Role of Exenatide in Type 1 Diabetes

A large study in people with type 1 diabetes (T1DM) showed that lowering blood sugars stopped
or delayed the occurrence of health problems. As a result of the study, treatment should try
to control blood sugars as near to normal as safely possible.

In people without diabetes, the "after meal" blood sugar level is very carefully controlled.
Insulin (the hormone that lowers blood sugar) and glucagon (hormone that raises blood sugar)
play a key role in keeping this careful balance. It is now known that a substance made by the
body called GLP-1 also helps with this careful balance. Glucagon like peptide-1 works in four
ways. First, it helps to stimulate the cells in the pancreas to produce more insulin.
Secondly, it helps to "dampen" the glucagon response (glucagon is released after a meal and
causes the blood sugar to rise). Thirdly, Glucagon like peptide-1 delays the digestion of
food in the stomach. Lastly, it seems to "dampen" the appetite, which causes a person to eat
less.

Exenatide is a medication that works very similar to Glucagon like peptide-1. Exenatide is
FDA approved for use in adults.

Study Design: Followed by a baseline study with insulin alone, subjects were randomized to
two different doses of exenatide (1.25 and 2.5 µ,g), administered in a double-blinded
randomized controlled manner, along with insulin as a single subcutaneous injection. Studies
were at least 3 weeks apart.

Baseline: At 0800 h, the pre-breakfast insulin bolus was administered based on patient's
usual insulin-to-carbohydrate ratio. Post-bolus, subjects drank 12 ounces of a standard
liquid meal (Boost High Protein Drink, 360 calories, 50 g carbohydrates, and 12 g fat),
enriched with 1 g of [13C] glucose within 10 min. Breath samples for 13CO2 analysis were
collected in duplicates at 17 time points until 1300 h. Usual insulin basal rates or glargine
were maintained during study.

On the days subjects received the study drug of 1.25 µ,g (~0.02 µ,g/kg) or 2.5 µ,g (~0.04
µ,g/kg) exenatide along with insulin, the prandial insulin was reduced by 20%.

Measurements: Plasma glucose was measured using a bedside YSI glucose analyzer (2300 Stat
Plus; Yellow Springs Instruments, Yellow Springs, OH) throughout the study at regularly timed
intervals. Delta plasma glucose area under the curve (AUC0 -120) was measured for the
exenatide treated groups vs. insulin monotherapy.

Inclusion Criteria:

***Subjects must be patients of the Texas Children's Hospital Diabetes Care Center***.

All of the following criteria must be met:

1. Between 12-21 years of age at the time of enrollment.

2. Have been diagnosed with Type 1 diabetes for at least 1 year and in good control
(HbA1C less than 8.5%).

3. Subjects must be otherwise healthy except for the Type 1 Diabetes and treated
hypothyroidism.

4. Menstruating women must have a negative pregnancy test.

5. Hemoglobin equal to or greater than 12 g/dL before each study.

6. Weight greater than 44 kg.

7. Tanner stage greater than 3

Exclusion Criteria:

1. Any chronic disease: leukemia, asthma, inflammatory bowel disease, cystic fibrosis,
juvenile rheumatoid arthritis etc or on treatment that might directly or indirectly
affect glucose homeostasis, except for diabetes and hypothyroidism; stable on
medications.

2. Lack of a supportive family environment as detected by the clinicians and/or social
workers.

3. Positive pregnancy test in menstruating young women.

4. BMI greater than 90th percentile for age or less than 10th percentile for age.

5. Lactating and nursing mothers.