Introduction

Pancreatic islets are small clusters of endocrine

cells in the pancreas that include insulinproducing beta cells. In type 1 diabetes—also

known as juvenile or insulin-dependent

diabetes—the body’s immune system specifically

destroys the beta cells, resulting in a loss of insulin

production. Pancreas transplants have been used

as a way to restore insulin production, but require

long-term treatment to prevent immune rejection

of the transplanted organ. Islet transplantation

offers a potential alternative to whole-organ

pancreas transplantation, but early attempts rarely

succeeded. Following the introduction of the

Edmonton transplant protocol in 1999,

developed at the University of Alberta in Canada,

major islet transplant centers have developed and

refined new procedures, are enlisting patients into

clinical studies and following their progress, and

are reporting detailed data to a new transplant

registry. This report represents the current state of

the evidence in a field where clinical research is

actively progressing.

Whole-organ pancreas transplants were initially

performed in patients with type 1 diabetes who

were undergoing kidney transplants (for kidney

failure), with the pancreas transplanted either at

the same time as the kidney or in a later

operation. Compared with patients receiving

only a cadaver kidney transplant, patients

receiving a simultaneous pancreas–kidney

transplant have improved long term survival—

although immediately after surgery, during the

early post-transplant period, survival is worse.1–3

Transplant of a pancreas together with a kidney

also has positive effects on low blood

sugar/hypoglycemia,4,5 kidney complications,6,7

and high blood pressure/hypertension.8

Over the past decade, pancreas transplant alone

(PTA) has been used selectively in some type 1

diabetes patients. Patients considered for this

approach are those for whom the potential benefit

of the procedure is expected to offset the adverse

consequences of lifelong immunosuppressive

therapy, which keeps their immune system from

rejecting the transplanted organ. PTA is

recommended only for patients with a history of

frequent and severe metabolic complications,

severe and incapacitating clinical and emotional

problems with receiving insulin shots, or

consistent failure of insulin-based management to

prevent acute complications.9 The results of the

Diabetes Control and Complications Trial

(DCCT) demonstrate that intensive insulin

therapy significantly improves control of blood

sugar (glucose) levels and reduces the risk of

secondary complications, such as eye problems,

nerve damage, kidney damage, and cardiovascular

disease.10 However, there is a small population of

patients with unstable type 1 diabetes who,

nevertheless, have difficulty maintaining glucose

control with administration of insulin injections.

Some of these patients develop severe

hypoglycemia without the usual associated

warning signs.11 Untreated, severe hypoglycemic

episodes may result in coma, seizures, and death.

Such patients may require constant supervision by

a family member or caretaker. Following the

introduction of the Edmonton protocol, islet

transplantation has largely been used in patients

who are candidates for PTA; most have been

selected due to their severe and frequent

hypoglycemic episodes.

Transplanted islets are infused into the portal

vein through a catheter and lodge in the liver.

Because islet transplantation does not require a

large abdominal incision, it is a less-invasive

alternative to whole-organ transplantation and

avoids the unhealthy side-effects of complex

surgery. However, early protocols resulted in only

around 10 percent of patients achieving insulin

independence at 1 year after the procedure.

Nevertheless, interest in this approach remained

Evidence Report/Technology Assessment

Number 98

Islet Transplantation in Patients with Type 1

Diabetes Mellitus

Summary

Agency for Healthcare Research and Quality

Advancing Excellence in Health Care • www.ahrq.gov

Agency for Healthcare Research and Quality Evidence-Based

Practice
2

high due to improvement in long-term diabetic consequences

in studies of islet-transplanted animals and in those patients

undergoing islet transplant who were able to maintain insulin

independence. For example, in the pre-Edmonton era, one

center reported reduced cardiovascular mortality and kidney

damage in their few patients with long-term, successfully

transplanted islets.12

Improved results for insulin independence and maintenance

of normal blood glucose levels have been achieved with newer

protocols that use a low-dose immunosuppressive therapy

without glucocorticoid drugs, improved islet preparation, and

infuse a minimum islet mass of 9,000 islet-equivalents per

kilogram (IEq/kg) of body weight. The first of these protocols

was the Edmonton protocol;13 subsequent protocols have been

developed at other centers (e.g., Universities of Minnesota and

Miami).14,15 As interest in establishing new islet transplant

centers increases, institutional collaborations with established

preparation centers will play a large role due to the startup costs

for an islet preparation facility, regulatory issues, and

complexity of the isolation procedure.16 Currently, the Division

of Clinical Research at the National Institutes of Health’s

National Center for Research Resources, supports 10 Islet Cell

Resource Centers in the U.S. These centers isolate, purify,

characterize, and distribute human pancreatic islets for

subsequent transplantation in approved clinical protocols (for

additional information see http://www.ncrr.nih.gov/

clinical/cr_icr.asp)

