Islet Transplantation in Type 1 Diabetics Using the Edmonton Protocol of Steroid Free Immunosuppression

LAY SUMMARY:

More than 1 million North Americans have type 1 diabetes. Each year, approximately 30,000
new cases of type 1 diabetes are diagnosed in the United States. Type 1 diabetes destroys
islets, a cluster of cells within the pancreas that produce insulin. Insulin is a hormone
with many effects. However, the most important effect of insulin is to control the level of
sugar in the blood. People with Type 1 diabetes no longer produce insulin and must take
insulin injections to live. Despite steady improvements in the management of this disease,
its victims remain at increased risk for stroke, heart attack, kidney failure, amputation,
blindness, nerve damage and premature death. The life expectancy of a teenager is reduced by
thirty years from the time of onset of the disease. Unfortunately, many type 1 diabetics
cannot control their blood sugars in spite of very careful monitoring and the frequent
injection of insulin. This group of patients is considered to have labile or "brittle"
diabetes. These "brittle" diabetics can often have wide swings in their blood sugar levels
that can be life threatening. Hypoglycemia, or low blood sugars, occurs when too much
insulin is in the bloodstream. When this occurs, it is vital that patients eat or drink
something right away that will increase their blood sugars. Many diabetics lose the ability
to recognize when their blood sugars are getting dangerously low. These episodes of
hypoglycemia can lead to coma, and possibly death, if not recognized and treated right away.
Patients can also experience extreme increases in blood sugars, or hyperglycemia, as a
result of emotional or physical stress. Hyperglycemia can result in dehydration, confusion,
and a condition called ketoacidosis, which can lead to death. When this happens, insulin
must be given as soon as possible.

Islet transplantation can restore the body's ability to make insulin and, in turn, restore
normal blood sugar levels.

Since the 1960's, doctors and scientists have attempted to replace this islet function by
performing whole organ pancreas transplantation. While the results of pancreas
transplantation have improved dramatically in recent years, this approach has largely been
limited to patients with kidney disease who have also needed a kidney transplant. This is
because of the risks associated with the surgical procedure and the immunosuppressive drugs
required to prevent rejection or the destruction of the transplanted pancreas by the body's
immune system. Transplantation of a whole pancreas requires a major operation that is done
through an incision in the abdomen. The patient must be under general anesthesia, or asleep,
for the entire procedure. Recent clinical experience suggests that islet transplantation may
be a useful approach to correct diabetes in humans.

Islet transplantation offers a direct approach to the treatment of type 1 diabetes. A large
number of experimental studies carried out in many laboratories over the last decade have
documented the beneficial effects of islet transplants in experimental animals. These
experiments have confirmed both the efficiency and safety of islet transplantation.

The inability to isolate enough islets from a single pancreas has been one obstacle to
successful islet transplantation. A certain number of islets must be isolated, or separated,
from a single pancreas in order to use them for transplant. If this minimum number of islets
is not obtained, then the islets do not effectively reverse diabetes. Progress in isolating
the islets from a human pancreas has been dramatic in the last several years. Advances in
equipment and technology have lead to increases in the number of islets that can be isolated
from a single pancreas.

After successful isolation, the islets can be injected through a catheter into the patient's
liver during a thirty-minute procedure. A group of doctors at the University of Alberta in
Edmonton, Canada has had promising results in human islet transplantation. Normal sugar
levels have been documented after human islet transplants. Also, recent improvements in
immunosuppressive drug treatments have resulted in sustained insulin-independence in
selected type 1 diabetic patients. The traditional method of transplant immunosuppression
includes using some form of a steroid drug. Steroids have been found to injure or kill the
islets after transplant. The doctors in Edmonton, Canada established an immunosuppression
formula that does not use steroids. The objective of the study here at Emory University is
to reproduce the successful results of human islet transplantation that have been achieved
by the doctors at the University of Alberta using steroid free immunosuppression.

