Effect of Pioglitazone and Exenatide on Body Weight and Beta Cell Function

The thiazolidinedione (TZD) class of drugs has been shown to improve insulin sensitivity in
skeletal muscle, liver, and adipocytes and to have anti-inflammatory and cardioprotective
effects. The beta cell function, measured by the insulin secretion/insulin resistance index
during the OGTT, improves significantly. In the present study, we will perform a more
definitive assessment of beta cell function in TZD-treated diabetic patients by measuring the
maximal insulin secretory capacity using a maximal hyperglycemic stimulus combined with an
intravenous arginine stimulus.

Despite the beneficial effects of pioglitazone to improve insulin sensitivity and reduce
cardiovascular events in high risk type 2 diabetic patients, weight gain has been a limiting
factor for primary care physicians even though pioglitazone treatment leads to a
redistribution of fat out of muscle/liver/visceral area to subcutaneous fat.

Exenatide (Byetta) is 39 amino acid peptide which exhibits biological actions similar to
GLP-1. In clinical trials exenatide reduces HbA1c by 1-1.2% in subjects with type 2 diabetes
and promotes moderate weight loss which is sustained for up to 2 years.

In this proposal we will examine the effect of combination therapy with pioglitazone plus
exenatide on body weight, fat topography, beta cell function, glycemic control, and plasma
lipid levels in subjects with type 2 diabetes mellitus compared to monotherapy with each
agent separately. We postulate that combination therapy will result in significant weight
loss (in contrast to the weight gain which accompanies pioglitazone treatment) and have an
additive, or even synergistic, effect to improve beta cell function and glycemic control in
type 2 diabetic patients who are inadequately controlled on oral agent therapy with metformin
alone, a sulfonylurea alone, or combination of metformin plus a sulfonylurea. We will also
compare the insulin secretion in healthy control subjects (NGT, n=15) and subjects with
impaired glucose tolerance (IGT, n=15) to evaluate the relative decline in beta cell function
in T2DM compared to NGT and IGT subjects. NGT and IGT subjects will participate only in a
OGTT and a Hyperglycemic clamp- they will not receive any medication.

Inclusion Criteria:

1. Diabetic patients must be on diet therapy alone or diet plus a sulfonylurea, or diet
plus metformin, or diet plus sulfonylurea/metformin and have a HbA1c ≥ 7.0%.

2. Patients must have the following laboratory values:

Hematocrit ≥ 34 vol% Serum creatinine ≤ 1.8 mg/dl AST (SGOT) ≤ 2 times upper limit of
normal ALT (SGPT) ≤ 2 times upper limit of normal Alkaline phosphatase ≤ 2 times upper
limit of normal

3. Patients must have been on a stable dose of allowed chronic medications for 30 days
prior to entering the study.

4. Body weight must be stable (± 3-4 pounds) over the three months prior to study

5. The normal healthy control group will be age, weight (BMI), and gender matched with
the diabetic group and must have a normal OGTT according to ADA criteria.

6. Subjects with IFG/IGT will have a FPG (100-125mg/dl) and/or 2-h plasma glucose
(140-199mg/dl) according to ADA criteria.

Exclusion Criteria:

1. Patients must not have type 1 diabetes.

2. Patients must not have a fasting plasma glucose of greater than 270 mg/dl or HbA1c >
10.0%.

3. Patients must not have received a thiazolidinedione or insulin for more than one week
during the year prior to randomization.

4. Patients with a history of clinically significant heart disease (New York Heart
Classification greater than class 2.