Effect Of Exenatide Treatment on Liver Fat Content in Patients With Diabetes

Obesity is characterized as generalized expansion of all adipose tissue depots, an increase
in tissue lipid content, and dyslipidemia, insulin resistance, and type 2 diabetes. The
adipocyte functions not only as a storage depot for fat but as an endocrine organ that
releases hormones in response to specific extracellular stimuli or changes in metabolic
status. These secreted proteins, carry out a variety of diverse functions, and they have
been referred to collectively as adipokines. The adipokines have been postulated to play
important roles in the pathogenesis of insulin resistance, hypertension, disorders of
coagulation, dyslipidemia, and glucose intolerance, abnormalities associated with insulin
resistance syndrome.

These observations are of considerable interest because recent studies have provided
evidence that increased hepatic fat content is an important determinant of hepatic insulin
resistance in type 2 diabetic patients. Fatty liver is common in type 2 diabetic patients.
The mechanisms responsible for the increase in hepatic fat content are unclear. It has been
suggested that fatty liver results from accelerated fatty acid mobilization from expanded
visceral fat stores and their deposition in the liver as well as decreased hepatic fatty
acid oxidation. Weight loss in humans with Non Alcoholic Fatty Liver Disease (NAFLD) is
associated with a decrease in hepatic fat content. In addition, thiazolidinediones have been
shown to reduce hepatic fat content and improve hepatic insulin sensitivity in patients with
type 2 diabetes as well as in non-diabetic patients with NAFLD. The thiazolidinediones
initiate their action by binding the peroxisome proliferator activator receptors (PPAR) ,
which primarily are located on adipocytes. Treatment of insulin-resistant mice as well as
type 2 diabetic patients with insulin sensitizing PPAR activators, such as
thiazolidinediones, and increases plasma adiponectin levels. Indirect evidence suggests that
adiponectin might mediate some of the insulin-sensitizing effects of PPAR agonists.

Exenatide, a Glucagon Like Peptide-1 (GLP-1) receptor agonist approved for treatment of type
2 diabetes, elicited dose-dependent reductions in body weight in association with improved
glycemic control in type 2 diabetic patients. In animal models of obesity, exenatide reduces
hepatic fat. However, the effect of exenatide treatment in combination with a
thiazolidinedione on liver fat content and plasma adipocytokines levels in patients with
type 2 diabetes remains to be investigated.

Inclusion Criteria:

1. Patients must range in age from 30 to 70 years.

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

3. 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
or be surgically sterilized.

4. Patients must meet the American Diabetes Association Criteria for diagnosis of type 2
diabetes mellitus.

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

6. Patients must have Hematocrit greater than 34%.

7. Subjects whose body weight has been stable (±1 Kg) over the three months prior to
study will be included.

Exclusion Criteria:

1, Type 1 diabetes.

2. 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 (CHF), or clinically significant
cardiac, liver or kidney disease (creatinine greater than 1.8 mg/dl).