In this research study, Investigators will be comparing the effects of a medication Saxagliptin versus placebo (a similar looking pill that contains no medication) on inflammation in the body.

Research Hypothesis DPP-4 inhibition by saxagliptin (ONGLYZA™) reduces adipose tissue inflammation in obese individuals and this is characterized by decreases in a) reactive oxygen species (ROS) production, b) toll-like receptors (TLR) and NF-kappa B pathway activation, c) expression of pro-inflammatory genes, d) macrophage infiltration, and e) secretion of pro-inflammatory factors.

This is a randomized, prospective, double-blind study. Randomization to Saxagliptin and placebo will be in a 2:1 fashion. Treatment duration will be approximately 6 weeks.

Inclusion Criteria:

1. Signed Written Informed Consent

   1. Before any study procedures are performed, subjects will have the details of the study described to them, and they will be given a written informed consent document to read. Then, if subjects consent to participate in the study, they will indicate that consent by signing and dating the informed consent document in the presence of study personnel.
   2. Subjects must be able to communicate meaningfully with the investigator and legally competent to provide informed written consent.

2. Target Population

   1. Body mass index 27.5-37.5 kg/m2
   2. Stable body weight (not varying >10% during the last 6 months)

3. Age and Reproductive Status

   1. Men and women, ages 21 to 70 years.

   2. Women must be sterilized by hysterectomy or postmenopausal or on acceptable birth control if of childbearing potential.

   3. Women of childbearing potential (WOCBP) include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal. Post menopause is defined as:

      • Amenorrhea ≥12 consecutive months without another cause and a documented serum follicle stimulating hormone (FSH) level >35 mIU/mL, or
      • Women with irregular menstrual periods and a documented serum FSH level >35 mIU/mL, or NOTE: FSH level testing is not required for women ≥62 years old with amenorrhea of ≥1 year
      • Women on hormone replacement therapy (HRT) Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (e.g., vasectomy) should be considered to be of childbearing potential.

Exclusion Criteria:

1. Sex and Reproductive Status

   1. WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period
   2. Women who are pregnant or breastfeeding

2. Target Disease Exceptions

   1. Gastrointestinal disease (including gastrectomy, chronic pancreatitis, bariatric surgery and gastroparesis)
   2. Hepatic disease (ALT, AST >2.5 times the upper limit of normal, high sensitivity CRP ≥1 mg/L)
   3. Kidney disease (serum creatinine >1.6 mg/dl, Creatinine Clearance 50 mL/min)
   4. Hypertension (blood pressure > 150/95 mmHg) at Screening for the mean of three consecutive readings performed in a sitting position after a 5-minute resting period. If treatment for hypertension has recently been initiated, subjects must be clinically stable for 4 weeks prior to Screening
   5. Cardiac disease (myocardial infarction within past year, clinically significant arrhythmia, unstable angina, congestive heart failure, or coronary artery bypass surgery within 1 year or expected to require coronary bypass surgery within 12 months of study entry).

3. Medical History and Concurrent Diseases

   1. Type 1 diabetes mellitus
   2. Type 2 diabetes mellitus
   3. History of diabetic ketoacidosis or hyperosmolar nonketotic coma
   4. Malignancy other than basal cell or squamous cell skin cancer
   5. Significant clinical allergic rhinitis or asthma, regularly requiring inhaled corticosteroids and/or antihistamines

4. Additional Laboratory Test Findings

   1. Hemoglobin <12 g/dl in men, <11 g/dl in women
   2. Abnormal prothrombin or partial thromboplastin time
   3. Clinically abnormal thyroid stimulating hormone (TSH)
   4. 2 hour glucose > 170mg/dl in standard oral glucose tolerance test (OGTT)

5. Allergies and Adverse Drug Reactions

   a. Subjects with a history of a serious hypersensitivity reaction to saxagliptin, such as anaphylaxis, angioedema,or exfoliative skin conditions.

6. Prohibited Treatments and/or Therapies

   1. Treatment with strong systemic cytochrome P450 3A4/5 (CYP 3A4/5) inhibitors
   2. Treatment with any of the following medications during screening or their expected use during the study: recent systemic glucocorticoids (for more than 2 weeks), any anti-hyperglycemic agents, antineoplastic agents, transplant medications, drugs for weight loss, niacin, fibrates, or anti-retroviral medications
   3. Treatment with beta-blockers, antihistamines or inhaled corticosteroids within 3 months prior to screening
   4. Start or change of hormonal replacement therapy within 3 months prior to screening

7. Other Exclusion Criteria

   1. Prisoners, or subjects who are involuntarily incarcerated
   2. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness
   3. Currently abusing alcohol or drugs, or have a history of alcohol or drug abuse that in the investigator's opinion could cause the subject to be non-compliant; or have a general history of non-compliance with medications
   4. Any acute febrile illness within 2 weeks of screening with a temperature 100°F

Subject to VA regulation.