Effects of Fatty Acid Delivery on Heart Metabolism and Function in Type 2 Diabetes (T2DM

Type 2 Diabetes Mellitus, (T2DM) is the most common type of diabetes. In Type 2 Diabetes
Mellitus (T2DM), the body does not properly process sugars and, as a result, there is an
excess amount of sugar in the blood. Eventually, the high blood sugar levels can lead to
heart disease, nerve damage, kidney problems, or blindness. Typical Type 2 Diabetes Mellitus
(T2DM) treatments target maintenance of blood sugar levels. Previous studies on Type 2
Diabetes Mellitus (T2DM) have indicated that in people who have high amounts of fats in the
blood, the body relies more heavily on fats than sugars as an energy source. This dependence
on fats for energy has been shown to have a negative effect on heart function. There is
reason to believe that lowering the levels of fats in the blood will enhance the ability of
the heart and the whole body to efficiently use both fats and sugars as energy sources. This
study will evaluate the effectiveness of treatment strategies that are designed to reach
target levels of sugar and fat in the blood for treating people with Type 2 Diabetes Mellitus
(T2DM).

Participation in this double-blind study will last between 4 and 6 months. First,
participants will undergo a medical screening and medication adjustment period, expected to
last 6 months. The medical screening, lasting about 1 hour, will involve completing a medical
history, physical exam, pregnancy test if applicable, and blood test to measure various
factors that contribute to diabetes control. Participants will also be asked permission to
store 1 tablespoon of their blood for up to 10 years to be used in future studies concerning
genetics and heart energy metabolism. During the medication adjustment period, study
physicians will adjust the participants' medications, offer advice on diabetes education and
nutrition, and record any side effects from the medications. For newly diagnosed Type 2
Diabetes Mellitus (T2DM) participants, the study physician may recommend medication changes
to assure a hemoglobin A1c (HgA1c) level of less than 7.5%. If participants have already
achieved this level, they will be asked to continue present medications and to also begin
taking the medication metformin for the 30 days before they undergo several imaging studies.
Next, participants will complete routine tests that evaluate the pumping function of the
heart, including an electrocardiogram (ECG) performed before and during exercise, a body
composition study using a dual energy x-ray absorptiometry (DEXA) scan, and a magnetic
resonance imaging (MRI) test. Each of these tests will last between 30 and 90 minutes.

After the qualifying tests, participants will return for the first of two separate imaging
days that will include the same tests. The second imaging day will occur at the end of the
medication period, approximately 2 months after the first imaging day. The first tests will
be a whole body metabolism study and a heart metabolism imaging study, performed
simultaneously. The whole body metabolism study will involve the injection of two tracers of
metabolism, one for glucose and one for fatty acids. The heart metabolism imaging study will
involve a positron-emission tomographic (PET) scan to take pictures of the heart and will
include blood draws. The final imaging test will be a resting echocardiogram (ECHO) to
measure heart function.

Following completion of the first day of imaging tests, participants will be randomly
assigned to one of three possible treatment groups: Group A ,B, or C. Group A will take
Metformin alone.Group B will take Metformin and Rosiglitazone. Group C will take Metformin
and Lovaza. Participants will be seen monthly for the next 4 months, during which study
medication will be distributed and blood pressure, heart rate, weight, and any side effects,
such as lower extremity swelling, will be measured. If there is a noticeable increase in
swelling, study physicians may adjust medication dosages. During visits at Months 2 and 4,
blood samples will be taken to measure liver and organ function and HgA1c. At the completion
of the 4-month medication treatment, participants will undergo repeat imaging tests. If
needed, participants will be offered the opportunity to attend one or more follow-up visits
to re-establish a medication routine.

Inclusion Criteria:

- Meets Americans with Disabilities Act (ADA) criteria for T2DM; if newly diagnosed,
must have fasting blood glucose greater than 126 mg/dl on two occasions, a random
blood glucose greater than 200 mg/dl with symptoms, or a diagnostic oral glucose
tolerance test

- Weight of less than 350 pounds

- Hemoglobin A1c of equal to or less than 7.5% at study entry or willing to go on one of
the following therapies to achieve necessary percentage: metformin monotherapy greater
than 1000 mg daily for at least 30 days or metformin greater than 1000 mg daily plus
any combination of sulfonylurea, glipizide, or alpha-glucosidase inhibitor

- Blood pressure less than 140/90 mm Hg at study entry

- LDL level less than 130 mg/dL if on stable lipid lowering regimen

- Willing to undergo normal rest/stress (treadmill or dobutamine) echocardiogram

- If currently taking thyroid replacement therapy, must be on a stable dose of thyroid
replacement and must have a thyroid function blood test that is in the normal range

- Willing to use an effective form of birth control throughout the study

Exclusion Criteria:

- Received therapy with an insulin sensitizer of the thiazolidinedione class within 6
months prior to study entry

- Required insulin therapy for more than 2 weeks in the year prior to study entry

- History of angina, heart attack, coronary artery bypass grafting (CABG), stroke,
congestive heart failure (CHF), or peripheral vascular disease (PVD)

- Known coronary artery disease (CAD) with residual lesions of greater than 50%

- Current smoker

- Use or expected use of corticosteroids in any form

- Serum triglycerides greater than 400 mg/dl on a fasting sample at study entry

- Any contraindication to a thiazolidinedione (TZD) insulin sensitizer, metformin, or
other drugs likely to be used during the study

- Liver disease with liver function test (LFT) greater than 2 times the upper limit of
normal (ULN)

- Serum creatinine greater than 1.5 mg/dl for women and 1.6 mg/dl for men OR greater
than 2+ proteinuria on urine dipstick