The Effects of Exenatide on Post-Meal Sugar Peaks and Vascular Health in Obese/Pre-Diabetic Young Adults
The Effects of Exenatide on Post-Meal Sugar Peaks and Vascular Health in Obese/Pre-Diabetic Young Adults
The primary aim of this study is to evaluate the effect of exenatide on daily glycemic
 excursions obtained by continuous glucose monitoring system (CGMS). The CGMS summary
 parameters that we are most interested in include:

 -  The percent of glucose values above 140 mg/dl and/or AUC of glucose values above 140
 mg/dl

 -  AUC of glucose values over 100 mg/dl during three days

 -  Maximal meal-related glucose excursions

 -  Three-day mean glucose (including low readings - below 100 mg/dl)

 Secondary Study Endpoints:

 Secondary endpoints will include:

 -  glucose tolerance status as assessed by OGTT

 -  Vascular function scores as assessed by PAT, FMD and step test.

 -  Biochemical markers of vascular health, including inflammatory markers, markers of
 oxidative stress and microalbuminuria.

 -  Changes in BMI
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