• If you are citizen of an European Union member nation, you may not use this service unless you are at least 16 years old.

  • You already know Dokkio is an AI-powered assistant to organize & manage your digital files & messages. Very soon, Dokkio will support Outlook as well as One Drive. Check it out today!


Islet Transplantation

Page history last edited by Robert Rushakoff, MD 15 years, 1 month ago


The Web diabetesmanager


Islet Transplantation


Breay W Paty, MD, BA 






Islet transplantation is a method of restoring endogenous insulin secretion in selected patients with type 1 diabetes by transplanting insulin-secreting islet cells isolated from cadaveric donor pancreases, into eligible recipients. Since the introduction of steroid-free immunosuppressive regimens in the late 1990s, the 1-year insulin independence rate of islet recipients, at experienced transplant centers, has risen from less than 10% to approximately 75% (1). These results are a marked improvement in the clinical outcome of islet transplantation. However, a number of issues continue to challenge the wider application of islet transplantation in the treatment of type 1 diabetes. There is still a general requirement for at least two donor pancreases for each islet transplant recipient. Also the necessity for toxic immunosuppressive therapy and a gradual decline in insulin independence rates over time continue to make this procedure unsuitable for the majority of people with type 1 diabetes. Nevertheless, the recent improvement in islet engraftment has stimulated further investigation of beta cell replacement as a potential therapy for type 1 diabetes.



Experimental isolation of rodent islets began in the 1960s to characterize islet morphology and cellular physiology (2). By the end of the decade the mass isolation of rodent islets was readily achievable. However, the large size (70g) and fibrous quality of the human pancreas makes human islet isolation more difficult. By the 1980s, successful islet isolation and transplantation was achieved in dogs and pigs (3-7).

In 1988 Ricordi et al introduced a semi-automated method of isolating human islets using collagenase digestion and mechanical agitation inside a stainless-steel chamber containing glass (or steel) marbles, and a 500 μm mesh screen to separate insulin-secreting islets from pancreatic stromal tissue (8). The liberated islets were sampled frequently to avoid over-digestion and fragmentation. This process has now become the standard method for the isolation of human islets for transplantation. The adaptation of a COBE cell separation technique using Ficoll density gradients has produced greater purity of islets preparations, although this technique tends to reduce the overall islet yield (9).



Figure 1. Schematic representation of islet isolation and transplantation using the Ricordi Chamber, purification with Ficoll gradients and infusion of islets into the portal vein resulting in implantation within hepatic sinusoids.




In the early 1990s, a number of human islet transplant trials were attempted, and despite achieving insulin independence in a few recipients, the results were generally disappointing (10-15). By 1999, the International Islet Transplant Registry recorded a total of 447 human islet allografts performed worldwide (16). The results showed that insulin independence was achieved only in exceptional cases, when more than 6000 Islets/kg had been infused and when the cold storage time of the donated pancreas was less than 8 hours (17). Although 28% of cases showed detectable serum C-peptide levels after one year (18), the overall 1-year insulin independence rate was only 8% (16). By the late 1990s, steroid-free immunosuppressive protocols introduced for islet-after-kidney transplants, reported early insulin independence rates of up to 66% although this was not generally sustained for long periods (19; 20). Soon, progress in islet isolation techniques and the use of newer immunosuppressive agents would lead to a dramatic and sustained improvement in islet graft function (21).


Current Era

Since 1999, the combination of steroid-free immunosuppression with newer immunosuppressive agents and the use of at least two separate islet infusions has led to the achievement of insulin independence in the majority of recipients (22). These results are a consistent and marked improvement of islet graft survival and function. The avoidance of long-term glucocorticoids appeared to be especially beneficial because of their well-documented diabetogenic effects, through both direct toxic effects on beta cell function and indirect increases in peripheral and hepatic insulin resistance (23; 24).

Also, improvements in islet isolation techniques, such as the use of the two-layer method of pancreas preservation (25; 26), controlled ductal perfusion (27) and use of low endotoxin-containing collagenase blends (Liberase®, Roche Diagnostics, Indianapolis, IN) for pancreatic digestion have helped improve islet yield, purity and viability. Donor factors that appear to play a role the outcome of clinical islet transplantation are donor age, weight, gender, previous medical history, the presence of hyperglycemia, and the duration of organ ischemia after cardiac arrest (28-30). The technical skills of the local pancreas procurement team can also affect islet yield (29). Furthermore, the process of islet isolation remains time-consuming (6-8 hours per isolation) and labor intensive. Even under ideal circumstances, an estimated yield of only 20-50% of the potential number of pancreatic islets (1-2 million) can be expected. Encouraging results were reported in a series of patients who were transplanted with islets isolated at a remote center (31) indicating that it may be possible and more cost effective to isolate islets at a central (or regional) laboratory for subsequent transplantation at peripheral centers. Continued progress in addressing each of these issues will no doubt contribute to increasing islet yields and further improvement in the viability of islet transplants.


Clinical and Metabolic Outcomes

Islet transplantation is generally performed using percutaneous transhepatic portal venous catheterization under fluoroscopic guidance. In circumstances when the risk of intraperitoneal hemorrhage is thought to be elevated, a mini-laparotomy approach with catheterization of a mesenteric vein is sometimes used (1; 32; 33). Islets are infused by gravity into the portal circulation and flow with the portal blood to lodge in the hepatic sinusoids. Islet survival after transplantation has been estimated at only 10-20% (34). This low rate of islet survival is likely due to a number of factors including hypoxia and the initiation of an inflammatory cascade including the so-called instant blood mediated inflammatory reaction (IBMIR), which may trigger the release of tissue factors detrimental to islet survival (35; 36).

