The purpose of this study is to evaluate the safety, tolerability, and efficacy of ISIS-PTP1BRx + oral antidiabetic drug/s (metformin and/or sulfonylurea) versus placebo + oral antidiabetic drug/s.

Inclusion Criteria:

• Body mass index (BMI) >/= 27 kg/m2
• HbA1c between 7.5% and 10.5% (inclusive)
• C-Peptide (fasting) greater than or equal to 500 pmol/L
• On stable dose of metformin alone or in combination with a stable dose of sulfonylurea for >/= 3 months prior to screening, and remain on stable dose throughout the study
• Agree to conduct home-based (fasted) blood glucose testing as directed

Exclusion Criteria:

• Clinically significant abnormalities in medical history or physical exam
• Serum creatinine > ULN at Screening
• Clinical signs or symptoms of liver disease, acute or chronic hepatitis, or ALT or AST > 1.5x ULN at Screening
• History of renal transplantation or renal dialysis
• GFR < 60 mL/min at Screening
• History of diabetic ketoacidosis
• History of greater than 3 episodes of severe hypoglycemia within 6 months of screening
• Allergy to sulfur containing drugs
• Treatment with other drugs or medications not allowed per study specific Disallowed Concomitant Medicines
• Any other significant illness or condition that may interfere with the patient participating or completing the study
• Inability or unwillingness to comply with protocol or study procedures