Effect of EGCG on the Body's Response to Insulin

Green tea is a functional food whose consumption is associated with improved cardiovascular
morbidity and mortality in several large epidemiological studies. One third of the solids in
green tea are composed of the bioactive polyphenol epigallocatechin 3-gallate (EGCG).
Studies in both cell- and animal-based models (from our lab and elsewhere) suggest that EGCG
may mimic and/or augment beneficial metabolic, vascular, and anti-inflammatory actions of
insulin. Indeed, we have recently shown that 3-week EGCG therapy of SHR rats (genetic model
of hypertension with features of human metabolic syndrome including insulin resistance,
hyperinsulinemia, endothelial dysfunction, and overweight) lowers blood pressure, improves
endothelial dysfunction, increases insulin sensitivity, and raises adiponectin levels nearly
as effectively as treatment with the conventional ACE-inhibitor enalapril. Obesity, type 2
diabetes, and hypertension are all important interrelated public health problems that are
characterized by reciprocal relationships between insulin resistance and endothelial
dysfunction. Thus, therapies for these diseases that improve insulin resistance often
simultaneously improve endothelial function and vice versa. Based on results from cellular,
physiological, and epidemiological studies, we hypothesize that oral EGCG administration
will simultaneously ameliorate insulin resistance and lower blood pressure in human subjects
with obesity. To test these hypotheses, we will conduct a randomized, placebo-controlled,
double-blind, cross-over study to evaluate potential beneficial effects of EGCG to modulate
insulin sensitivity, blood pressure, vascular function, and inflammatory markers in two
groups of subjects (lean healthy controls, obesity). After a 2-week EGCG-free run-in period,
each subject will be randomized to receive EGCG or placebo capsules (400 mg p.o. B.I.D.) for
4 weeks. This will be followed by a 2-week EGCG-free washout period after which subjects
will cross-over to the other treatment arm. At baseline, and after each 4-week treatment
period, we will assess insulin sensitivity (hyperinsulinemic isoglycemic glucose clamp
technique) and vascular function. Regarding vascular function, we will measure basal and
insulin-stimulated brachial artery blood flow (large conduit artery assessed by Doppler
ultrasound) as well as capillary recruitment in forearm skeletal muscle (small nutritive
arterioles assessed by ultrasound with microbubble contrast). Blood pressure will be
measured weekly in the UMB GCRC throughout the duration of the study. EGCG pharmacokinetics
will be measured at the beginning of each glucose clamp study day after oral administration
of a single dose of EGCG or placebo. Finally, various plasma markers of inflammation will be
measured at baseline and at the end of each treatment arm to evaluate potential changes that
may be related to improvements in metabolic and/or vascular function. This study will
explore whether EGCG, a single compound thought to be a major bioactive component of green
tea, is effective at improving insulin resistance and lowering blood pressure in subjects
with obesity. Results from this study may have important implications for understanding
potential health benefits of functional foods that contain bioactive polyphenols including
green tea, dark chocolate, and red wine.

- 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 HbA(1C) less than 6.5%, fasting blood glucose
less than 100 mg/dL, blood pressure less than 120/80, and BMI between 20-25 kg/m(2).
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 HbA(1C) less than 6.5%,
fasting blood glucose less than 110 mg/dl, blood pressure less than 140/90, and BMI
between 30-40 kg/m(2).

EXCLUSION CRITERIA:

ALL SUBJECTS:

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 is greater than 65 yrs, BMI greater
than or equal to 40 kg/m(2), 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 the 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 with known hypersensitivity to octafluoropropane, recent eye surgery, or with
known cardiac shunts will also be excluded from participating because of potential adverse
effects from microbubble contrast agent.

Subjects will be excluded if they are unable to give informed consent for all procedures.

Currently, type 2 diabetes is not rare in children, however children are excluded from
this study because children do not typically take EGCG and do not typically have
hypertension or type 2 diabetes mellitus.