At the University of Alberta the mean number of islets transplanted during a single infusion is 393,554 ± 10,582 IE (5,783 ± 142 IE/kg). The mean cumulative number of islets received by individuals receiving at least two islet infusions is 799,912 1617; 30,220 islet equivalents (IE) (11,910 ± 469 IE/kg ) (1). The median time between first and second transplants was 2.5 months and between second and third transplants was 1.8 months. The criteria for islet suitability for transplantation include an adequate islet mass (> 5000 IE/kg), ABO compatibility (HLA matching is not required), negative gram stain, endotoxin load < 5 EU/kg, total islet volume < 10cc (most < 5cc), islet purity > 30% (most > 50%). In vitro islet viability is assessed using membrane dye exclusion testing (fluoresceine diacetate/propidium bromide) and insulin secretory function is determined using a static incubation method.


Islets for transplantation are obtained from two sequential donors in most cases. After transplantation, all patients are monitored for 24-48 hours with frequent capillary glucose readings and periodic complete blood counts and liver enzyme measurements. An abdominal ultrasound is performed the day after transplantation to rule out portal venous thrombosis or intraperitoneal hemorrhage. The most common immediate post-transplant symptoms are transient abdominal pain (52%), nausea, and rarely vomiting in patients who develop post-transplant ileus. The mean hospital stay is 1 day (range: 1 - 2 days) (37).


After the first islet infusion, daily insulin requirements are reduced by a mean of 52% (range: 12 - 100%) and glycemic stability is usually greatly improved. Eight percent (5/65) of subjects transplanted by November 2004 became insulin independent after a single islet infusion (1). However, most recipients do not attain insulin independence before receiving a second islet infusion (37). The University of Minnesota has described a series of eight women who all became insulin independent after receiving islets isolated from a single donor (mean: 7271 ± 1035 SD IE/kg) (32). These excellent results may be partly due to careful selection of recipients, quality of donor islets, and possibly the use of anti-thymocyte globulin and etanercept for induction of immunosuppression.


The one-year rate of sustained insulin independence for all recipients transplanted under a tacrolimus/sirolimus-based protocol is approximately 75% by Kaplan-Meier survival analysis (Figure 2B). However, there is a gradual loss of islet function over time, with a 2-year insulin independence rate of less than 60% and a five year rate of around 10% (1). Despite these declines, most patients (~80%) have persistently positive C-peptide (Figure 2A). Mean glycated hemoglobin (A1C) is generally normalized in insulin independent recipients (Figure 3) and near normal in recipients who remain C-peptide positive. As expected, A1C tends to rise in those patients who lose all graft function. The reasons for the decline or complete loss of islet function after transplantation are not clear, but may involve direct immunosuppressive toxicity, allo or recurrent autoimmune rejection, or potentially islet cell apoptosis reflecting the natural life cycle of islets in the native pancreas (38).



Figure 2. Survival analysis for (A) C-peptide secretion and (B) insulin independence over time for all those who completed the islet transplant procedures. The curves are dated from the time of the final transplant. Copyright 2005 American Diabetes Association from Diabetes, Vol. 54, 2005; 2060-2069. Reprinted with permission from The American Diabetes Association.




Figure 3. HbA1c (mean ± SE), over time post-transplantation in those subjects who lost all graft function (—●), those subjects whose graft function remained but had to resume insulin (—○), and those subjects who remained insulin independent (—♦). The group off insulin was significantly different from the others. Copyright 2005 American Diabetes Association from Diabetes, Vol. 54, 2005; 2060-2069. Reprinted with permission from The American Diabetes Association.



Assessing in vivo graft function is challenging because there is no direct measure of functional islet mass after transplantation. Glucose-stimulated insulin secretion in islet recipients as measured by acute insulin response to glucose (AIRg) remains substantially lower than normal (21 1617; 5% of control), but is sustained up to two years after transplantation (Figure 4). Acute insulin response to arginine (AIRarg) is somewhat higher (56 ± 11% of control), although it is also substantially below normal (37).



Figure 4. AIRg over time in insulin independent subjects (n = 11) before and after islet transplantation. The number of subjects studied is shown across the top of the figure. Mean values ± SE are provided for each time point. All values of islet transplant recipients are significantly different from control subjects. Copyright 2002 American Diabetes Association from Diabetes, Vol. 51, 2002; 2148-2157. Reprinted with permission from The American Diabetes Association.



Complications of Islet Transplantation

Adverse events associated with islet transplantation are listed in Table 1. The most common procedure-related events are abdominal pain and nausea, occurring in over 50% of patients. A more severe complication is intraperitoneal hemorrhage, which has occurred in approximately 10% of recipients (39). The exact cause of bleeding in each case is often difficult to determine; however the peri-operative use of heparin to avoid portal vein thrombosis likely plays a role. The use of fibrin tissue sealant (Tisseel®, Baxter Corp., Mississauga, ON) and embolization coils in the hepatic catheter tract appears to be effective in minimizing bleeding risk (40). Portal hypertension can occur acutely during the islet infusion and peak pressures may increase with sequential infusions. However, beyond the acute phase of transplantation, portal pressures appear to normalize (41).



