Pre-diabetes in Subject With Impaired Fasting Glucose (IFG) and Impaired Glucose Tolerance (IGT)

SPECIFIC AIMS:

1. To examine the effect of the following pharmacologic interventions on beta cell
function, insulin sensitivity, and glucose tolerance status in individuals with isolated
impaired glucose tolerance (IGT): (i) treatment with the renal Sodium-glucose
co-transporter 2 (SGLT2) inhibitor inhibitor, dapagliflozin; (ii) treatment with the
inhibitors of dipeptidyl peptidase 4, also DPP4, saxagliptin ; (iii) treatment with the
thiazolidinedione, pioglitazone; (iv) treatment with the biguanide, metformin.

2. To examine the effect of the following pharmacologic interventions on beta cell
function, insulin sensitivity, and glucose tolerance status in individuals with isolated
impaired fasting glucose (IFG): (i) treatment with the renal SGLT2 inhibitor,
dapagliflozin; (ii) treatment with the DPP4 inhibitor, saxagliptin; (iii) treatment with
the thiazolidinedione, pioglitazone; (iv) treatment with the biguanide, metformin.

3. To examine the effect of the following pharmacologic interventions on beta cell
function, insulin sensitivity, and glucose tolerance status in individuals with combined
impaired glucose tolerance (IGT) plus impaired fasting glucose (IFG): i) treatment with
the renal SGLT2 inhibitor, dapagliflozin; (ii) treatment with the DPP4 inhibitor,
saxagliptin; (iii) treatment with the thiazolidinedione, pioglitazone; (iv) treatment
with the biguanide, metformin.

Inclusion Criteria:

- NGT subjects will serve as controls and will be matched in age, gender, ethnicity, and
BMI to IGT and IFG subjects

1. Male or female subjects between the ages of 18 and 65 years of age, inclusive, at
Screening.

2. FPG < 100 mg/dl and 2-h PG < 140 mg/dl

3. BMI = 24-40 kg/m2;

4. Stable body weight (±4lbs) over the preceding 3 months

5. Subjects with no evidence of major organ system disease as determined by physical
exam, history, and screening laboratory data

6. Females of childbearing potential with a negative pregnancy test at Screening and
Treatment visits, using one of the following forms of contraception for the
duration of participation in the study (i.e., until Follow-up 7-14 days post last
dose):

- Oral contraceptive

- Injectable progesterone

- Subdermal implant

- Spermicidal foam/gel/film/cream/suppository

- Diaphragm with spermicide

- Copper or hormonal containing IUD

- Sterile male partner vasectomized > 6 month pre-dosing.

7. Evidence of a personally signed and dated informed consent document indicating
that the subject has been informed of all pertinent aspects of the study.

8. Subjects must be willing and able to comply with scheduled visits, treatment,
laboratory tests and study procedures.

Exclusion Criteria:

1. Recent (i.e., within three (3) months prior to Screening) evidence or medical history
of unstable concurrent disease such as: documented evidence or history of clinically
significant hematological, endocrine, pulmonary, gastrointestinal, cardiovascular,
hepatic, psychiatric, immunological, or clinically significant neurological disease.

2. Subjects with a family history of diabetes in a first degree relative

3. BMI of less than 24 or greater than 40 kg/m2

4. Unstable body weight (change of greater than ±4lbs over the preceding 3 months

5. Subjects participating in an excessively heavy exercise program

6. Subject with a feeding/sleeping schedule different from a daytime feeding/night time
sleeping schedule

7. Subjects taking medications known to alter glucose metabolism (with the exception of
metformin and/or pioglitazone) or which effect brain neurosynaptic function are
excluded.

8. Subjects with evidence of major organ system disease as determined by physical exam,
history, and screening laboratory data

9. Pregnant subjects or subjects unwilling to use birth control during their study
enrollment

10. Blood donation of approximately 1 pint (500 mL) within 8 weeks prior to Screening.

11. Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or
investigational product administration or may interfere with the interpretation of
study results and, in the judgment of the investigator, would make the subject
inappropriate for entry into this study

12. Subjects with hematuria will be excluded.

13. Subjects with evidence or prior history of heart failure will be excluded

14. Subjects with family history of pancreatic, bladder, and breast cancer will be
excluded.

15. Subjects with history of pancreatitis will be excluded.

16. Subjects with eGFR < 60 ±5 ml/min.1.73m2 will be excluded.

17. Subjects with elevated serum creatinine (>1.5 mg/dl males/1.4 mg/dl females) will be
excluded.

18. Subjects with a history of orthostatic hypotension (>15/10 mmHg) will be excluded.

19. Subjects with liver enzymes (ALT, AST) >3-fold above upper normal limit will be
excluded.

20. Subjects with a history of hypersensitivity to pioglitazone, dapagliflozin, or
Saxagliptin will be excluded.