Effect of Prolonged PDE-5 Inhibition on Insulin Signaling in Skeletal Muscle.

Participants enrolled in the study titled " Renin-angiotensin and fibrinolysis interaction
in humans: effect of long-term PDE5 inhibition on glucose Homeostasis, (Specific aim 2)"
will be offered the opportunity to participate in this sub-study.

We will obtain skeletal muscle biopsies from 16 subjects who are enrolled in specific aim 2.
Eight subjects will be in the sildenafil group and 8 subjects will be in the placebo group.

Inclusion Criteria:

Age > 18 years and BMI > 25 kg/M2 (> 23 kg/M2 among Asian Americans) and ≤40kg/m2 Impaired
fasting glucose (100-125mg/dL) and/or impaired glucose tolerance (2-hr plasma glucose
140-199 mg/dL) and/or hemoglobin A1c 5.7-6.4%

Exclusion Criteria:

- Diabetes type 1 or type 2, as defined by a fasting glucose of 126 mg/dL or greater, a
two-hour plasma glucose of 200 mg/dL or greater, or the use of anti-diabetic
medication.

- The use of nitrates or any disease that might require the use of nitrates.

- The use of any potent CYP3A4 inhibitor.

- Subjects who have participated in a weight-reduction program during the last 6 month
or whose weight has increased or decreased more than 2 kg over the preceding 6
months.

- Pregnancy. Women of child-bearing potential will be required to have undergone tubal
ligation or to be using barrier or hormonal methods of birth control.

- Breast-feeding.

- Cardiovascular disease such as myocardial infarction within 6 months prior to
enrollment, presence of angina pectoris, significant arrhythmia, congestive heart
failure, deep vein thrombosis, pulmonary embolism, second or third degree heart
block, mitral valve stenosis, aortic stenosis or hypertrophic cardiomyopathy.

- Treatment with anticoagulants.

- Treatment with metformin.

- History of serious neurologic disease such as cerebral hemorrhage, stroke, or
transient ischemic attack.

- History or presence of immunological or hematological disorders.

- Diagnosis of asthma on current inhaled corticosteroid therapy.

- Clinically significant gastrointestinal impairment that could interfere with drug
absorption.

- Impaired hepatic function (aspartate amino transaminase and/or alanine amino
transaminase >1.5 x upper limit of normal range)

- Impaired renal function (serum creatinine >1.5 mg/dl).

- Hematocrit <35%.

- Any underlying or acute disease requiring regular medication which could possibly
pose a threat to the subject or make implementation of the protocol or interpretation
of the study results difficult.

- Treatment with chronic systemic glucocorticoid therapy (more than 7 consecutive days
in 1 month).

- Treatment with lithium salts.

- History of alcohol or drug abuse.

- Treatment with any investigational drug in the 1 month preceding the study.

- Mental conditions rendering the subject unable to understand the nature, scope and
possible consequences of the study.

- Inability to comply with the protocol, e.g. uncooperative attitude, inability to
return for follow-up visits, and unlikelihood of completing.