Inclusion Criteria:
1. Male and female subjects age 18 to 70 years of age.
2. Subjects who are able to provide written informed consent and to comply with study procedures.
3. Clinical history compatible with T1D (onset \< 40 yrs old and insulin dependent for \> 5 yrs at enrollment.
4. Absent stimulated c-peptide (\< 0.3 ng/mL) in response to a (Boost® 6 mL/kg BW to a maximum of 360 mL; another equivalent product), measured at 60 and 90 min after start of consumption.
5. Subjects who are \> 3 months post-renal transplant who are taking appropriate calcineurin inhibitor (CNI) based maintenance immunosuppression (\[tacrolimus alone or in conjunction with sirolimus, mycophenolate mofetil, myfortic, or azathioprine; or cyclosporine in conjunction with sirolimus, mycophenolate mofetil, or myfortic ± Prednisone ≤ 10 mg/day).
6. Stable renal function as defined by a creatinine of no more than one third greater than the average creatinine determination performed in the 3 previous months prior to islet transplant, until rejection, obstruction or infection is ruled out.
7. Reduced awareness of hypoglycemia manifested a Clarke score \>4 and at least 1 episode of severe hypoglycemia in the past 12 months prior to study enrollment. This criterion requires that there has been involvement in intensive diabetes management under the direction of an endocrinologist, diabetologist, or diabetes specialist prior to study enrollment. Intensive diabetes management is defined as self-monitoring of glucose values no less than 3 times each day averaged over each week and by the administration of three or more insulin injections each day or insulin pump therapy. Severe hypoglycemia is defined as an event with one of the following symptoms: memory loss; confusion; uncontrollable behavior; irrational behavior; unusual difficulty in awakening; suspected seizure; seizure; loss of consciousness; or visual symptoms, and which was associated with either a BG level \< 54 mg/dl \[3.0 mmol/L\] or prompt recovery after oral carbohydrate, IV glucose, or glucagon administration.
Exclusion Criteria:
1. Weight more than 100 kg or body mass index (BMI) \> 30 kg/m2.
2. Insulin requirement of \>1.0 IU/kg/day or \<15 U/day.
3. Other (non-kidney) organ transplants except prior failed pancreatic graft where graft failure is attributed to thrombosis within the first 4 weeks or to other technical reasons that require graft pancreatectomy; with the graft pancreatectomy occurring more than 6 months prior to enrollment.
4. Untreated or unstable proliferative diabetic retinopathy.
5. Blood Pressure: SBP \> 160 mmHg or DBP \>100 mmHg despite treatment with antihypertensive agents.
6. Calculated GFR of ≤ 40 mL/min/1.73 m2 using the subject's measured serum creatinine and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. (59)
7. Proteinuria (albumin/creatinine ratio or ACr \> 300mg/g) of new onset since kidney transplantation.
8. Calculated panel-reactive anti-HLA antibodies \> 50%. Subjects with calculated panel reactive anti-HLA antibodies ≤ 50% will be excluded if any of the following are detected:
* Positive cross-match
* Islet donor-directed anti-HLA antibodies detected by Luminex® Single Antigen/specificity bead assay including weakly reactive antibodies that would not be detected by a flow cross-match
9. For female subjects: Positive pregnancy test, presently breast-feeding, or unwillingness to use effective contraceptive measures for the duration of the study and 4 months after discontinuation. For male subjects: intent to procreate during the duration of the study or within 4 months after discontinuation or unwillingness to use effective measures of contraception. Oral contraceptives, Norplant®, Depo-Provera®, and barrier devices with spermicide are acceptable contraceptive methods; condoms used alone are not acceptable.
10. Active infection including hepatitis B, hepatitis C, HIV, or TB. A positive skin test (PPD) in itself is not an exclusion, and will be followed up by a QuantiFERON® gold assay.
11. Negative screen for EBV IgG.
12. Invasive Aspergillus, Histoplasmosis, and Coccidioidomycosis infection within 1 year prior to study entry.
13. Any history of malignancy except for completely resected squamous or basal cell carcinoma of the skin.
14. Known active alcohol or substance abuse.
15. Severe co-existing cardiac disease, characterized by any one of these conditions:
* Recent MI (within past 6 months),
* Evidence of ischemia on functional cardiac exam within the last year,
* Left ventricular ejection fraction \< 30%,
* Valvular disease requiring replacement with prosthetic valve.
16. Persistent elevation of liver function tests at time of study entry. Persistent SGOT (AST), SGPT (ALT), alkaline phosphatase values \> 1.5, or total bilirubin \> 1 times normal upper limits will exclude a subject.
17. Active infections (except mild skin and nail fungal infections).
18. Acute or chronic pancreatitis.
19. Active peptic ulcer disease or gastritis, symptomatic gallstones, or portal hypertension.
20. Treatment with any anti-diabetic medication other than insulin within 4 weeks of enrollment.
21. Use of any investigational agents within 4 weeks of enrollment.
22. Administration of live attenuated vaccine(s) within 2 months of enrollment.
23. Any medical condition that, in the opinion of the investigator, will interfere with safe study completion.
24. Positive screen for BK viremia at time of screening.
25. Untreated hyperlipidemia - TC \> 200 mg/dL, TGC \> 200 mg/dL, LDL \> 130 mg/dL
26. Use of glucocorticoids for non-transplant-related indications.
