Islet Cell Transplantation in Patients With Type I Diabetes With Previous Kidney Transplantation

• To reverse hyperglycemia and insulin dependency by islet cell transplantation, in patients with Type 1 Diabetes Mellitus who have a stable kidney allograft;
• To eliminate the incidence of hypoglycemic coma and unawareness by islet cell transplantation;
• To assess long-term function of successful islet cell transplants;
• To determine whether the natural history of the microvascular, macrovascular and neuropathic complications of Diabetes Mellitus are altered following successful transplantation of islet cells.
• To assess the effect of exenatide to improve islet graft function and survival in subjects that demonstrate partial graft loss and have returned to using exogenous insulin.
• To assess the ability of exenatide to improve islet survival at time of islet transplantation

Inclusion criteria

• Patients between 18 and 60 years of age.
• Patients with type 1 diabetes mellitus.
• Patients with a renal transplant that is more than 6 months old.
• Patients with stable renal graft function for the preceding 6 months, i.e. no episodes of rejection and changes in serum creatinine no more than 0.5 mg/dl from baseline.
• Patients who are taking tacrolimus, sirolimus +/- steroids for maintenance immunosuppression for at least 6 months and are tolerating levels satisfactory for islet transplantation without severe complications.
• Patients with a body mass index (BMI) of less than or equal to 26.

Exclusion criteria

• Stimulated or basal C-peptide > 0.3 ng/ml.
• Patients with unstable renal function - serum creatinine greater than 0.5 mg/dl above baseline.
• Patients with proteinuria (albuminuria > 300 mg in 24 hours +/- protein) of new onset since kidney transplantation. If proteinuria or albuminuria is thought to originate from the native kidney(s) this will not be an exclusion criterion.
• Patients with corrected creatinine clearance of less than 40.
• Patients weighing more than 80 kg.
• Patients with a body mass index (BMI) of greater than 26.
• Insulin requirement > 1.0 U/kg/d.
• Anemia (hemoglobin: males < 11.0 g/dl; females < 10.0 g/dl).
• Abnormal liver function tests (consistently > 1.5 x normal range).
• Unstable diabetic retinopathy.
• Evidence of acute or chronic active Epstein-Barr virus (EBV) infection (IgM ≥ IgG). Patients will be eligible if serological testing becomes consistent with previous exposure (i.e. IgG > IgM).
• Patients with history of malignancy or current malignancy other than non-melanomatous skin cancer, or finding of any lesions or symptoms during screening that are suspicious for malignancy, until properly investigated and ruled out.
• Patients with elevation of prostate-specific antigen > 4 unless malignancy has been excluded.
• Patients with unstable cardiovascular status.
• Patients with active infections until adequately treated, unless treatment is not judged as necessary by the investigators (including, but not limited to, mild skin and nail fungal infections).
• Patients with serological evidence of infection with HIV, human t cell lymphotropic virus 1 (HTLV 1), HTLV 2, or hepatitis B (patients with serology consistent with previous vaccination and a history of vaccination are acceptable).
• Patients with history and/or serological evidence of hepatitis C (those patients with hepatitis C, already transplanted in this protocol will continue in this trial).
• Positive tuberculin test (unless proof of adequate treatment for latent tuberculosis can be provided).
• Patients with active peptic ulcer disease, gallstones, hepatic hemangioma, or portal hypertension.
• Patients who are pregnant or breastfeeding, or who intend to procreate.
• Patients who are sexually active females who are not:

• post-menopausal,
• surgically sterile, or
• using an acceptable method of contraception (oral contraceptives, Norplant, Depo-Provera, and barrier devices combined with spermicidal gel are acceptable; condoms used alone are not acceptable).
• Active alcohol or substance abuse; smoking in the last 6 months.
• Patients with evidence of sensitization, i.e. panel reactive antibody (PRA) testing greater than 20%.
• Lack of updated immunizations per current Centers for Disease Control (CDC) guidelines, as well as immunization against hepatitis B, pneumococcus, and influenza (during season), unless medically contraindicated.
• Patients with psychogenic factors, which are judged at psychological evaluation, which make it unsafe to undergo islet transplantation, or which preclude therapeutic compliance.
• Patients with any condition or any circumstance that would make it unsafe to undergo an islet transplant.