This is a four-way crossover (non-parallel) study with each subject receiving three of the four arms. The study will enroll approximately 30 adult subjects with T2DM from age 20 to 75 inclusive.

Following a 7-10 day Screening period, eligible subjects will enter a 3-day single-blind placebo run-in. On Day 4, each subject will be randomized to a treatment sequence that will include three treatment assignments for each of three treatment Periods according to the randomization scheme.

Following the screening, eligible subjects entered a 3-day, single-blind placebo run-in. On Day 4, each subject was randomized to a treatment sequence that included three treatment assignments for each of three treatment Periods according to the randomization scheme.

Pre-assignment Details The number of participants receiving each Intervention, in each Period, is reported.

Subjects received the randomized treatment from Day 4 through Day 8. There was a 24-hour single-blind placebo washout on Day 9. Each subject received placebo for one of the three treatment periods. Each subject also received 1 of the 3 active doses randomly in each of the two other treatment periods respectively. The dosing order is random.

Inclusion Criteria:

• Male or female subjects, age 20 to 75 years, inclusive with type 2 diabetes mellitus.

• At Visit 2/Period 1/Day 1, subjects will have been treated for their diabetes by metformin (≥1000 mg/day; any type and regimen), metformin and a DPP-4 inhibitor ( Dipeptidyl-Peptidase)-4), metformin and an SGLT-2 (Sodium-glucose co-transporter 2) inhibitor, metformin and TZD (Thiazolidinediones), or metformin and sulfonylurea. Subjects will have been on a stable regimen of metformin (defined as the same metformin dose and type) and other treatments for at least 8 weeks prior to Visit 2/Period 1/Day 1.

• Body Mass Index (BMI) between 25 and 40 kg/m2, inclusive, at Screening.

• Hemoglobin A1c (HbA1c) between ≥7.5 and ≤10.5% at Screening.

• Fasting serum glucose greater than or equal to 126 mg/dL at Screening.

• Females of childbearing potential must have a negative serum pregnancy test result at Screening and a negative urine pregnancy test at Visit 2/Day 1 for all study Periods.

• Females who are not of childbearing potential are defined as:

  i. Postmenopausal (defined as at least 12 months with no menses in women ≥45 years of age) ii. Has had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy, or bilateral tubal ligation/occlusion at least 6 weeks prior to screening; OR iii. Has a congenital or acquired condition that prevents childbearing.

• Females of childbearing potential agree to avoid becoming pregnant while receiving study treatment and for 14 days after the last dose of study treatment by complying with one of the following:

  i. practice abstinence† from heterosexual activity OR ii. Use (or have her partner use) acceptable contraception during heterosexual activity.

Exclusion Criteria:

• Usage of anti-diabetic agents other than metformin, sulfonylurea, SGLT-2 inhibitors, TZD, or DPP-4 inhibitors within 6 weeks prior to Visit 2/Period 1/Day 1.

• Presence of any clinically significant endocrine disease according to the Investigator (euthyroid subjects on replacement therapy will be included if the dosage of thyroxine is stable for at least six weeks prior to Screening).

• Clinical diagnosis of type 1 diabetes.

• Fasting serum glucose >300 mg/dL at Screening; a single repeat test is allowable.

• Evidence of unawareness of hypoglycemia, a documented plasma glucose ≤50 mg/dL in the absence of symptoms of hypoglycemia at Screening.

• Presence of any clinically significant condition (in the opinion of the Investigator) that might interfere with the evaluation of study medication, such as significant renal, hepatic, gastrointestinal (GI), cardiovascular (CV), immune disease, blood dyscrasias or any disorders causing hemolysis or unstable red blood cells, or clinically important hematological disorders (i.e. aplastic anemia, myeloproliferative or myelodysplastic syndromes, thrombocytopenia) at Screening.

• Presence or history of cancer within the past 5 years of Screening, with the exception of adequately-treated localized basal cell skin cancer or in situ uterine cervical cancer.

  1. A subject with a history of malignancy >5 years prior to Screening should have no evidence of residual or recurrent disease.
  2. A subject with a history of melanoma, leukemia, lymphoma, or renal carcinoma is excluded.

• Laboratory abnormalities at Screening including:

  1. C-peptide < 1.0 ng/mL;
  2. Positive pregnancy test in females of childbearing potential (at Screening and Visit 2/Periods 1-3/Day 1);
  3. Abnormal serum thyrotropin (TSH) levels below the lower limit of normal or >1.5X (1.5 times) the upper limit of normal
  4. Elevated liver enzymes (alanine transaminase (ALT), alanine aminotransferase (AST), alkaline phosphatase) >2X the upper limit of normal.
  5. Very high triglyceride levels (>600 mg/dL); a single repeat test is allowable.
  6. Any relevant abnormality that would interfere with the efficacy or the safety assessments during study treatment administration.

• Positive history of active liver disease (other than non-alcoholic hepatic steatosis), including chronic hepatitis B or C, primary biliary cirrhosis, or active symptomatic gallbladder disease.

• Positive history of HIV.

• Use of the following medications:

  1. History of use of insulin for more than 1 week within 6 months prior to and none within 6 weeks prior to Visit 2/Period 1/Day 1.
  2. History of use of aprotinin at any time prior to Screening (e.g., Trasylol, any type or dose).
  3. Administration of thyroid preparations or thyroxine (except in subjects on stable replacement therapy) within 6 weeks prior to Screening.
  4. Administration of systemic long-acting corticosteroids within two months or prolonged use (more than one week) of other systemic corticosteroids or inhaled corticosteroids (if daily dosage is > 1,000 μg equivalent beclomethasone) within 30 days prior to Screening. Intra-articular and/or topical corticosteroids are not considered systemic.
  5. Use of medications known to modify glucose metabolism or to decrease the ability to recover from hypoglycemia such as oral, parenteral, and inhaled steroids (as discussed above), and immunosuppressive or immunomodulating agents.

• Subject is on a weight loss program and is not in the maintenance phase, or subject has started weight loss medication (e.g., orlistat or liraglutide), within 8 weeks prior to Screening. Subjects who have had bariatric surgery are also excluded.

• Subject is pregnant or breast-feeding.

• Subject has a Screening systolic blood pressure ≥165 mmHg or diastolic blood pressure ≥100 mmHg. Subjects will be allowed to take a BP rescue medication.

• Subject is a user of recreational or illicit drugs or has had a recent history (within 1 year of Screening) of drug or alcohol abuse or dependence. (Note: Alcohol abuse includes heavy alcohol intake as defined by >3 drinks per day or >14 drinks per week, or binge drinking) at Screening.

• Any clinically significant ECG abnormality at Screening or cardiovascular disease. Clinically significant cardiovascular disease will include:

  1. History of stroke, transient ischemic attack, or myocardial infarction within 6 months prior to Screening,
  2. History of or currently have New York Heart Associate Class II-IV heart failure prior to Screening, or

• One or more contraindications to metformin.

• At the Principal Investigator's discretion, any condition or other factor that is deemed unsuitable for subject enrollment into the study.

ITT Population

One Year