Table 1. Adverse Events Associated with clinical islet transplantation (approximate % incidence)

Procedure-related (%)

Immunosuppressive-related (%)

Elevated liver enzymes (54%)

Oral ulcers (96%)

Decline in GFR (50%)

Abdominal pain (50%)

Anemia (60%)

Proteinuria (50%)

Nausea/vomiting (50%)

Diarrhea (50%)

Peripheral edema (30%)

Fatty liver (long term) (20%)

Weight loss (50%)

Acne (10%)

Peritoneal hemorrhage (15%)

Fatigue (50%)

Tremor (<10%)

Portal vein thrombosis (4%)

LDL Elevation (50%)

Neutropenia (<10%)

Gall-bladder puncture (3%)

Hypertension (50%)

Misc. – Arthralgia, pneumonitis, hematuria, infection



Branch portal vein thrombosis has occurred in 4% of recipients. These thromboses have been limited in extent and have resolved with appropriate anticoagulation. While the risk of portal vein thrombosis can never be completely avoided, it is anticipated that the use of purer islet preparations, greater expertise in portal vein catheterization and improved anticoagulation regimens will continue to reduce this risk. Catheter-related puncture of the gallbladder (3%), and post-transplant elevation of liver enzymes (54%) also occur although these tend to be resolve without further intervention (37).


The most common adverse effect of immunosuppressive therapy is mucosal ulceration involving the tongue or buccal mucosa. It occurs in the vast majority (96%) of recipients and is presumed to be a consequence of sirolimus therapy. The ulcers tend to be dose-dependent, are generally superficial and self-limited. Rarely, more severe ulceration occur which can compromise oral intake or require surgical debridement. In such cases, careful monitoring of the patient’s nutritional and intravascular volume status and serum immunosuppressive levels are important to avoid further adverse consequences. Increased use of lipid-lowering therapy (pre-transplant: 12%; post-transplant: 50%) has also been observed. Initiation or increased use of antihypertensive agents has been required in approximately half of all patients. Post-transplant anemia is commonly

observed (> 50%). A reduction in total WBC count is also frequently seen (mean pre-transplant WBC: 6.2 ± 0.3 × 109; mean post-transplant WBC: 4.9 ± 0.3 × 109), but severe neutropenia (absolute count < 500 cells/μL) is uncommon (< 10% of patients). Weight loss is also commonly seen after transplant (mean pre-transplant weight: 70.3 ± 2.3 kg; mean post-transplant weight: 65.4 ± 2.3 kg) (37).


Another finding that has raised cautious concern is the appearance on magnetic resonance imaging (MRI) of intrahepatic periportal steatosis occurring in a minority of islet recipients (Figure 5) (42; 43). This finding is presumed to be due to the local effects of insulin from transplanted islets on cellular metabolism of surrounding liver parenchyma. A recent MRI survey of islet recipients indicates that such changes can be detected in approximately 20% of patients. These effects appear to be reversible, since complete resolution of MRI changes has been seen in a patient whose graft failed completely. These changes are also thought to be benign, but their significance on underlying hepatic metabolism is not known.


Figure 5. Magnetic resonance imaging (MRI): axial and coronal planes of the liver after islet transplantation. (A) In-phase T1 images, (B) out-of-phase T1 images demonstrating localized fatty changes within the liver (arrows). These changes are thought to be benign and resolve with loss of the islet graft. Copyright 2004 American Diabetes Association from Diabetes, Vol. 5, 2004: 1311-7. Reprinted with permission from The American Diabetes Association.



The impact of islet transplantation on diabetic microvascular complications remains uncertain. Tacrolimus (a calcineurin inhibitor) is known to be nephrotoxic and, in combination with sirolimus, may be partially responsible for a slight elevation of serum creatinine seen in patients after transplantation (mean pre-Tx creatinine: 80 μmol/l, range 69-90; mean post-Tx creatinine: 92 μmol/l, range 77-115). Among islet recipients using the Edmonton protocol at the University of Alberta, a reduction of creatinine clearance (pre-Tx: 1.8 ml/s per 1.73 m2; post-Tx: 1.6 ml/s per 1.73 m2, p = NS) has been seen. A reduction in glomerular filtration rate (GFR) has also been observed (GFR pre-transplant: 98 ± 2.9; 12 months post-transplant: 92 ± 4.1; 24 months post-transplant: 85 ± 5.1) (44). In prior studies of intensive insulin therapy in type 1 diabetes, worsening diabetic retinopathy has been well described (45; 46). It is unclear whether this is also the case after islet transplantation, although post-transplant retinal bleeds have been observed. However, because of the limited duration of follow-up, no firm conclusions can yet be drawn regarding the long-term effects of islet transplantation on chronic diabetic complications.


Infections are a recognized risk of long-term immunosuppression. The risk of severe infection in solid organ recipients appears to be related to the combination of surgical complications and/or nosocomial infection. Among islet recipients at the University of Alberta, a single presumed pulmonary fungal infection has been observed. The patient developed symptoms of cough and dyspnea and chest x-ray demonstrated a right-sided cavitating lesion. Cultures of blood and pulmonary washings were negative and the patient responded well to intravenous antifungal therapy with complete resolution of the lesion. Notably, very little CMV transmission has been seen (1; 47), even though the rate of recipient-donor CMV mismatch is high (80%). The low rate of CMV transmission may be due to the high degree of islet purification, which eliminates lymphocytes from the islet preparation, making CMV transmission less likely.


The risk of post-transplant malignancy is also of potential concern. Based on historical data in other transplant populations, the estimated risk squamous cell skin cancer is ~ 10% and post-transplant lymphoproliferative disorder (PTLD) ~ 1-2%. So far, the only malignancy detected has been a small papillary thyroid cancer in one recipient. It is not clear whether this neoplasm is immunosuppressive-related. A larger cohort and a longer period of follow-up will be needed to determine the true underlying risk of malignancy in this setting.


Islet Transplantation: Advantages and Disadvantages

There are a number of theoretical advantages to islet transplantation over multiple daily injection (MDI) insulin regimens for patients with type 1 diabetes. The most obvious benefit is the achievement of "physiologic" insulin secretion in those patients who are able to achieve insulin independence. Even before the landmark Diabetes Complications and Control Trial (DCCT), the challenge for most diabetic patients and their health care providers has been to maintain blood glucose levels as close to normal as possible while minimizing the risk of hypoglycemia (45). This balance has been difficult to achieve in many patients and the risk of severe hypoglycemia remains the major limiting factor in the management of type 1 diabetes (48). For this reason, the ability to replace destroyed beta cells and re-establish endogenous insulin secretion is an attractive solution.