The Emory Islet Transplant Program will enroll ten patients, ages 18 to 65, in the study.
Each of the ten patients will receive at least 2 islet transplants from 2 different organ
donors. A third transplant may be required based on the patient's insulin requirements after
the 1st two transplants. Each patient will be placed on immunosuppressive drugs to prevent
the body from rejecting or destroying the transplanted islets. Each patient will have
his/her blood sugar levels and insulin requirements monitored very closely after each
transplant. The patients will also have various tests to determine if their diabetic
complications improve, remain the same, or become worse. The patients will be asked to
record any episodes of hypoglycemia or low blood sugars while participating in this study.
Emory will examine whether or not there is a decrease in how often the episodes occur.
Patients will also undergo regular eye exams to document retinal changes or improvements
that may occur after transplant. At this time it is not known whether islet transplantation
slows or stops the progression of common diabetic complications. More experience and
research is needed before this can be determined. One focus of our research will be to study
diabetic complications in patients who receive islet transplants.

The major goal of the Emory Islet Transplant Program is for patients participating in this
study to be free of the need for insulin injections after 2 islet transplants. Because many
advances have been made in islet transplantation, the transplant team at Emory would like to
participate in this promising treatment of type 1 diabetes and, most importantly, help those
who suffer from this disease become free from daily insulin injections and avoid the
devastating complications that happen as a result of diabetes.

Inclusion Criteria:

- Type 1 diabetes mellitus diagnosed > 5 years previously

- Body mass index less than or equal to 26

- 18 to 65 years of age

- Compliance with an optimized diabetic management plan as assessed by an Emory
University endocrinologist

- Checking and recording blood sugars at least 3 times per day

- Intensive insulin therapy (injecting insulin at least 3 times a day or using an
insulin pump)

- Severe hypoglycemia and/or hyperglycemia. Severe hypoglycemia is defined by: episodes
requiring assistance by others and/or hypoglycemic unawareness (the inability to
recognize blood glucose < 54 mg/dL). Severe hyperglycemia is defined by: two episodes
of ketoacidosis requiring hospitalization within the past year.

Exclusion Criteria:

- Renal dysfunction

- Severe co-existing cardiac disease, characterized by any one of these conditions:
recent myocardial infarction (within past six months); angiographic evidence of
non-correctable coronary artery disease; or evidence of ischemia on a dobutamine
stress echocardiogram.

- Current bacterial or fungal infection

- Macroproteinuria

- Baseline hemoglobin < 11.4 gm/dL in women; < 12.9 gm/dL in men.

- Hyperlipidemia

- Positive tests for human immunodeficiency virus (HIV), or hepatitis B or C

- Negative antibody test for varicella zoster virus (subjects may be reconsidered if
they receive the vaccination and convert to a positive antibody)

- History of malignancy (except squamous or basal cell skin carcinoma)

- Previous/concurrent organ transplantation

- Presence of HLA panel reactive antibodies > 20%

- Active peptic ulcer disease

- Evidence of gallbladder disease including cholecystitis and cholelithiasis

- Evidence of liver disease including hepatic neoplasm, portal hypertension, or
persistently abnormal liver function tests.

- Persistent coagulopathy or current use of anticoagulants (not including aspirin)

- Sickle cell anemia

- Positive pregnancy test, intent for future pregnancy, failure to follow effective
contraceptive measures, or presently breastfeeding

- Active alcohol or substance abuse. This includes smoking (must be abstinent for six
months). Active alcohol abuse should be considered using the current National
Institute on Alcohol Abuse and Alcoholism (NIAAA) definitions.

- Psychiatric disorder making the subject not a suitable candidate for transplantation

- Current use of systemic steroid medications

- Evidence of insulin resistance (insulin requirement > 1.2 units/kg/day)

- Inability to provide informed consent

- Any condition or any circumstance that makes it unsafe to undergo an islet transplant