Effect of Exenatide on Liver and Heart Fat and Inflammation

Type 2 diabetics and insulin resistant individuals have an excess of fat in the liver which
is not attributable to alcohol or other known causes of liver disease, a condition defined
as nonalcoholic fatty liver disease (NAFLD). The fatty liver is insulin resistant.
Individuals with a fatty liver are more likely to have excess intra-abdominal fat as well as
a reduction in circulating plasma adiponectin levels. We have previously shown that type 2
diabetes and its associated Non Alcoholic Fatty Liver Disease (NAFLD) is characterized by
increased hepatic fat content, decreased circulating adiponectin levels, and hepatic and
peripheral (muscle) insulin resistance. Weight loss in humans with Non Alcoholic Fatty Liver
Disease is associated with a decrease in hepatic fat content. Exenatide, an incretin based
anti-diabetes therapy, enhances glucose-dependent insulin secretion and glucose-dependent
suppression of inappropriately high glucagon secretion, improves glycemic control in
patients with type 2 diabetes and is associated with weight loss. In rodent studies,
exenatide reduces hepatic and myocardial fat and reduces vascular inflammation independent
of changes in weight. Exenatide has also been shown to increase plasma adiponectin levels in
humans and rodents. Furthermore type 2 diabetics are characterized by an increase in both
hepatic and myocardial fat and left ventricular dysfunction, particularly diastolic
dysfunction. However, the effect of exenatide therapy on liver and myocardial fat content,
as well as left ventricular function in patients with type 2 diabetes has not been
previously studied.

Inclusion Criteria:

1. Patients must be able to communicate meaningfully with the investigator and must be
legally competent to provide written informed consent.

2. Patients may be of either sex. Female patients must be non-lactating and must either
be at least two years post-menopausal, or be using adequate contraceptive
precautions.

3. Patients must range in age from 30 to 70 years, inclusive.

4. Patients must meet the American Diabetes Association (ADA) criteria (ADA 1997
Criteria: fasting plasma glucose greater than or equal to 126 mg/dl) for the
diagnosis of type 2 diabetes mellitus.

5. Patients must be on diet therapy and/or metformin treatment for type 2 diabetes
(stable dose)and have a fasting plasma glucose concentration between 126 and 260
mg/dl

6. Patients must have Hematocrit greater than 34 vol%.

7. Subjects whose body weight has been stable over the three months prior to study
enrollment will be included.

Exclusion Criteria:

1. Patients must not have type 1 diabetes.

2. Patients must not have a fasting plasma glucose greater than 260 mg/dl.

3. Patients must not have received a thiazolidinedione for at least 3 months prior to
randomization.

4. Patients must not be on insulin treatment or have received insulin for more than one
week within the previous year prior to entry. Patients should not be on
sulfonylureas, sitagliptin, or exenatide treatment.

5. Patients taking systemic glucocorticoids or other medications known to affect glucose
tolerance are excluded.

6. Patients taking medications that affect gastrointestinal motility will be excluded.

7. Patients with a history of Congestive Heart Failure, or clinically significant
cardiac, liver or kidney disease (creatinine greater than 1.5 mg/dl).