Currently, a limitation on transplanting islets is that two or

more donor organs are usually required for successful

transplantation. The low availability of donor pancreas organs

limits the number of pancreas or islet transplants that can be

performed. For 2002, the Organ Procurement and

Transplantation Network reported 6,187 total deceased organ

donors, 1,870 pancreas organs recovered, and 1,461 pancreas

organs transplanted.17 A smaller, unreported number of

pancreas organs are also collected and preserved (harvested)

specifically for islet transplantation research.18 In contrast, a

total of 9,691 individual kidneys were harvested and

transplanted from the same group of organ donors.

Islet preparations are subject to regulation by the U.S. Food

and Drug Administration (FDA) as biological products and as

drugs. Because the use of cells derived from whole organs

meets the criteria for a biologic product to be regulated under

the Public Health Service Act, the FDA classifies

transplantation of allogeneic (not genetically identical to the

recipient) islets as somatic cell therapy, which requires

premarket approval.19 Islets also meet the definition of a drug

under the Federal Food, Drug, and Cosmetic Act. Clinical

studies to determine the safety and effectiveness outcomes of

allogeneic islet transplantation must be conducted under FDA’s

investigational new drug (IND) regulations. At least 35 IND

applications have been submitted to the FDA,19 but, as of this

writing, no center has as yet submitted a biologics license

application. 

Outcomes of interest to the authors of this evidence report

are early and long-term clinical diabetic outcomes, biologic

outcomes that are indicators of graft function and glycemic

(blood-sugar) control, and adverse outcomes. Early clinical

outcome measures are insulin independence, percent of prior

insulin use, hypoglycemic episodes, and quality of life. For

patients with type I diabetes, improvement in long-term

diabetic outcomes is the measure of ultimate success of islet

transplantation. The objective is to reduce or eliminate longterm diabetic complications such as eye disease, nerve damage,

kidney damage, and cardiovascular disease. Measurement of Cpeptide and HbA1c (glycated hemoglobin) are biological

outcomes that are indicators of graft function and glycemic

control, respectively. Potential adverse events of islet transplant

may be direct consequences of the procedure (for example,

hemorrhage or thrombosis from through-the-skin access to the

portal vein) or the continued immunosuppression needed to

maintain viability and function of the transplanted islets.

Adverse effects of immunosuppression may be near-term (such

as mouth ulceration, diarrhea, or anemia) or long-term

(including kidney disease, post-transplant cancers of the

immune system, other cancers, and cytomegalovirus or other

infections). 

A consensus definition of successful islet transplantation was

proposed at a recent meeting of the FDA Biological Response

Modifiers Advisory Committee: restoration of sustained

euglycemia with no or a reduced exogenous insulin

requirement.20 Clinical outcome parameters that can be used to

measure success are insulin independence or percent of prior

insulin use, frequency and severity of hypoglycemic episodes,

and quality of life. However, in the absence of well-controlled

and well-reported studies, insulin independence is the most

persuasive measure available to establish the success of the

procedure.

The National Institute of Diabetes and Digestive and

Kidney Diseases (NIDDK) initiated and funded the

Collaborative Islet Transplant Registry (CITR) in September

2001. The CITR will develop and implement reporting

standards, compile data on islet transplants in the U.S. and

Canada, and perform and communicate analyses of outcomes

(http://spitfire.emmes.com/study/isl/index.html).

Unfortunately, the first CITR report was not yet available at

the time this evidence report was prepared. In the future, the

Registry will be the most comprehensive source of data on the

outcomes of islet transplant. While the CITR will provide

aggregated data on outcomes, published studies from individual

centers still remains the best source of detailed results and of

data on center-specific outcomes.