Accordingly, the most immediate benefit of islet transplantation is stabilization of blood glucose (Figure 6). This effect is often observed after the first islet infusion, even though most recipients still require insulin at this stage. Presumably, the endogenous insulin secretion from their newly transplanted islets acts as a “buffer” for injected insulin, thereby reducing the amplitude of glycemic excursions. Among insulin-independent patients, glucose is even more stable, although glucose tolerance is usually not completely normal.


Figure 6. Representative continuous glucose monitor 72-hr glucose profiles demonstrating a marked improvement in glycemic stability post-islet transplant (B) compared to pre-islet transplant (A).



Compared to whole pancreas transplantation, islet transplantation offers some potential advantages. It is a much less invasive procedure and therefore is considered to be generally safer (49). Furthermore, islets have the potential to be manipulated in vitro prior to transplantation to possibly improve graft survival and function (50). However, the decline in insulin independence observed after islet transplantation has reduced the expectation that this technique in its current state can deliver long-term freedom from insulin in the majority of patients. Finally, although cadaveric islets are currently the mainstay of endocrine cell replacement, alternative cell sources, such as stem cells or cloned beta cells, hold great promise to provide a ready source of transplantable insulin-secreting tissue that would not be limited by the supply of donor organs (51-53).

A number of questions also remain regarding the physiologic impact of intrahepatically transplanted islets. It appears that alpha cells within transplanted islets may not respond appropriately to hypoglycemia (54) although mixed results have been seen (55). In the native pancreas, alpha cells secrete glucagon in response to hypoglycemia (plasma glucose < 60 mg/dl), this does not appear to occur in transplanted islets. A study comparing the glucagon response in intrahepatically-transplanted dogs with those transplanted in the gastric omentum demonstrated that glucagon secretion was absent in the intrahepatically-transplanted animals but intact in the omentally-transplanted ones (56). The physiologic explanation for this finding is not clear, although it may involve a failure of the intrahepatic site to adequately stimulate transplanted islets during periods of hypoglycemia. Clearly many unanswered questions remain regarding the physiologic impact of transplanted islets on glucose homeostasis and hepatic metabolism.


Who should get an Islet Transplant?

The criteria for selecting candidates for islet transplantation continue to evolve and the risk-benefit calculation for each patient remains somewhat subjective. In many respects, the current selection criteria are similar to those for whole pancreas transplantation (57). Since the procedural risks of islet transplantation are lower than that of pancreas transplantation, one could argue that the selection criteria could be less restrictive. Although, the post-transplant decline in insulin independence has made it more important to select candidates who will clearly benefit from a stabilization of glucose control, even if insulin independence is never achieved. Currently, three basic criteria are used for the selection of islet transplant candidates. These are: 1) frequent episodes of severe, undetected hypoglycemia, 2) severe glycemic lability, or 3) progressive diabetic complications, despite optimization of insulin injection therapy. The percentage of recipients meeting at least one of these criteria is listed in Table 2.



Table 2.  Selection criteria for islet transplant candidates at the University of Alberta

Selection Criteria

% Transplanted

Frequent Undetected Hypoglycemia


Glycemic Lability


Progressive Diabetic Complications




Of the three principle criteria, the first two are the most immediately correctable with islet transplantation (Figure 6). Glycemic lability and frequent severe hypoglycemia are generally eliminated after transplantation, even in those patients who do not achieve insulin independence. However, there appears to be a re-emergence of hypoglycemia in recipients who lose graft function (Figure 7) (58). The impact of islet transplantation on secondary diabetic complications remains unclear. Early reports from small, non-randomized series of patients suggest that there may be stabilization of diabetic retinopathy and neuropathy (59) and improvement in cardiovascular function in islet-after-kidney transplant recipients (60). However, the full impact of islet transplantation, especially in patients without kidney transplants, will require much longer follow-up to be clearly understood. Therefore, patient selection currently focuses on individuals with very labile glucose and/or frequent undetected hypoglycemia. In general, transplant candidates who meet only the "progressive complications" criterion without meeting at least one of the other two are not accepted for transplantation.


Figure 7. The HYPO score pre and post transplant in those who remain C-peptide positive. Pre-transplant n = 31, at one year n = 40, at two years n = 29, at three years n = 15, at four years n = 7and at 5 years n = 5. Copyright 2005 American Diabetes Association from Diabetes, Vol. 54, 2005; 2060-2069. Reprinted with permission from The American Diabetes Association.



To assess glycemic lability, the mean amplitude of glycemic excursion (MAGE) has been used, which compares the standard deviation of capillary glucose values measured seven times per day over a two-day period (61; 62). A MAGE score greater than ten is thought to represent poor glycemic control. The risk of hypoglycemia is also difficult to assess, since there is no objective standard by which it can be measured. Currently, clinical judgment, using the patient's blood glucose records and history of hypoglycemic events remain the best tools by which these risks can be judged. Recently a scoring system has been developed by which glycemic lability and hypoglycemia may be more objectively compared (63). Another method for assessing glycemic lability may be the continuous glucose monitor (64). It is anticipated that such methods will aid in the appropriate selection of islet transplant candidates.


