Investigating the Use of Quercetin on Glucose Absorption in Obesity, and Obesity With Type 2 Diabetes

Postprandial hyperglycemia and the resultant hyperinsulinemia contribute to the
cardiovascular complications seen in obesity and in type 2 diabetes. Epidemiological studies
suggest that slow absorption of carbohydrates dampens glucose and insulin peaks, and reduces
cardiovascular morbidity. The polyphenol quercetin is the most abundant flavanoid in
plant-derived foods, and is sold as a dietary supplement. In vitro, quercetin is a potent and
reversible inhibitor of glucose transport by the intestinal glucose transporter GLUT2. In
vivo quercetin inhibits post absorptive glucose peaks in obese, diabetic rats. We hypothesize
that quercetin blunts intestinal glucose absorption in humans, and attenuates postprandial
hyperglycemia. We propose to test, in a double blind placebo controlled study, whether
coadministration of 1 or 2 grams of quercetin with glucose will reduce plasma glucose
concentrations during a 6 hour oral glucose tolerance test with 3 to 6 grams of 3-O-methyl
glucose (3OMG) in non-diabetic obese subjects and in obese type 2 diabetic subjects. The
glucose dose may be varied from 0 to 100 grams to better understand the competition between
3OMG and glucose. 3OMG is a non-metabolizable glucose analogue and is excreted unaltered in
urine. 3OMG is not found in food and thus glucose absorption can be studies easily without
the problem of a high baseline value. The use of 3OMG will provide a more accurate and true
measures of glucose absorption. Study subjects will be 19 - 65 years with a body mass index
greater than or equal to 30, without complications of diabetes, or on any medication other
than oral hypoglycemic agents and aspirin. We will study 16 obese non diabetic subjects and
16 obese type 2 diabetics. Each subject will have 3 oral glucose tolerance tests, and will
serve as his or her own control. We will compare the peak plasma glucose concentrations
achieved during oral glucose tolerance tests and the area under the curve of plasma glucose
to determine whether quercetin inhibits glucose absorption in humans. Such inhibition may
partially explain the protective effects of plant derived foods on cardiovascular disease,
and enable us to use quercetin or related compounds to dampen intestinal glucose absorption.
We will also measure quercetin concentrations in the plasma, in circulating white blood cells
and in urine to determine quercetin pharmacokinetics. Additionally, to determine the optimal
3OMG dose, we will study the absorption of glucose and 3OMG, without quercetin, in 12
non-diabetic obese subjects and 12 lean subjects to serve as controls.

- INCLUSION CRITERIA:

Subjects to be recruited for the study will be male and female subjects between the ages of
18 and 65, able to give informed consent, with mild to moderate type 2 diabetes (such that
fasting blood sugar <200mg/dl or HbA1C < 8.5), in otherwise good general health, with no
other significant illnesses, blood pressure <=160/90 mmHg with or without medication, with
no known severe target organ damage. End organ damage includes the following: proliferative
retinopathy, serum creatinine >2, ischemic heart disease, congestive heart failure, known
gastroparesis, peripheral vascular disease and severe peripheral neuropathy. Diabetic
subjects must have a BMI greater than or equal to 30. Subjects will be taken off
hypoglycemic agents for 3 to 7 days prior to each part of the study. This is to remove a
confounding factor that may affect blood glucose concentrations attained during the OGTT,
independent of the effect of quercetin. Whether these oral hypoglycemic agents have
physiologically significant interaction with quercetin is not known. Severity of diabetes
and biological duration of action of the drug will determine when to initiate this hold
(from 3 to 7 days prior to OGTT). During the time that the subjects are off oral
hypoglycemic agents, they will monitor their fasting blood glucose daily by glucometer.
Therefore, for subjects with diabetes, only those subjects who self-monitor blood glucose
are eligible for inclusion. If the fasting blood glucose in the morning exceeds 300 mg/dl,
the subject will be withdrawn from the study and appropriate therapy resumed. Obese
volunteers, with a BMI greater than or equal to 30, must be in good health, with no known
illness. Healthy, normal weight subjects (BMI <25) will also be recruited as control
subjects for the sampling study without querecetin. An upper age limit of 65 years was
chosen to minimize renal toxicity of quercetin, as GFR declines with age and quercetin
might produce mild though reversible renal impairment.

EXCLUSION CRITERIA:

Exclusion criteria will include the following: significant digestive abnormalities such as
malabsorption or chronic diarrhea; significant organ malfunction including (but not limited
to) liver disease, pulmonary disease, ischemic heart disease, heart failure, stroke,
peripheral vascular disease, hypertension (BP >160/90), and anemia (hematocrit < 30); other
serious or chronic illness; history of serious or chronic illness; any significant
complications from diabetes such as kidney damage (renal insufficiency, serum creatinine
>2), eye damage (proliferative retinopathy), severe diabetic neuropathy, coronary artery
disease, or symptomatic peripheral vascular disease; smoking; alcohol or drug abuse;
smokers; pregnancy (a urine pregnancy test will be performed on all women with reproductive
age before each part of the study); lactation; positive HIV or hepatitis (B or C) screening
tests (subjects will be notified of these test results). Diabetic subjects who choose not
to self-monitor glucose daily by glucometer will be excluded.