Methods 

As much as possible, the protocol for this review was

designed prospectively to define: study objectives; search

strategy; patient populations of interest; study selection criteria;

outcomes of interest; data elements to be abstracted and
methods for abstraction; and methods for study quality

assessment.

The report addresses the following four key questions:

1. What are the outcomes for selected diabetes patients treated

with islet transplantation compared with similar patients who

receive whole-organ pancreas transplants or medical

(nontransplant) management of their disease? Are similar

outcomes achievable outside of the investigational setting?

2. What criteria should be used to select patients for islet

transplantation and what are the outcomes for relevant patient

subgroups? 

3. What are the incidence and severity of adverse effects

associated with the islet transplantation procedure and with

the immunosuppressive regimens? How do these compare with

the adverse effects associated with whole-organ pancreas

transplantation or medical management?

4. What is the evidence that the insulin independence or

significantly reduced insulin dependence achieved with islet

transplantation can be maintained long-term after the initial

transplant, or with additional transplants in the event of

failure of the original procedure? How often must successive

transplants be performed?

This report is limited to transplantation of unaltered human

allogeneic islets harvested from donor organs. Thus, cultured

islets from donor organs are included, but the following are

excluded: autologous islets (from the patient’s own pancreas),

islets from pig pancreas, genetically altered islets, and islets

prepared from stem cells. 

The MEDLINE database was searched through October

2003 for recently published research articles and for relevant

background information. Search was limited to articles with an

English-language abstract. Bibliographies of relevant articles

were also searched and the project’s Technical Expert Panel was

queried for additional relevant articles. Registry data, recent

meeting abstracts, and presentations by investigators from key

research centers were also sought. 

For all of the key questions, studies were included if they:

• reported prospective trials of islet transplantation; AND

• reported on outcomes of interest with at least 3 months of

followup; AND

• used a transplant protocol based on the Edmonton

protocol or a subsequently developed protocol designed to

improve upon aspects of the procedure; AND

• provided sufficient details on trial design, methods, and

outcomes to assess study quality; AND

• were available as a full-length publication, abstract, or

poster/slide presentation provided by the original presenter.

All abstracts initially retrieved by the search strategy were

reviewed by one researcher who also reviewed the full-text

articles to determine whether study selection criteria were met.

Selected papers were abstracted by a single reviewer and

evidence tables were fact-checked by a second reviewer. After

initial review of the evidence on islet transplantation, the

decision was made that it was premature to compare this

technique with whole-organ pancreas transplants; hence, a

systematic review of the evidence on pancreas transplant

outcomes was not undertaken for this report.

Results

Although more than 2,000 abstracts were reviewed, almost

all indexed clinical studies were completed prior to the

adoption of the Edmonton protocol. As a result, few articles

were retrieved and included in this review. Of the studies

relevant to the Edmonton protocol, only 12 published

articles13,14,16,21–29 reported efficacy and adverse outcomes, and

two additional articles30,31 reported only adverse outcomes. 

Due to the scarcity of published articles, abstracts and

presentations from five scientific conferences were reviewed,

and those meeting the selection criteria were summarized as

supplementary sources that provide preliminary results of

studies anticipated to be fully reported in the next 2 years.

Because summary data from the CITR is not yet available, a

summary of results from transplant groups attending the 2002

Second Annual Annenberg Symposium, in Rancho Mirage,

CA, represents the only available effort to collate islet transplant

data from active centers and is also included in this report.

It was not possible to summarize and pool together the most

recent outcomes from each reporting center for several reasons.

First, some centers reported different outcomes on different

numbers of patients in more than one publication, precluding

an accurate synthesis. Second, different centers reported the

same type of outcome in different ways. Thus, a standardized

data collection, such as that in progress by the CITR, will be

needed for an accurate and complete data summary. For these

reasons, data in this report are generally presented by center.

Moreover, reports on the outcomes of islet transplantation from

a single center often combine results from patients treated on

different protocols. Protocol characteristics are noted in the

evidence tables for published reports, but this review makes no

attempt to compare the outcomes of different protocols. 

