Effects of Hesperidin on Insulin Sensitivity

This study will examine whether hesperidin, a major component of citrus fruits, affects how
the body responds to insulin in healthy and obese people. Insulin is not as effective in
people who are overweight, have high blood pressure or diabetes. This condition is known as
insulin resistance. Laboratory studies suggest that hesperidin treatment lowers blood
pressure, lowers blood sugar and increases blood flow. This study will see if hesperidin
improves insulin resistance or insulin's effects on blood flow in people with insulin
resistance.

Healthy normal weight or overweight people between 21 and 65 years of age may be eligible
for this study. Participants are randomly assigned to take hesperidin or a placebo (inactive
dummy pill ) for a 4-week treatment phase. In addition to treatment, participants undergo
the following procedures during the study period:

Screening, including medical history, physical examination and blood and urine tests.

Complete a dietary and physical activity questionnaire and consult with a dietitian

Blood and urine tests

At-home and clinic blood pressure monitoring

Glucose clamp test to measure how the body responds to insulin. This test is done two times
during the study. A needle is placed in a vein in each of the subject's arms, one for
sampling blood and the other for infusing insulin, glucose and potassium. Glucose and
insulin levels, electrolytes, lipids, fatty acids, cytokines and hesperidin levels are
measured. We will also use tracer-labeled glucose to determine how much glucose the body
produces in the fasting state and during the clamp. This type of glucose has low levels of
radiation.

Forearm blood flow measurement with finger plethysmography device. Before beginning the
glucose clamp test, a test of how well the blood vessels relax is done. A device that
measures the blood flow in the vessels of the forefingers is used. The test is performed at
the before the glucose clamp test and again 2 hours after the beginning of the clamp.

Inclusion Criteria:

Healthy Subjects - Men and women in good general health with no significant underlying
illnesses who are between the ages of 21 - 65 years of age with HbA1C < 5.7 %, fasting
blood glucose < 100 mg/dL, blood pressure less than 120/80, and BMI between 20 - 25 kg/m2.
Subjects should have never smoked tobacco or not smoked within the previous year.

Obese Subjects - Men and women in good general health with no significant underlying
illnesses except obesity who are between the ages of 21 - 65 years of age with HbA1C < 5.7
%, fasting blood glucose < 100 mg/dl, blood pressure less than 130/90, and BMI between 30
- 45 kg/m2.

Exclusion Criteria:

- Subjects will be excluded from our study if they are pregnant, breastfeeding, or if
they plan pregnancy prior to the end of the study. In addition, subjects will be
excluded if their age > 65 yrs, BMI ≥ 45 kg/m2, or have liver disease (including
liver transaminase levels greater than twice the upper limit of normal), pulmonary
disease, renal insufficiency (serum creatinine greater than 2.0 mg/dl), coronary
heart disease, heart failure (New York Heart Association heart failure Class III or
IV), peripheral vascular disease, coagulopathy, Major depressive disorder, actively
smoking or used tobacco within last year, history of cancer, in treatment for any
form of cancer, positive tests for HIV, hepatitis B or C, or take systemic
corticosteroids, thiazolidinediones (within 3 months), insulin, or anticoagulants,
use food supplements that cannot be discontinued, regular intake of 8 or more cups of
tea per week within 3 months prior to study entry, regular alcoholic beverage intake
of more than two drinks per day (a drink corresponds to approximately 12 ounces of
beer, 4 ounces of table wine, and between 1 and 1.5 ounces of 80-proof spirits), poor
compliance during run-in period or regular use of medications that affect insulin
sensitivity, blood pressure or vascular function and that cannot be discontinued. In
addition, history of any other medical disease, laboratory abnormalities, or
psychological conditions that would make the subject (based upon the principal
investigator's judgment) unsuitable for study enrollment. Subjects will be excluded
if they are unable to give informed consent for all procedures.