A Study of Single and Multiple Doses of Oral Insulin or Placebo in Subjects With Type 2 Diabetes Mellitus

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.
• A subject with a history of malignancy >5 years prior to Screening should have no evidence of residual or recurrent disease.
• A subject with a history of melanoma, leukemia, lymphoma, or renal carcinoma is excluded.
• Laboratory abnormalities at Screening including:
• C-peptide 1.5X (1.5 times) the upper limit of normal
• Elevated liver enzymes (alanine transaminase (ALT), alanine aminotransferase (AST), alkaline phosphatase) >2X the upper limit of normal.
• Very high triglyceride levels (>600 mg/dL); a single repeat test is allowable.
• 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 medica