The Effects of Exenatide on Post-Meal Sugar Peaks and Vascular Health in Obese/Pre-Diabetic Young Adults

Obese insulin resistant adolescents with impaired glucose tolerance (IGT) or evidence of
glucose excursions ≥ 140 mg/dl on CGMS will be enrolled in a two armed randomized, parallel
group - open label study. There will also be a lean control group for baseline assessments
only.

One arm will be exenatide the other arm will be no drug. Subjects will be stratified
according to state of glucose tolerance. Stratification will also occur according to gender
and family history of premature cardiovascular disease.

Obese adolescents age 16-25 years with a family history of type 2 diabetes, whom have
completed or reached tanner IV stage of pubertal development and have normal or impaired
oral glucose tolerance. Obese adolescents age 13-15 with a family history of type 2
diabetes, whom have completed or reached tanner III stage of pubertal development and have
impaired oral glucose tolerance with a 2-hour glucose of 180-199 mg/dl will also be invited
to participate. For cardiovascular assessment only age matched lean control subjects without
diabetes will be recruited.

Obese subjects will have a baseline and post intervention oral glucose tolerance test
(OGTT), screening labs (liver/kidney functions, lipid profile, thyroid function tests, CBC,
metabolic and cardiovascular laboratory parameters -- such as inflammatory cytokines and
pro-thrombotic factors), wear a CGMS for 3-days on 3 separate occasions (baseline, 2-month
and 4-month), have a standardized snack once during each CGMS session, collect urine samples
for microalbumin and have vascular tests (PAT, FMD and exercise step test) done at baseline
and post intervention.

Subjects randomized to treatment will undergo a four month intervention with exenatide on
the following dosing schedule: exenatide - 5 μg twice a day for 7 days, followed by
exenatide 10 μg twice a day for the remainder of the four month intervention.

Lean Control Subjects:

As for obese subjects, lean subjects will be asked to bring in first morning voids for
testing of microalbuminuria. They will also have endothelial function tests (PAT, FMD and
step test) as well as CGMS placement. A set of screening labs will also be drawn (fasting
glucose, insulin, thyroid function and lipid profile will be drawn). Furthermore blood will
be collected for analysis of novel cardiovascular parameters (such as inflammatory cytokines
and pro-thrombotic factors). However lean subjects will not have an OGTT done and will not
be offered drug intervention. The endothelial function testing in the lean controls will
serve as control data for the vascular function testing in the obese children. The CGMS
data of the lean controls will allow us to better interpret changes in the post-meal
excursions seen in obese children after exenatide intervention. Similar to obese subjects,
lean subjects will be instructed to take a standardized snack in the afternoon prior to
returning for CGMS removal. The snack will be provided for them to take home at the end of
their CGMS placement visit and will include two pop-tarts and an orange soda. Lean control
subjects will wear the CGMS for three days. At the end of the monitoring period the subject
will return for their CGMS removal visit.

Obese subjects:

Major Inclusion Criteria:

- Obesity (BMI > 97%tile for age and sex matched normative data)

- Insulin resistance: fasting insulin> 25 mIU/ml

- Good general health, taking no medication on a chronic basis

- Age 16-25 yrs, late pubertal stage (girls: breast: Tanner stage IV to V, boys:
testicular volume > 15 ml) or age 13-15 yrs (with a family history of type 2
diabetes, whom have completed or reached tanner stage III and have impaired oral
glucose tolerance with a 2-hour glucose of 180-199 mg/dl)

- Girls who are sexually active must use adequate birth control methods (such as
barrier method or oral contraception) and must have a negative pregnancy test

- Normal liver function tests

Major Exclusion Criteria:

- Hx of gallstones

- Elevated triglycerides >400 mg/dl

- Hx of alcohol use/ binge drinking

- Raynaud's syndrome

- Pregnancy or breastfeeding mothers

- Cigarette smokers

- Anemia (Hct < 35)

- Baseline creatinine > 1.0 mg

- Abnormal liver transaminases > 2.0 X the upper limit of normal

- Presence of endocrinopathies except for adequately treated hypothyroidism

- Presence or history of gastrointestinal disorders (inflammatory bowl disease,
irritable bowl disease, hernia, ileus)

- Presence of significant chronic illness of any kind.

- Use of any drugs that might be expected to affect glucose tolerance, insulin
resistance or weight gain, cardiovascular health.

- Psychiatric disorders

- History of substance abuse

Lean Control Subjects (only for cardiovascular studies and CGMS):

Inclusion Criteria:

- Lean (BMI < 85%tile for age and sex matched normative data)

- Fasting insulin <15 mIU/m

- Fasting glucose <100 mg/dll

- Excellent general health, having no acute or chronic health problems and taking no
current medications

- Age 13-25 yrs, in puberty (age matched with obese subjects)

- Girls who are sexually active must use adequate birth control methods (such as
barrier method or oral contraception) and must have a negative pregnancy test

Exclusion Criteria:

- Raynaud's syndrome

- Pregnancy or breastfeeding mothers

- Cigarette smokers

- Psychiatric disorders

- History of substance abuse

- First degree relative with either T1DM or T2DM

- Presence of acanthosis nigricans