Published data on the clinical outcomes of islet-only

transplantation are limited by small patient numbers, few

transplant centers, short duration of followup, and by lack of

standardized methods of reporting outcomes. Data are also

lacking on quality-of-life outcomes. Meeting abstracts and

presentations supplemented published reports with larger

numbers of patients and reporting transplant centers. Efforts

are ongoing to update and expand long-term transplant results

and quality-of-life data, disseminate protocols to additional

centers, and standardize reporting of outcomes. The available

evidence is summarized below:

• Islet-alone transplantation has been used in a highly

selected population of type 1 diabetic patients who have

been selected for transplantation based on a history of

frequent and severe metabolic complications, severe and

3
4

incapacitating clinical and emotional problems with

exogenous insulin therapy, or consistent failure of insulinbased management to prevent acute complications. 

• There are sufficient data to conclude that there is a high

rate of technical success for islet-alone transplantation.

Five centers published reports14,16,21,25,29 on 47 patients who

completed a transplant protocol. Of these, patients 44 (94

percent) achieved insulin independence over the 3-month

post-transplant period.

• Clinical outcomes from presently available data can be

summarized as follows: 

- Published data from three centers14,21,29 report that 28 of

37 patients (76 percent of those completing a transplant

protocol) maintained insulin independence for 1 year.

Four centers that followed 104 patients for at least 12

months report insulin independence in 50 to 90 percent

of patients in recent abstracts. 

- Only one published study (from the Edmonton group)22

reported four of six patients remained insulin

independent after 2 years of followup. In one abstract

from Edmonton, 48 patients underwent transplantation

and 15 were followed for 2 or more years. Statistical

analysis estimated that the probability of remaining

insulin-independent at 2 years was 64 percent.

- Two institutions published14,22 detailed information on

23 transplant patients who had at least 1 year of

followup. Of these, 19 (83 percent) had normal bloodsugar levels without hypoglycemic episodes (were

euglycemic), and needed no or reduced amounts of

additional insulin.

- All published series report that hypoglycemic episodes

were less frequent or intense in insulin-independent

transplant patients. In three series14,22,29 reporting on 26

patients who completed the transplant protocol,

hypoglycemic episodes were also reduced in nine

patients who exhibited continued C-peptide secretion,

but who were not insulin independent at 1 year.

Abstracts report this outcome less consistently but,

where reported, hypoglycemic episodes were eliminated

in insulin-independent patients. 

- In each published series14,16,22,25,26,29 and for all insulinindependent patients, mean HbA1c decreased from

greater than 7 percent to less than 6.5 percent; 7 percent

or less is recommended to avoid or delay progression of

diabetic complications. Where reported in meeting

abstracts, in most cases the mean HbA1c level after

transplantation was less than 6.5 percent; this level, was

maintained for up to 3 years post-transplant in two

series (13 patients reported on, total).

• Data are scant on the effects of islet transplantation on

long-term diabetic consequences. In one publication,22 the

Edmonton group reported on 17 subjects who completed

the transplant protocol. Damage to the retina progressed

in three patients and required laser photocoagulation

treatment. Nine patients either started or increased

treatment for high blood pressure. Cholesterol rose in 15

patients, of whom 11 required statin therapy. There were

no major changes in nerve damage. Serum creatinine and

urine protein levels only showed significant changes in two

patients with pre-existing kidney disease.

• Infrequent but serious adverse events (such as portal vein

thrombosis or hemorrhage) have occurred in patients given

islet transplants, but it is not possible from present data to

estimate their frequency.14,21,29 Recent changes in the

transplant procedure reportedly minimize the risks of these

adverse events. No procedure-related deaths have been

reported among patients who received islets alone.

Notably, no publication or abstracts reported

cytomegalovirus infection in any patients given islet-only

transplants. Post-transplant immune system cancers also

have not been reported so far, but this may reflect the small

number of subjects studied.

• The available evidence is insufficient to evaluate the longterm consequences of immune system suppression, any

long-term effects of the islet graft, and the potential need

for and consequences of supplemental islet transplants.

• The majority of transplants using the newer protocols have

been of islets alone. However, it has been reported

(mainly in meeting abstracts and presentations) that 30

islet transplants after or simultaneous with kidney

transplants have been attempted; in most cases, followup is

less than 1 year. The present evidence is insufficient to

permit conclusions for this type of transplant.

