• Insulin independence one year following the transplant.@@@ [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  

• To estimate the islet cell survival by evaluating: Arginine Stimulated C-Peptide response, Insulin dose, Incidence of severe hypoglycemia, Monthly monitoring of Hgb A1c. [ Time Frame: Varied depending on variable measured ] [ Designated as safety issue: Yes ]
  

Drug: Isolated human pancreatic islets of Langerhans
N/A

We will test whether pancreatic islets isolated from cadaveric human donor pancreata can be transplanted into the portal vein of patients with type 1 diabetes mellitus (T1DM) in such a way so as to achieve insulin independence for the recipient. The protocol will employ a defined islet isolation procedure, percutaneous islet infusion into the recipient's portal vein via an intra-portal catheter, tight glycemic control during the peri-transplant period, and a novel immunosuppressive protocol that avoids glucocorticoids. Up to 20 patients between the ages of 18 and 65 who have been diagnosed with T1DM for at least five years and who have no detectable endogenous insulin producing capacity will be enrolled. Since the study calls for at least 10,000 islet equivalents (IEQs) per kilogram recipient body weight to be transplanted, and since a typical human pancreas yields approximately 2.0 to 4.0 x 10(5) IEQs, most protocol enrollees will require islets isolated from two different donors. Islets will be transplanted shortly after isolation, and since human donor pancreata are available at unpredictable times, the timing of the islet transplant procedure will also be unpredictable. The study's primary end-point will be insulin independence at one year following the transplantation of at least 10,000 IEQs per kilogram recipient body weight. Secondary endpoints will be evidence of partial islet function as reflected by stimulated c-peptide secretion, a Hgb A1c of 7.0 % or less, and the absence of severe hypoglycemia. Additional secondary endpoints will be to determine: 1) if any immune parameters are predictive of islet loss, 2) if islet transplantation has any effect on renal function and 3) if the protocol influences fasting lipid profiles.

• INCLUSION CRITERIA:

Patients with T1DM for at least 5 years will be eligible for the study provided they exhibit one of the following:

• Hypoglycemia unawareness, as defined by inability to sense hypoglycemia until the blood glucose falls to less than 54 mg/dl or greater than one hypoglycemia reaction in the preceding 20 months and that required outside help and was not explained by a clear precipitant;
• Metabolic instability, as defined by: a) recurrent hypoglycemic or ketoacidotic events requiring more than two hospitalization within the preceding 12 months, b) disruption in quality of life or direct potential danger to the patient or others around them, with more than two hospital admissions or more than four weeks off school or work, or where the individual is no longer able to provide essential care for others; or
• Evidence of early but progressive secondary diabetic complications but which have not progressed to end-stage renal failure
• Failure of intensive insulin management, as judged by an endocrinologist independent of study investigators

EXCLUSION CRITERIA:

• Significant cardiac disease as defined by: a) a history of a myocardial infarction with the past 6 months or b) coronary angiographic evidence of non-correctable arteriopathy, or c) evidence of ischemia on a functional cardiac examination
• Active alcoholism or other substance abuse (including cigarette smoking) within the past 6 months
• Failure to clear a psychological or psychiatric screen (as assessed by psychological or psychiatric consultation)
• A history of non-adherence. If adherence has been questionable, then an adherence agreement must be entered and compliance demonstrated for at least 3 months
• Active infection including hepatitis B or C, HIV positivity, a positive Mantoux test (unless previously immunized with BCG), or any X-ray evidence of pulmonary infection
• History of malignancy except squamous and basal cell skin cancer, unless disease free for at least 5 years, and cleared by an independent oncological consultation
• Obesity (defined by a body mass index of greater than 28) or total body weight greater than 75 kilograms
• C-peptide values greater than or equal to 0.3 pm/ml following a 5.0 gram intravenous arginine infusion
• Inability to provide informed consent
• Age less than 18 or older than age 65
• Creatinine clearance of less than 60 ml/min/m2, or macroalbuminuria of greater than 300 mg/24h
• Baseline Hb of less than 12 g/dl in women, or less than 13 g/dl in men
• WBC count of less than 3,000/mm(3) or a platelet count of less than 100,000/mm(3)
• Baseline LFTs outside of normal range
• Presence of gallstones, liver hemangioma, or evidence of portal hypertension on baseline U/S
• Untreated proliferative retinopathy
• Female patients must not have a positive pregnancy test and must not have the intent for future pregnancy. Any female subject of reproductive age must be able and willing to use an acceptable method of contraception (oral contraceptives, Norplant, Depo-Provera, and barrier devices are acceptable; condoms used alone are not acceptable)
• Female subjects must not be breastfeeding
• Previous transplant, or evidence of known previous or current anti-HLA antibody
• Insulin requirement of greater than 0.7 iU/kg/day
• HbA1C of greater than 12%
• Inability to reach the hospital for transplantation within 6 hrs of notification. (Ability to reach NIH within the allotted time frame will be determined by the PI for out of town patients)
• Untreated hyperlipidemia