The Effect of Blueberries on Enhancing Insulin Sensitivity in Humans: A Pilot Study

Insulin resistance is a key pathophysiologic feature of the "metabolic syndrome" and is
strongly associated with co-existing cardiovascular risk factors and accelerated
atherosclerosis. Due to the clinical consequences associated with insulin resistance in
subjects with metabolic syndrome and type 2 diabetes, clinical regimens directed at
increasing insulin sensitivity in vivo remain one of the most desirable goals of treatment.
Although it is well established that lifestyle modification can improve insulin resistance
and effectively improve many of the risk factors associated with the metabolic syndrome, the
success of maintaining lifestyle changes in humans over a chronic period is poor. Therefore,
strategies to improve insulin resistance by pharmacological means have represented the
traditional approach for clinical medicine. However, because of the widespread use of
dietary supplements by the general public, nutritional supplementation with the use of
botanical extracts that effectively increase insulin sensitivity represent a very attractive
and novel approach.

Unfortunately, considerable controversy exists regarding the effect of botanical supplements
on the metabolic syndrome in large part because efficacy data for many of the supplements
used for this purpose consists of only uncontrolled studies and anecdotal reports. As such,
there is a paucity of data in humans in regard to the effect of botanicals to improve
measures of insulin action in vivo or on cellular aspects of insulin action. However,
several lines of evidence in both in vitro and in vivo models suggest that botanicals may
modulate intracellular pathways of glucose metabolism. Specifically, preclinical data with
use of extracts from grapes and blueberries suggest that components of these botanical
mixtures, e.g. anthocyanins and resveratrol, may play a role in enhancing cellular pathways
of insulin action. On a clinical level, if cellular pathways of insulin action are enhanced,
e.g. PI-3 kinase activity, this should be associated with an increase in whole body glucose
disposal as reflected in measures assessing insulin sensitivity. However, there is limited
experience in human studies for which insulin sensitivity has been assessed with use of
"gold standard" techniques assessing in vivo insulin action. Therefore, this project's
overall objective is to examine the role of a specific botanical (i.e., blueberry powder) on
insulin action in vivo with use of hyperinsulinemic-euglycemic clamps. This pilot trial is
designed to evaluate a fixed consumption of blueberry powder and to provide data of the
effect so that a larger, more comprehensive study can be planned. To accomplish our goal, we
will conduct a randomized, placebo-controlled pilot clinical study with blueberry powder
designed to assess insulin sensitivity in subjects who are obese and insulin resistant. We
hypothesize that blueberry powder will be effective, when compared to placebo, to increase
insulin action in vivo. If so, this pilot trial will provide the necessary background to
progress to studies in subjects with Type 2 diabetes. An increase in insulin sensitivity in
patients with Type 2 diabetes will be expected to markedly reduce glucose levels.

Inclusion Criteria:

- Subjects ≥ 20 years of age.

- Subjects not currently treated with diabetes medication.

- Subjects with fasting blood glucose at time of screening is ≤ 110 mg/dL.

- Subjects with a Body Mass Index (BMI) ≥ 32 and ≤ 45.

- Written Informed Consent obtained PRIOR to performing any screening tests or study
procedures.

- Subjects who have glucose disposal rate ≤ 650 mg/min assessed clinically at visit 4

Exclusion Criteria:

- Subjects with a prior history of Type 2 diabetes.

- Women who are pregnant or who are lactating.

- Women of childbearing potential who are not using an effective method of birth
control, condoms with spermicidal gel or foam, contraceptive patch, are not
surgically sterilized, or not at least 2 years postmenopausal.

- Subjects who have type 1 diabetes.

- Subjects who are currently on thiazolidinediones (rosiglitazone or pioglitazone) or
who have taken these agents in the previous 12 weeks.

- Subjects who are on concomitant therapy with glucocorticoids (except topical or
inhalant glucocorticoids). Other medications that have an effect on glucose
homeostasis (i.e. ACE inhibitors) are acceptable if they have been administered in a
stable dosage during the preceding 6 months and dosage will continue unchanged during
the study.

- Subjects with a history or evidence of significant gastrointestinal dysfunction.

- Subjects who have chronic use of laxatives or cathartics. The use of stool softeners
is acceptable. Use of bulking agents, if required, should remain constant.

- Subjects who are taking concomitant therapy with medications known to be nephrotoxic,
such as aminoglycosides, methicillin, and cyclosporin.

- Subjects who have evidence of clinically significant renal dysfunction or disease,
e.g. serum creatinine >1.5 mg/dL in males and >1.4 mg/dL in females and/or BUN >50
mg/dL, proteinuria of >1 gram/day or 4+ proteinuria on dipstick urinalysis.

- Subjects with clinically significant cardiovascular dysfunction and/or history
(within the preceding 6 months) of significant cardiovascular dysfunction, e.g.,
congestive heart failure or serious arrhythmia, myocardial infarction, cardiac
surgery; transient ischemic attacks or cerebrovascular accident during the preceding
six months; diagnosis of symptomatic autonomic neuropathy with a history of
orthostatic hypertension, syncope, or hypertension with a systolic blood pressure of
≥180 mm Hg and diastolic blood pressure ≥110 mm Hg at the time of screening visit.

- Subjects who have evidence within the preceding 6 months of hepatic disease or
dysfunction, e.g. AST, ALT, alkaline phosphatase or total bilirubin twice the upper
limit of normal; hepatitis; jaundice; cirrhosis.

- Subjects with clinically significant pulmonary, neurologic, hematologic, immunologic,
neoplastic or metabolic disease.

- Subjects with evidence or recurrence of malignancy within the past five years, other
than excised basal cell carcinoma.

- Subjects for whom surgery is anticipated during the study period.

- Subjects with an history of substance abuse or alcoholism within the past 5 years, or
significant psychiatric disorder that would interfere with the subject's ability to
complete the study.

- Subjects who have donated blood during the month prior to study entry or planned
during the study.

- Subjects who have participated in other studies using an investigational drug during
the preceding 3 months.

- Subjects who are current smokers or have smoked within the previous 6 months. No
smoking will be allowed during the study.

- Subjects who are allergic to blueberries.

- Subjects who are lactose intolerant.

- Subjects who consume and drink daily servings of berries (i.e., blueberries,
strawberries, bilberries, cranberries, elderberries, and raspberries), grapes, fruit
juices that contain berries and grapes, and wine more than 3 times per week.

- Subjects that have had a fluctuation in body weight >5% in the preceding 2 months.

- Subjects who are taking prescription or over the counter medication or supplements
for desired weight loss.