Severe Hypoglycemia Is Rare After Islet Transplantation

Inislet transplantation as performed by the centers, clusters ofinsulin-producing cells, called islets, are extracted from a donorpancreas and infused into the portal vein of the recipient’s liver. Ina successful transplant, the islets become embedded in the liver andbegin producing insulin. Islet transplantation (http://diabetes.niddk.nih.gov/dm/pubs/pancreaticislet/index.htm)is an experimental procedure reserved for people with severe orcomplicated type 1 diabetes. Because of the risks associated with islettransplantation, patients chosen for the procedure were those who hadthe greatest need and potential for benefit, such as those with ahistory of hypoglycemia unawareness.

Type 1 diabetes, whichaffects up to 1 million people in the United States, develops when thebody’s immune system destroys the insulin-producing beta cells of thepancreas. This form of diabetes usually strikes children and youngadults, who need several insulin injections a day or an insulin pump tosurvive. Insulin is not a cure, however. Eventually, most people withtype 1 diabetes develop one or more complications of the disease,including damage to the heart and blood vessels, eyes, nerves, andkidneys.

Most people with type 1 diabetes know the signs of lowblood glucose and take steps to counteract it before their glucose dipsfurther and leads to a loss of consciousness. However, some patientswith brittle or difficult-to-control diabetes, who can’t sense thattheir blood glucose is too low, may lose consciousness anywhere andwithout warning. Nearly all patients receiving a transplant had severehypoglycemia episodes requiring another person’s help before thetransplant, but such events are very rare in the year after asuccessful transplant, the CITR reports. One infusion of islets, thoughnot always enough to keep blood glucose in the normal range, generallylowered insulin needs and alleviated episodes of severely low bloodglucose in most patients.

One year after the last infusion, 58percent of recipients no longer had to inject insulin. Those who stillneeded insulin a year after their last infusion had a 69 percentreduction in insulin requirements. However, in 19 recipients followedby the registry, the donor islets failed to function. Transplantfailures, as measured by blood glucose levels and confirmed by a testof C-peptide, occurred as early as 30 days after the recipient's firstislet infusion to more than 2 years after the last infusion.

Eighteenof the 19 centers contributed data on adverse events, including 77serious adverse events. About 58 percent of the serious events requiredinpatient hospitalization, and 22 percent were considered lifethreatening. Seventeen percent of the serious events were linked to theislet infusion procedure (e.g., infection or bleeding), and 27 percentwere related to medications that suppress the immune system (e.g.,anemia, nerve damage, and low numbers of white blood cells). Recipientsreceived immunosuppressive drugs that usually included daclizumab atthe beginning of the procedure to prevent immune rejection of donorislets, then sirolimus and tacrolimus to maintain immunosuppression.

“Theregistry is still quite young, but it’s doing a very good job ofproviding critical information on the results of islettransplantation,” said Dr. Michael Appel, who oversees the project forthe NIDDK. “As the registry matures, researchers will be able to usethe data to identify factors that increase risk and those that promotesuccess. This information will help centers refine their protocolsbased on objective information.”

Centers’ participation in theCITR is voluntary. The registry’s second report gives information ondonor and patient characteristics, pancreas procurement and isletprocessing, immunosuppressive medications, functional potency of thedonor islets, patients’ lab results, and adverse events. “We’re gettingcritical information on the factors that influence the success of islettransplantation,” said Dr. Rodolfo Alejandro, director of ClinicalIslet Transplantation at the University of Miami’s Diabetes ResearchInstitute.

Recipients had type 1 diabetes an average of 29 yearsbefore the transplant. Most — 118 — received an islet transplant alone.An additional 19 patients had an islet transplant after receiving akidney transplant. One patient received an autograft transplant of hisown islets that were extracted after pancreatic surgery and theninfused into the liver. Forty patients received one islet infusion, 69received two, and 28 received three. A single patient received fourinfusions.

Recipients, 66 percent of whom were women, were anaverage age of 42 years (range 24 to 64 years). Their average weightwas in the healthy range. Before the procedure, nearly half therecipients were using an insulin pump. Their average level ofhemoglobin A1c (HbA1c), which reflects blood glucose control over theprevious 3 months, was 7.6 percent, compared to a normal HbA1c of 6percent. HbA1c levels generally improved with each infusion, as didlevels of C-peptide, a measure of insulin secretion.

“Theregistry is disseminating much needed data on the safety and efficacyof islet transplantation to investigators, health care professionals,providers, payers, and patients. We believe that the registry willcontribute to a better understanding of trends in islettransplantation,” said Dr. Bernhard Hering of the University ofMinnesota, CITR’s Medical Director and Chair of its Scientific AdvisoryCommittee. Hering is a participating investigator in NIH-fundedstudies, scheduled to begin early next year, that aim to improve thesafety and efficacy of islet transplantation: http://www.nih.gov/news/pr/oct2004/niddk-04.htm.

TheCITR’s mission is to expedite progress and promote safety in islettransplantation by collecting, analyzing, and communicating data onislet transplantation. NIDDK established the registry in 2001 through acontract awarded to the EMMES Corporation. The CITR is one of theprojects made possible by a special funding program awarded by theCongress to HHS for type 1 diabetes research. For a description ofprojects funded by this program, see http://www.niddk.nih.gov/federal/planning/type1_specialfund/.

From1990 to 1999, only 8 percent of islet transplants resulted in insulinindependence for more than 1 year. In 2000, however, a group ofresearchers led by Dr. James Shapiro at the University of Alberta inEdmonton, Canada, reported much greater success in patientstransplanted with higher numbers of islets and treated with animmuno-suppressive regimen that omitted glucocorticoids, now thought tobe toxic to islets. In the next few years, other researchers replicatedthe Canadian team’s “Edmonton protocol,” and many centers have adoptedthis approach to islet transplantation, with some modifications.

Thescarcity of islets poses a major obstacle to wider testing of islettransplantation as a treatment for type 1 diabetes. Organs from about7,000 deceased donors become available each year. Because of thefragility of the pancreas, only about 3,500 pancreata are suitable fortransplantation, and many of these organs are used for whole organtransplantation. To improve the potential of cell replacement therapyfor diabetes, NIH-funded research is focusing on understanding theinsulin-producing beta cell and its regeneration and on efforts todevelop alternative sources of beta cells. Researchers are also workingon ways to coax the immune system into accepting donor cells or tissueswithout suppressing the whole immune system.

Because of isletscarcity and the risks associated with the procedure and lifelongimmunosuppression, islet transplantation is not being tested as atreatment for most people with type 1 diabetes. Nor is it being testedin type 2 diabetes, the most common form of diabetes. People with thisform of diabetes are less likely to suffer from severe swings in bloodglucose and hypoglycemia unawareness. Moreover, islet transplantationcannot correct insulin resistance, an underlying disorder of type 2diabetes that is marked by the inability of cells to use insulineffectively.

Single copies of the CITR report may be ordered free of charge from the registry (www.citregistry.org)or from NIDDK's National Diabetes Information Clearinghouse at1-800-860-8747. For information about the steps you can take to controldiabetes, see http://www.ndep.nih.gov/.

NIDDKis part of the National Institutes of Health (NIH), the FederalGovernment’s primary agency for biomedical and behavioral research. NIHis a component of the U. S. Department of Health and Human Services.NIDDK information about islet transplantation and diabetes is availableonline at www.niddk.nih.gov.