Effect of Chronic Exenatide Therapy on Beta Cell Function and Insulin Sensitivity in T2DM

In this study, the researchers hope to learn about SGLT2 inhibition on EGP (endogenous glucose production) and plasma glucose concentration in diabetic subjects. Researchers will examine diabetes and the role of increased plasma glucagon, decline in plasma insulin, and fall in plasma glucose concentration.

This study will examine whether the coadministration of exenatide plus dapagliflozin will prevent the increase in EGP and result in an additive or even synergistic decrease in plasma glucose concentration compared to each agent alone.

Eligibility Criteria:
Inclusion Criteria:

1. BMI = 25-35 kg/m\^2
2. must be drug naïve and/or on a stable dose (more than 3 months) of metformin and/or sulfonylurea
3. HbA1c \>7.0% and \<10.0%
4. Other than diabetes, subjects must be in good general health as determined by physical exam, medical history, blood chemistries, CBC, TSH, T4, EKG and urinanalysis.
5. Only subjects whose body weight has been stable (± 3 lbs) over the preceding three months and who do not participate in an excessively heavy exercise program will be included.

Exclusion Criteria:

1. Presence of significant systemic disease, heart problems including congestive heart failure, unstable angina or acute myocardial infarction, current infectious liver disease, acute stroke or transient ischemic attacks, history of pancreatitis, urosepsis and pyelonephritis, genital mycotic infections, or Type 1 diabetes mellitus
2. Any hepatic diseases in the past (infectious liver disease, viral hepatitis, toxic hepatic damage, jaundice of unknown etiology) or severe hepatic insufficiency and/or significant abnormal liver function tests defined as aspartate aminotransferase (AST) \>3x upper limit of normal (ULN) and/or alanine aminotransferase (ALT) \>3x ULN
3. Renal impairment (e.g., serum creatinine levels ≥1.4 mg/dL for women or ≥1.5 mg/dl for men, or eGFR \<60 mL/min/1.73 m2) or history of unstable or rapidly progressing renal disease or end stage renal disease.
4. Uncontrolled thyroid disease , Cushing's syndrome, congenital adrenal hyperplasia or hyperprolactinemia
5. Significantly elevated triglyceride levels (fasting triglyceride \> 400 mg/dl), uncontrolled increased LDL-C
6. Untreated or poorly controlled hypertension (sitting blood pressure \> 160/95 mm Hg)
7. Use of anti-obesity drugs or weight loss medications (prescription or OTC) and medications known to exacerbate glucose tolerance (such as isotretinoin, , GnRH agonists, glucocorticoids, anabolic steroids, C-19 progestins) stopped for at least 8 weeks. Use of anti-androgens that act peripherally to reduce hirsutism such as 5-alpha reductase inhibitors (finesteride, spironolactone, flutamide) stopped for at least 4 weeks
8. Prior history of a malignant disease requiring chemotherapy, prior history of bladder cancer regardless treatment
9. Patients at risk for volume depletion due to co-existing conditions or concomitant medications, such as loop diuretics should have careful monitoring of their volume status
10. History of unexplained microscopic or gross hematuria, or microscopic hematuria at visit 1, confirmed by a follow-up sample at next scheduled visit.
11. Presence of hypersensitivity to dapagliflozin or other SGLT2 inhibitors (e.g. anaphylaxis, angioedema, exfoliative skin conditions
12. Known hypersensitivity or contraindications to use GLP1 receptor agonists (exenatide, liraglutide)
13. Use of , thiazolidinediones, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT2 inhibitors stopped for at least 8 weeks.
14. Eating disorders (anorexia, bulimia) or gastrointestinal disorders
15. Suspected pregnancy (documented negative serum β-hCG test), desiring pregnancy in next 6 months, breastfeeding, or known pregnancy in last 2 months
16. Active history of illicit substance abuse or significant intake of alcohol
17. Having a history of bariatric surgery
18. Patient not willing to use two barrier method contraception during study period (unless sterilized or have an IUD)
19. Debilitating uncontrolled psychiatric disorder such as psychosis or neurological condition that might confound outcome variables
20. Inability or refusal to comply with protocol
21. Current participation or participation in an experimental drug study in previous three months