Future directions for Islet Transplantation

The relative improvement in outcome for islet transplantation has led to an expansion of clinical islet transplant research worldwide. However, several major hurdles need to be overcome before islet transplantation can be more broadly applied in the treatment of diabetes. The continued general requirement for two donor organs for each islet recipient remains a major limiting factor (32). To this end, further developments in islet isolation technique will, no doubt, continue to improve islet yield. These include the use of a two-layer perfluorocarbon cold storage method for islets isolated from ischemically damaged pancreases (65), the use of antioxidants such as vitamin E to reduce oxidative stress during isolation (66), the use of protease inhibitors during the isolation process to avoid overdigestion of islets (67), and improved pancreas procurement techniques to reduce warm ischemic times (68). Improving initial islet engraftment by reducing early non-specific cytokine-mediated inflammation using agents such as infliximab (anti-TNF-α monoclonal antibody) and etanercept (anti-TNF-α fusion protein) is also a promising area of study.


The development of new immunosuppressive regimens also continues to progress. A recent study of combination therapy using everolimus (a TOR-inhibitor) and the experimental drug FTY-720 (instead of a calcineurin inhibitor) with basiliximab (an IL-2 inhibitor) induction, in non-human primates showed promising results (four out of five islet recipients were insulin free at six months) (69). Trials examining the efficacy of co-stimulatory blockade (blocking both direct and indirect alloantigen recognition pathways) using humanized anti-CD154 monoclonal antibody initially showed promising results in primates (70). However, the unusual occurrence of thromboembolic events in another trial in kidney transplant recipients led to halting further clinical trials using this agent until this issue can be resolved (71). Other selective co-stimulatory blockers that have been or are being studied are hCTLA4Ig (72) and LEA29Y (73). Similarly, potential tolerance-inducing agents such as the anti-CD52 monoclonal antibody Campath-1H (74) and the anti-CD3 monoclonal antibody OKT3 ala-ala have shown potential benefit in early diabetes prevention trials (75).


Stem cell research has also generated a great deal of interest for its immense potential as a possible unlimited source for transplantable insulin-secreting cells. Several studies have demonstrated that insulin-secretion can be induced from both embryonic stem cells (51; 76) and adult pancreatic ductal stem cells (77-79). While the clinical use of stem cells is not currently feasible, they have great potential to replace the use of cadaveric islets with potentially unlimited non-immunogenic cells (80; 81). Finally, islet encapsulation and xenotransplantation continue to be examined as potential means of overcoming the limited supply of donor islets. Although, the barriers to xenotransplantation are considerable, including immunological incompatibility and the potential transmission of zoonoses to human recipients.



Clinical islet transplantation can provide insulin independence in the majority of properly selected type 1 diabetic patients if an adequate transplant islet mass is infused, toxic immunosuppressive drugs such as glucocorticoids are avoided, and allo and autoimmune destruction of transplanted islets is minimized. However, the general requirement for at least two donor pancreases for each islet transplant recipient, suboptimal islet engraftment, a decline in islet function over time, and the lifelong need for immunosuppressive therapy continue to make this procedure unsuitable for the majority of type 1 diabetic patients.

For islet transplantation to become more widely utilized in the treatment of diabetes, the current severe lack of transplantable insulin-secreting tissue must be overcome. To accomplish this, the pancreas donor supply must be increased and in the future, alternative cell sources such as stem cells or animal-derived islets may also become available for transplantation. Furthermore, the efficacy and side effect profile of immunosuppressive agents must continue to be improved to enable consistent islet engraftment and fewer adverse effects in islet recipients. Despite these challenges, the recent progress that has occurred in the area of islet transplantation has reinforced the potential of endocrine cell replacement for the treatment of diabetes and given hope to many diabetic patients that they may one day be free from the risk of secondary complications and the daily burden of insulin injections.



Thanks to Dr. James Shapiro, Dr. Edmond Ryan, Dr. Peter Senior and Ms. Sharleen Imes for their valuable input


1. Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV: Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 343:230-238, 2000

2. Shapiro A, Ryan EA, Paty B, McDonald C, Senior P, McReady T, Oberholzer J, Kneteman N, Rajotte R, Bigam D, O'Kelly K, Lakey J: Three-year follow-up in clinical islet alone transplant with the Edmonton Protocol, and preliminary impact of infliximab and campath-1H. Am J Transplantation 3 (Suppl 5):296 (Abstract), 2003

3. Shapiro AM, Hering B, Ricordi C, Dimercurio B, Lindblad R, Cagliero E, Brendel M, Robertson RP, Berney T, Oberholzer J, Secchi A, Brennan D, Ramos E, Viviano L, Ryan E, Lakey J: International multicenter trial of islet transplantation using the edmonton protocol in patients with type I diabetes. Am J Transplantation 3 (Suppl 5):152, 2003

4. Petersson B: Isolation and characterization of different types of pancreatic islet cells in guinea-pigs. Acta Endocrinol (Copenh) 53:480-488., 1966

5. Noel J, Rabinovitch A, Olson L, Kyriakides G, Miller J, Mintz DH: A method for large-scale, high-yield isolation of canine pancreatic islets of Langerhans. Metabolism 31:184-187., 1982

6. Ricordi C, Finke EH, Lacy PE: A method for the mass isolation of islets from the adult pig pancreas. Diabetes 35:649-653., 1986

7. Rajotte RV, Warnock GL, Evans MG, Ellis D, Dawidson I: Isolation of viable islets of Langerhans from collagenase-perfused canine and human pancreata. Transplant Proc 19:918-922., 1987

8. Warnock GL, Cattral MS, Rajotte RV: Normoglycemia after implantation of purified islet cells in dogs. Can J Surg 31:421-426., 1988

9. Warnock GL, Cattral MS, Evans MG, Kneteman NM, Rajotte RV: Mass isolation of pure canine islets. Transplant Proc 21:3371-3372., 1989

10. Ricordi C, Lacy PE, Finke EH, Olack BJ, Scharp DW: Automated method for isolation of human pancreatic islets. Diabetes 37:413-420., 1988

