of Thiazolidinediones

In phase I, subjects who are eligible based on height and weight and general health
information will sign informed consent. In phase II, subjects will be screened to ensure that
they fit the inclusion/exclusion criteria, including an oral glucose tolerance test. Other
blood tests will be performed to check complete blood count, lipids, liver functions and
electrolytes.

Qualifying volunteers will enter phase III, which will consist of outpatient radioimaging and
body composition, metabolic testing (intravenous glucose tolerance test), and tissue
biopsies. Blood will also be drawn for genetic testing and for microarray studies of
leukocytes. Written medication information and instructions for pioglitazone, discharge
instructions and satisfaction surveys following the tissue biopsy procedures will be given to
subjects during the study. During phase IV, subjects will begin pioglitazone therapy. Every 4
weeks throughout the drug intervention, glycemic control, lipoprotein profile, and weight
will be monitored. After 12 weeks of pioglitazone therapy, the X-ray and MR measurements of
body composition, the biopsies and the metabolic tests performed during phase III will be
repeated (phase V), and blood will be drawn for microarray studies of leukocytes.

Thereafter, subjects will have the option to be enrolled in a 10 week, behavioral weight loss
program (phase VI). Following the 10-week weight loss program, a few outcome measurements
will be repeated (phase VII).

Throughout the study, Women of Child Bearing Potential (WCBP) will have HCG urine pregnancy
tests. Pregnancy tests will only be performed on Women of childbearing potential, meaning
women who are pre-menopausal and who have not had surgical sterilization. Women who have not
had a hysterectomy or tubal ligation at least six months prior to signing informed consent or
have been postmenopausal for at least one year, will be instructed to practice one of the
following methods of birth control throughout the study: oral, transdermal, or implantable
hormonal contraceptives, intrauterine device, diaphragm plus spermicide, condom plus
spermicide, or abstinence. Pioglitazone may reduce the effectiveness of some hormonal types
of contraceptives. Women using hormonal methods of birth control will be advised to use a
barrier method as well. Female subjects are informed to notify the investigators immediately
if they think they might have become pregnant during the study.

Participants who are eligible have 10 visits over an approximate 15-week period. Participants
can choose to participate in an optional weight management program for an additional 10 weeks
after treatment and before their final visit.

Inclusion Criteria:

- Age 35-64

- BMI: ≥ 25 and ≤ 40

Exclusion Criteria:

- Pregnancy as determined by urine pregnancy test Breast-feeding, or planning to become
pregnant during the study

- Physical dimensions exceeding the limits of any equipment used

- Stage III or greater congestive heart failure

- Symptomatic peripheral vascular disease

- Stroke

- Severe hypertension (>170/100 mmHg)

- Anemia (Hgb and Hct < normal reference range)

- Receiving treatment for thyroid, pituitary, kidney or liver disease (except controlled
thyroid hormone replacement)

- History of diabetes (as told by doctor, or taking diabetic medications Fasting glucose
value diagnostic for diabetes 2-h oral glucose tolerance test diagnostic for diabetes

- Rheumatoid arthritis

- History of wrist, hip or leg fracture after the age of 45

- History of kidney stones

- Medications that the investigator judges will make interpretation of the results
difficult or increase the risk of participation (e.g. anticoagulants)

- Any disease or condition that the investigator judges will affect bone metabolism or
make interpretation of the results difficult or increase the risk of participation
(e.g. anemia, cardiac decompensation, intolerance to pioglitazone, lidocaine, or other
agents used)