The primary purpose of this trial is to assess the safety and tolerability of ISIS-SGLT2Rx when given at increasing single doses and to assess the safety and tolerability of the same doses when given multiple times.

To evaluate the safety and tolerability of a single subcutaneous injection of ISIS-SGLT2Rx administered at four increasing dose levels (50, 100, 200, 400 mg) and to evaluate the safety and tolerability of multiple doses of ISIS 388626 administered subcutaneously of either 6 or 13 weeks.

Inclusion Criteria:

• Age 18 to 65 years
• Male or female gender although females must be post-menopausal or surgically sterile (hysterectomy, oophorectomy or tubal ligation)
• Give written informed consent to participate in the study and availability for all study requirements
• Fasting plasma glucose </= the upper limit of the laboratory's reference range (ULN)
• HbA1c </= ULN
• BMI < 30 kg/m²
• Agree to maintain steady hydration throughout study participation and agree not to fluid restrict

Exclusion Criteria:

• Pregnant women, nursing mothers or women of childbearing potential
• Clinically significant abnormalities in medical history or physical examination
• Clinically significant abnormalities in laboratory examination (including ALT > ULN, AST > ULN, bilirubin > ULN, creatinine > ULN, urine protein positive by urine dipstick, platelets < lower limit of normal and any other clinically significant laboratory findings)
• Estimated GFR < 60 mL/min per 1.73m²
• History of clinically significant abnormalities in coagulation parameters
• Positive test result for HIV, hepatitis B virus, and/or hepatitis C virus
• Active infection requiring antiviral or antimicrobial therapy
• Subjects on chronic or acute prescription medication may be permitted after discussion with the Isis Medical Monitor
• Malignancy (with the exception of basal or squamous cell carcinoma of the skin if adequately treated and no recurrence for > 1 year)
• Any other concurrent condition which, in the opinion of the Investigator, would preclude participation in this study or interfere with compliance
• Past and present history of alcohol or drug abuse (defined as > 3 units daily)
• Undergoing or have undergone treatment with another investigational drug, biologic agent or device within 90 days prior to Screening
• Blood donation within three months of Screening