11. Robertson GS, Chadwick DR, Contractor H, James RF, London NJ: The optimization of large-scale density gradient isolation of human islets. Acta Diabetol 30:93-98, 1993

12. Warnock GL, Kneteman NM, Ryan E, Seelis RE, Rabinovitch A, Rajotte RV: Normoglycaemia after transplantation of freshly isolated and cryopreserved pancreatic islets in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 34:55-58., 1991

13. Ricordi C, Rilo HL, Carroll PB, Fontes P, Shapiro R, Tzakis AG, Alejandro R, Bebhoo R, Rastellini C, Fung JJ, et al.: Human islet allograft follow-up: long-term islet function and over 3 years of insulin independence. Transplant Proc 26:569., 1994

14. Carroll PB, Ricordi C, Rilo HR, Fontes P, Khan R, Tzakis AG, Shapiro R, Fung JJ, Starzl TE: Intrahepatic human islet transplantation at the University of Pittsburgh: results in 25 consecutive cases. Transplant Proc 24:3038-3039., 1992

15. Ricordi C, Tzakis A, Carroll P, Zeng Y, Rilo HL, Alejandro R, Shapiro R, Fung JJ, Demetris AJ, Bereiter DR, et al.: Human islet allotransplantation in 18 diabetic patients. Transplant Proc 24:961., 1992

16. Scharp DW, Lacy PE, Santiago JV, McCullough CS, Weide LG, Boyle PJ, Falqui L, Marchetti P, Ricordi C, Gingerich RL, et al.: Results of our first nine intraportal islet allografts in type 1, insulin-dependent diabetic patients. Transplantation 51:76-85., 1991

17. Hering BJ, Browatzki CC, Schultz A, Bretzel RG, Federlin KF: Clinical islet transplantation--registry report, accomplishments in the past and future research needs. Cell Transplant 2:269-282; discussion 283-305., 1993

18. Brendel M, Hering B, Schultz A, Bretzel R: International Islet Transplant Registry. Giessen, Germany, University of Giessen, 1999

19. Hering BJ, Brendel MD, Schultz AO, Schultz B, Bretzel RG: International islet transplant registry newsletter. Giessen, Germany, Justus-Liebig-University of Giessen, 1996

20. Bretzel RG, Brandhorst D, Brandhorst H, Eckhard M, Ernst W, Friemann S, Rau W, Weimar B, Rauber K, Hering BJ, Brendel MD: Improved survival of intraportal pancreatic islet cell allografts in patients with type-1 diabetes mellitus by refined peritransplant management. J Mol Med 77:140-143., 1999

21. Maffi P, Bertuzzi F, Guiducci D, Socci C, Aldrighetti L, Nano R: Peri-operative management influences the clinical outcome of islet transplantation. Amer J Transplant 1:181, 2001

22. Bertuzzi F, Grohovaz F, Maffi P, Caumo A, Aldrighetti L, Nano R, Hengster P, Calori G, Di Carlo V, Bonifacio E, Secchi A: Successful transplantation of human islets in recipients bearing a kidney graft. Diabetologia 45:77-84., 2002

23. Ryan EA, Lakey JR, Rajotte RV, Korbutt GS, Kin T, Imes S, Rabinovitch A, Elliott JF, Bigam D, Kneteman NM, Warnock GL, Larsen I, Shapiro AM: Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. Diabetes 50:710-719., 2001

24. Delaunay F, Khan A, Cintra A, Davani B, Ling ZC, Andersson A, Ostenson CG, Gustafsson J, Efendic S, Okret S: Pancreatic beta cells are important targets for the diabetogenic effects of glucocorticoids. J Clin Invest 100:2094-2098., 1997

25. Olefsky JM, Kimmerling G: Effects of glucocorticoids on carbohydrate metabolism. Am J Med Sci 271:202-210., 1976

26. Fabian MC, Lakey JR, Rajotte RV, Kneteman NM: The efficacy and toxicity of rapamycin in murine islet transplantation. In vitro and in vivo studies. Transplantation 56:1137-1142, 1993

27. Paty BW, Harmon JS, Marsh CL, Robertson RP: Inhibitory effects of immunosuppressive drugs on insulin secretion from HIT-T15 cells and Wistar rat islets. Transplantation 73:353-357., 2002

28. Kneteman NM, Lakey JR, Wagner T, Finegood D: The metabolic impact of rapamycin (sirolimus) in chronic canine islet graft recipients. Transplantation 61:1206-1210, 1996

29. Chen H, Wu J, Xu D, Luo H, Daloze P: Rapamycin reverses acute heart, kidney, and pancreas allograft rejection and prevents accelerated heart allograft rejection in the rat. Transplant Proc 25:719-720., 1993

30. Watson CJ, Friend PJ, Jamieson NV, Frick TW, Alexander G, Gimson AE, Calne R: Sirolimus: a potent new immunosuppressant for liver transplantation. Transplantation 67:505-509., 1999

31. Groth CG, Backman L, Morales JM, Calne R, Kreis H, Lang P, Touraine JL, Claesson K, Campistol JM, Durand D, Wramner L, Brattstrom C, Charpentier B: Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation 67:1036-1042., 1999

32. McAlister VC, Gao Z, Peltekian K, Domingues J, Mahalati K, MacDonald AS: Sirolimus-tacrolimus combination immunosuppression. Lancet 355:376-377., 2000

33. Chang GJ, Mahanty HD, Quan D, Freise CE, Ascher NL, Roberts JP, Stock PG, Hirose R: Experience with the use of sirolimus in liver transplantation--use in patients for whom calcineurin inhibitors are contraindicated. Liver Transpl 6:734-740., 2000

