Impact of Sitagliptin on Cardiovascular Exercise Performance in Type 2 Diabetes

Subjects will come for a total of nine testing visits during which evaluations will take
place. Visits are structured as follows:

1. After subjects review the study and give consent for study participation, a history and
physical exam will be performed. Ankle brachial index, autonomic nervous system function
tests, the Low-level Physical Activity Recall questionnaire and vital signs will be
performed.

2. Blood drawn for measurement of hemoglobin A1C, fasting glucose, fasting insulin, free
fatty acids and microalbuminuria, c-reactive protein, interleukin 6, adiponectin, and
creatinine and glycerol. Additional screening labs include complete blood count (CBC),
follicle-stimulating hormone, urine protein and a lipid panel to assess whether women
are pre- or post-menopausal (FSH), and overall health (CBC, lipids and urine protein). A
dietary survey will be administered for food preferences for the three day study diet
administered prior to visits 3-5 and 7-9. Dual-energy xray absorptiometry (DEXA) and
body composition tests will be done to ensure that groups are weight similar (using
fat-free mass). A pulmonary function test, resting electrocardiogram (EKG) and
familiarization bicycle test will be performed.

3. Subjects will receive a three day study diet prior to visit 3. A resting and exercise
EKG will be performed on the day of the visit. A graded exercise test will be done to
determine the VO2peak. Patients will have measures of cardiac function and endothelial
function on visit 3 by plethysmography and cardiac echo. Vital signs will be taken at
rest.

4. Subjects will receive a three day study diet prior to visit 4. Calf muscle magnetic
resonance spectroscopy (MRS) will be performed on a 3.0 T whole-body MRI scanner.

5. During visit 5, arterial stiffness/endothelial function will be non-invasively measured
by the Sphygmocor system. Subjects will also have three constant-load tests to measure
VO2 kinetics where oxygen saturation (StO2) will be measured during exercise. A resting
and exercise EKG and vital signs will be performed during the visit. Subjects will be
randomized to taking sitagliptin plus placebo or glimepiride plus placebo and all must
be taking metformin (1-2 grams /d) for 3 months. Sitagliptin and its placebo will be
administered 100 mg/d. Glimepiride and its placebo will be administered 2 mg/day. During
the treatment phase subjects will be given a log to keep track of their blood glucose
each day.

6. Visit 6 will consist of a physical exam with a clinician as well as a blood draw and
check of vital signs during sitagliptin or glimepiride treatment.

7. After 3 months of sitagliptin or glimepiride administration, Visit 3 will be repeated.
Additional testing to be performed during visit 7 will include a physical exam performed
by a study physician, blood work for covariate lab tests listed in Visit 2 and the
Low-level Physical Activity Recall(LoPAR) questionnaire.

8. During visit 8, visit 4 procedures will be repeated.

9. During visit 9, the testing performed during visit 5 will be repeated.

Inclusion Criteria:

1. Female subjects may be pre, peri or post-menopausal.

2. People who do not participate in a regular exercise program (> one bout of exercise
per week).

3. Presence of type 2 diabetes will be documented by chart review that will confirm the
diagnosis as well as the presence of treatment for diabetes.

4. Persons with type 2 diabetes will be accepted for study only if they have total
glycosylated hemoglobin levels (HbA1C) between 7 and 9.5% (adequate control) on
therapy.

5. Persons who are taking metformin 500-2000 mg/day only to control their T2D, but are
not taking any other diabetes medication in addition to or instead of metformin.

6. Persons not taking medication to control diabetes.

Exclusion Criteria:

1. Females of childbearing potential who are pregnant, planning to become pregnant or
breastfeeding.

2. Persons will be excluded if they have evidence of ischemic heart disease by history or
abnormal resting or exercise electrocardiogram (EKG) (> 1 mm ST segment depression),
regional wall motion abnormalities, left ventricular systolic dysfunction or
significant valvular disease.

3. Persons with angina or any other cardiac or pulmonary symptoms potentially limiting
exercise performance.

4. Presence of systolic blood pressure >190 at rest or >250 with exercise or diastolic
pressure >95 at rest or >115 with exercise.

5. Subjects who have peripheral arterial disease.

6. Subjects with proteinuria (urine protein >200 mg/dl) or a creatinine > 2 mg/dl,
suggestive of renal disease.

7. Persons with liver function impairment defined as elevated liver function tests three
times the upper limit.

8. Persons with a history of pancreatitis.

9. Subjects more than 140% of ideal body weight.

10. Patients on insulin therapy will not be included.

11. Current smokers will not be accepted for study since smoking can impair cardiovascular
exercise performance but people who have quit smoking for at least 1year will be
accepted for study.

12. Persons with autonomic dysfunction (>20 mm fall in upright blood pressure without a
change in heart rate) will be excluded.

13. Diabetic persons with clinically evident distal symmetrical neuropathy will be
excluded from further study, because of possible effects on exercise performance, by
evaluation of symptoms (numbness, paresthesia) and signs (elicited by vibration,
pinprick, light touch, ankle jerks).

14. Persons with diabetic ketoacidosis.

15. Persons with a serious hypersensitivity to sitagliptin, sulfonylureas or sulfonamides.

16. Inability to walk or ride a bike unassisted for a continuous 5 minutes.

17. Subjects will be excluded if they have any implanted metal in their body.

18. Subjects currently being treated with Digoxin.