Islet Transplantation Alone (ITA) in Patients With Difficult to Control Type I Diabetes Mellitus Using a Glucocorticoid-free Immunosuppressive Regimen

Type 1 diabetes is associated with the damage of a specific cell subtype of pancreatic islets
(clusters of cells in the pancreas that produce insulin and other metabolic hormones), which
makes patients depend on an outside source of insulin. Despite insulin treatment, type 1
diabetes mellitus causes a significant risk of long-term problems, including damage to the
heart, blood vessels, nerves, eyes and kidneys. The results of recent research studies
suggest that these complications are caused by poor glucose control.

Transplantation of islets offers the prospect of good glycemic (blood glucose) control
without the major surgical risks associated with whole pancreas transplant and may result in
not needing any insulin injections. In 2000, a group of investigators in Edmonton, Canada
showed that islet transplantation using a combination of anti-rejection drugs to help prevent
the rejection of transplanted islets was effective in eliminating insulin intake in 7
subjects who were followed up to 20 months. After 5 years, more than 60 patients have been
transplanted at Edmonton and only 1 in 10 remained off of insulin.

This study is being performed to confirm the results of the Edmonton study to see if islet
transplantation alone (ITA) is a safe and effective way of treating subjects with type 1
diabetes. This study uses a few additional medications and vitamin supplements that were not
included in the original Edmonton study. We hope this will improve the long-term outcome of
islet transplantation.

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
- 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 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).