34. Peltekian K, McAlister VC, Colohan S, Gao Z, Salazar AB, Bitter-Suermann H, MacDonald AS: De novo use of low-dose tacrolimus and sirolimus in liver transplantation. Transplant Proc 33:1341., 2001

35. Salazar A, McAlister VC, Kiberd BA, Bitter-Suermann H, Al-Kerithy MF, MacDonald AS: Sirolimus-tacrolimus combination for combined kidney-pancreas transplantation: effect on renal function. Transplant Proc 33:1038-1039., 2001

36. Strasser S, Alejandro R, Ricordi C, Todo S, Mintz DH: The effect of FK 506 on canine pancreatic islet cell function in beagle dogs. Transplant Proc 23:756-757., 1991

37. Fernandez LA, Lehmann R, Luzi L, Battezzati A, Angelico MC, Ricordi C, Tzakis A, Alejandro R: The effects of maintenance doses of FK506 versus cyclosporin A on glucose and lipid metabolism after orthotopic liver transplantation. Transplantation 68:1532-1541., 1999

38. Drachenberg CB, Klassen DK, Weir MR, Wiland A, Fink JC, Bartlett ST, Cangro CB, Blahut S, Papadimitriou JC: Islet cell damage associated with tacrolimus and cyclosporine: morphological features in pancreas allograft biopsies and clinical correlation. Transplantation 68:396-402., 1999

39. Lakey JR, Warnock GL, Rajotte RV, Suarez-Alamazor ME, Ao Z, Shapiro AM, Kneteman NM: Variables in organ donors that affect the recovery of human islets of Langerhans. Transplantation 61:1047-1053., 1996

40. Ryan EA, Lakey JR, Paty BW, Imes S, Korbutt GS, Kneteman NM, Bigam D, Rajotte RV, Shapiro AM: Successful islet transplantation: continued insulin reserve provides long term control. Diabetes 51:2148-2157, 2002

41. Bonner-Weir S: Beta-cell turnover: its assessment and implications. Diabetes 50 Suppl 1:S20-24., 2001

42. Owen RJ, Ryan EA, O'Kelly K, Lakey JR, McCarthy MC, Paty BW, Bigam DL, Kneteman NM, Korbutt GS, Rajotte RV, Shapiro AM: Percutaneous transhepatic pancreatic islet cell transplantation in type 1 diabetes mellitus: radiologic aspects. Radiology 229:165-170, 2003

43. Casey JJ, Lakey JR, Ryan EA, Paty BW, Owen R, O'Kelly K, Nanji S, Rajotte RV, Korbutt GS, Bigam D, Kneteman NN, Shapiro AM: Portal venous pressure changes after sequential clinical islet transplantation. Transplantation 74:913-915, 2002

44. Markmann JF, Rosen M, Siegelman ES, Soulen MC, Deng S, Barker CF, Naji A: Magnetic resonance-defined periportal steatosis following intraportal islet transplantation: a functional footprint of islet graft survival? Diabetes 52:1591-1594, 2003

45. Bhargava R, Senior PA, Ackerman TE, Ryan EA, Paty BW, Lakey J, Shapiro AM: Prevalence of hepatic steatosis after islet transplantation and its relation to graft function. Diabetes 53:1311-1317, 2004

46. Senior P, Zeman M, Paty B, Shapiro A, Ryan E: Renal outcomes after clinical islet allotransplantation at the University of Alberta - 4 year follow-up. Diabetes 53:A69 (Abstract 296-OR), 2004

47. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 329:977-986., 1993

48. Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol 116:874-886., 1998

49. Brendel MD, Hering BJ, Schultz AO, Bretzel RG: International islet transplant registry: Update of worldwide human islet transplantation (Abstract). In The XIX International Congress of The Transplantation Society Miami, FL, The Transplantation Society, 2002, p. 119

50. Hypoglycemia in the Diabetes Control and Complications Trial. The Diabetes Control and Complications Trial Research Group. Diabetes 46:271-286., 1997

51. Robertson RP, Davis C, Larsen J, Stratta R, Sutherland DE: Pancreas and islet transplantation for patients with diabetes. Diabetes Care 23:112-116, 2000

52. Kenyon NS, Harlan DM, Alejandro R, Ricordi C, Mintz DH: Islet Cell Transplantation. In Diabetes Mellitus: A Fundamental and Clinical Text LeRoith D, Taylor S, Olefsky JM, Eds. Philadelphia, Lippincott, Williams & Wilkins, 2000, p. 507-517

53. Lumelsky N, Blondel O, Laeng P, Velasco I, Ravin R, McKay R: Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science 292:1389-1394., 2001

54. Wakayama T, Tabar V, Rodriguez I, Perry AC, Studer L, Mombaerts P: Differentiation of embryonic stem cell lines generated from adult somatic cells by nuclear transfer. Science 292:740-743., 2001

55. Bonner-Weir S, Sharma A: Pancreatic stem cells. J Pathol 197:519-526., 2002

56. Stiller CR, Dupre J, Gent M, Jenner MR, Keown PA, Laupacis A, Martell R, Rodger NW, von Graffenried B, Wolfe BM: Effects of cyclosporine immunosuppression in insulin-dependent diabetes mellitus of recent onset. Science 223:1362-1367., 1984

57. Mahon JL, Dupre J, Stiller CR: Lessons learned from use of cyclosporine for insulin-dependent diabetes mellitus. The case for immunotherapy for insulin-dependent diabetics having residual insulin secretion. Ann N Y Acad Sci 696:351-363., 1993

58. Paty BW, Ryan EA, Shapiro AM, Lakey JR, Roberston RP: Hypoglycemic counterregulation and symptom recognition are not restored in insulin-independent islet transplant recipients. Diabetes, 2002