Discussion

The available evidence demonstrates the technical feasibility

and superior procedural success of islet transplantation using

the Edmonton and more recent protocols. Where 1-year

followup has been reported, most patients are insulin

independent and free of severe hypoglycemic episodes. At

present, 100 or more patients have been followed for 1 year

after transplantation, and the Edmonton group recently

reported on 15 patients followed for 2 years or more. Evidence

on longer-term outcomes or durability of the procedure is not

yet available. Therefore, it is not yet possible to assess the effects

on diabetic complications or the consequences of lifelong

immunosuppression. 

Reports from the CITR are expected in the near future.

These will provide systematic data on outcomes of patients

treated at the major islet transplant centers, and will eventually

accumulate data on long-term outcomes. The CITR plans to

collect data on patient characteristics at transplantation (for

post-Edmonton protocols only, and including retrospective

data) as well as long-term followup data on the secondary

complications of diabetes. The addition of data on the

presence and severity of retinopathy, nerve damage, and other

diabetic complications in the patients prior to transplantation
would aid the interpretation of long-term results. Randomized,

controlled trials of islet transplantation (in direct comparison to

no treatment or whole-organ transplantation) do not exist and

are unlikely to be conducted. Thus, pre- and post-procedure

evaluations, which are likely to be the only source of evidence

to evaluate this procedure, should proceed with the utmost

rigor. 

As is the case with many medical or surgical procedures,

outcomes may vary by center due to the transplant team’s

experience or specifics of the treatment. Moreover, such

variation can be difficult to discover when the number of

procedures is too small to reach firm statistical conclusions.

Center-specific data will complement aggregate data in

evaluating the outcomes of islet transplants, setting standards

for performance, and improving outcomes.

Long-term followup will outline the durability of islet graft

function and the need for repeat procedures. Uncertainties

remain: Should patients who fail to maintain insulin

independence be administered additional islet transplants?

Does reactivation of autoimmune reactions against beta cells

affect the success of subsequent transplants? Do the risks of the

procedure increase with successive transplants?

At present, the supply of donor pancreases stringently limits

the availability of islet transplants. However, refining the islet

isolation and transplant procedures could promote more

vigorous efforts at organ collection, and perhaps make islet

transplantation more available. Simultaneous transplant of

islets and kidneys is being attempted and may represent

another population of patients using islet transplantation.

Ongoing research on innovations in immunosuppression

regimens, and in techniques to prevent rejection or induce

tolerance of transplants, may eventually improve the benefit-torisk ratio of the procedure; methods of in vitro production may

also increase the availability of islets for transplantation. While

pancreas and islet transplantation are now the only means of

achieving physiologic insulin regulation, continuous glucose

monitoring and insulin infusion technologies are being

developed in hope of someday developing an artificial pancreas.

As innovations in the management of type I diabetes emerge,

risks and benefits, relative-effectiveness, and cost-effectiveness

for various patient populations should be carefully evaluated.

Availability of the Full Report

The full evidence report used to create this summary 

was prepared for the Agency for Healthcare Research and

Quality by the Blue Cross and Blue Shield Association

Technology Evaluation Center Evidence-based Practice Center

under Contract No. 290-02-0026. It is expected to be available

late in the summer of 2004. At that time, printed copies may

be obtained free of charge from the AHRQ Publications

Clearinghouse by calling (800)-358-9295. Inquiries should

include a request for Evidence Report/Technology Assessment

No. 98, Islet Transplantation in Patients with Type 1 Diabetes

Mellitus. In addition, Internet users will be able to access the

report and this summary online through AHRQ’s Website at

www.ahrq.gov 

Suggested Citation

Piper M, Seidenfeld J, Aronson N. Islet Transplantation in

Patients with Type 1 Diabetes Mellitus. Evidence

Report/Technology Assessment No. 98 (Prepared by Blue Cross

and Blue Shield Association Technology Evaluation Center

Evidence-based Practice Center under Contract No. 290-02-

0026). AHRQ Publication 04-E017-1. Rockville, MD: Agency

for Healthcare Research and Quality. July 2004. 

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www.ahrq.gov

AHRQ Pub. No. 04-E017-1

July 2004

ISSN 1530-440X