Inclusion Criteria:

• Difficult to control Type 1 diabetes mellitus (defined above). Documentation of negative basal and stimulated C-peptide (a basal level of < 0.2 ng/ml before IV administration of 1 mg of glucagon, and a glucagon stimulated C-peptide < 0.8 ng/ml) and diagnosis of diabetes for at least 5 years. When possible, patients will be evaluated with continuous glucose monitoring (GlucoseSensor ®) to determine the frequency and extent of hypo- and hyperglycemic episodes.
• No evidence of chronic renal failure or significant proteinuria (serum creatinine < 1.6 mg/dl, creatinine clearance >80 ml/min, and albumin excretion </= 300 mg/24 hr).
• No evidence of liver disease (liver enzymes < twice the upper limit of normal for each of ALT and AST, bilirubin < 2 mg/dl, albumin > 3.5 g/dl, and PT and PTT </= 1.1 x the upper limit of normal).
• Frequent episodes of symptomatic hypoglycemia (i.e. loss of consciousness, headaches, anxiety, irritability, trembling, sweating) more than once per week, documented hypoglycemic unawareness (i.e. no adrenergic and/or neurogenic symptoms with blood glucose < 54 mg/dl) two or more times in the past two months, or hypoglycemic episodes that required the assistance of another person more than once per month or hospitalization more than once over the past 20 months.
• Ability to comply with post-transplant regimen, including immunosuppression, insulin pump therapy and metabolic testing. Patients will be required to perform self-monitoring of blood glucose a minimum of four times daily, and provide complete records of blood glucose levels and insulin doses.
• Ability to give informed consent.
• Age greater than or equal to 18 years or less than or equal to 65 years.

Exclusion Criteria:

• Significant liver disease (including elevation of liver enzymes > twice the upper limit of normal for each of ALT and AST, bilirubin > 2 mg/dl, albumin < 3.5 g/dl, liver masses, portal vein thrombosis, evidence of portal hypertension, or significant, untreated gallbladder disease (i.e. gallstones).
• Significant cardiovascular disease, including non-correctable coronary artery disease with ejection fraction < 50% and/or recent myocardial infarction (within last 12 months); extensive peripheral vascular disease not correctable by surgery or untreated proliferative retinopathy.
• Recent unresolved acute infection, or chronic infection, including tuberculosis, HIV, HBV, HCV, CMV or positive skin test for TB.
• Any history of malignancy, except squamous or basal skin cancer or in situ cancer of the cervix.
• Recent history of non-compliance, or inability to demonstrate capacity to comply with strict blood glycemic control and insulin pump therapy.
• Psychiatric illness that is untreated, or likely to interfere significantly with transplantation despite treatment.
• Presence of preformed antibodies on panel reactive antibody screening > 20%.
• Body mass index (BMI) greater than 30.
• Age less than 18 years or greater than 65 years.
• Presence of a chronic disease that must be chronically treated with one or more of the following medications: glucocorticoids, diazoxide, bumetanide, haloperidol, chlorpromazine, desipramine, doxepin, imipramine, isoproterenol, levodopa, morphine, L-asparaginase, cyclophosphamide, isoniazid, heparin, nalidixic acid, or any other agents that may adversely influence glycemic control and which may confound the interpretation of Graft Success post-transplant.
• Pregnant women, women intending future pregnancy, women of reproductive potential who are unable or unwilling to follow effective contraceptive measures for the duration of immunosuppressive therapy, and women presently breast feeding are ineligible due to the unknown effects of these drugs on the fetus and nursing infant.
• Active alcohol or substance abuse, including cigarette smoking (must be abstinent for > 3 months).
• Hyperlipidemia (total cholesterol > 260 mg/dl, LDL > 130 mg/dl, and/or triglycerides > 300 mg/dl) despite appropriate treatment.
• Anemia (Hgb < 12 g/dl) or other hematologic disorders that require medical attention.
• Increased risk of bleeding (platelet count < 80,000; INR > 1.5), other chronic hemostasis disorders, or treatment with chronic anticoagulant therapy (i.e. heparin or warfarin).