59. Gupta V, Wahoff DC, Rooney DP, Poitout V, Sutherland DE, Kendall DM, Robertson RP: The defective glucagon response from transplanted intrahepatic pancreatic islets during hypoglycemia is transplantation site-determined. Diabetes 46:28-33, 1997

60. Pancreas transplantation for patients with diabetes. Diabetes Care: Clinical Practice Recommendations 25:S111, 2002

61. Service FJ, Molnar GD, Rosevear JW, Ackerman E, Gatewood LC, Taylor WF: Mean amplitude of glycemic excursions, a measure of diabetic instability. Diabetes 19:644-655., 1970

62. Service FJ, O'Brien PC, Rizza RA: Measurements of glucose control. Diabetes Care 10:225-237., 1987

63. Paty BW, Ryan EA, Senior PA, McDonald CG, Shapiro AM: The continuous glucose monitor in the assessment of glycemic lability and hypoglycemic risk in islet transplant recipients. Diabetes 52(Suppl 1):A98 (Abstract), 2003

64. Ryan EA, Shandro T, Green K, Paty BW, Bigam D, Shapiro AM, Vantyghem M: Assessment of the severity of hypoglycemia and glycemic lability in Type 1 diabetic subjects undergoing islet transplantation.(Submitted), 2003

65. Deai T, Tanioka Y, Suzuki Y, Kuroda Y: The effect of the two-layer cold storage method on islet isolation from ischemically damaged pancreas. Kobe J Med Sci 45:191-199., 1999

66. Ching CD, Harland RC, Collins BH, Kendall W, Hobbs H, Opara EC: A reliable method for isolation of viable porcine islet cells. Arch Surg 136:276-279., 2001

67. Lakey JR, Helms LM, Kin T, Korbutt GS, Rajotte RV, Shapiro AM, Warnock GL: Serine-protease inhibition during islet isolation increases islet yield from human pancreases with prolonged ischemia. Transplantation 72:565-570., 2001

68. Lakey JR, Kneteman NM, Rajotte RV, Wu DC, Bigam D, Shapiro AM: Effect of core pancreas temperature during cadaveric procurement on human islet isolation and functional viability. Transplantation 73:1106-1110., 2002

69. Wijkstrom M, Kenyon NS, Kirchhof N, Kenyon NM, Mullon C, Lake P, Cottens S, Ricordi C, Hering BJ: Islet allograft survival in nonhuman primates immunosuppressed with basiliximab, RAD, and FTY720. Transplantation 77:827-835, 2004

70. Kenyon NS, Chatzipetrou M, Masetti M, Ranuncoli A, Oliveira M, Wagner JL, Kirk AD, Harlan DM, Burkly LC, Ricordi C: Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154. Proc Natl Acad Sci U S A 96:8132-8137., 1999

71. Kawai T, Andrews D, Colvin RB, Sachs DH, Cosimi AB: Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand. Nat Med 6:114., 2000

72. Levisetti MG, Padrid PA, Szot GL, Mittal N, Meehan SM, Wardrip CL, Gray GS, Bruce DS, Thistlethwaite JR, Jr., Bluestone JA: Immunosuppressive effects of human CTLA4Ig in a non-human primate model of allogeneic pancreatic islet transplantation. J Immunol 159:5187-5191, 1997

73. Adams AB, Shirasugi N, Durham MM, Strobert E, Anderson D, Rees P, Cowan S, Xu H, Blinder Y, Cheung M, Hollenbaugh D, Kenyon NS, Pearson TC, Larsen CP: Calcineurin inhibitor-free CD28 blockade-based protocol protects allogeneic islets in nonhuman primates. Diabetes 51:265-270, 2002

74. Graca L, Honey K, Adams E, Cobbold SP, Waldmann H: Cutting edge: anti-CD154 therapeutic antibodies induce infectious transplantation tolerance. J Immunol 165:4783-4786., 2000

75. Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L, Donaldson D, Gitelman SE, Harlan DM, Xu D, Zivin RA, Bluestone JA: Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 346:1692-1698., 2002

76. Soria B, Roche E, Berna G, Leon-Quinto T, Reig JA, Martin F: Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. Diabetes 49:157-162., 2000

77. Bonner-Weir S, Taneja M, Weir GC, Tatarkiewicz K, Song KH, Sharma A, O'Neil JJ: In vitro cultivation of human islets from expanded ductal tissue. Proc Natl Acad Sci U S A 97:7999-8004., 2000

78. Ramiya VK, Maraist M, Arfors KE, Schatz DA, Peck AB, Cornelius JG: Reversal of insulin-dependent diabetes using islets generated in vitro from pancreatic stem cells. Nat Med 6:278-282., 2000

79. Peck AB, Cornelius JG, Chaudhari M, Shatz D, Ramiya VK: Use of in vitro-generated, stem cell-derived islets to cure type 1 diabetes: how close are we? Ann N Y Acad Sci 958:59-68., 2002

80. Shamblott MJ, Clark GO: Cell therapies for type 1 diabetes mellitus. Expert Opin Biol Ther 4:269-277, 2004

81. Doyle MJ, Sussel L: Engineering islets: lessons from stem cells and embryonic development. Endocrinol Metab Clin North Am 33:149-162, 2004

82. Valdez-Gomzalaez RA, Elliot RB, Dorantes LM, Escobar L, Garibay GN, Bracho E, Macias C, Silva L, Copeman L, Valencia P, White DJ: Porcine islet xenografts can survive and function in type 1 diabetic patients in the presence of both pre-existing and elicited anti-pig antibodies. In Proceedings of The XIXth Annual International Congress of The Transplantation Society Miami, FL, 2002


Comments (0)

You don't have permission to comment on this page.