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Pancreas and islet transplantation in diabetes mellitus

Pancreas and islet transplantation in diabetes mellitus
Author:
R Paul Robertson, MD
Section Editor:
Irl B Hirsch, MD
Deputy Editor:
Katya Rubinow, MD
Literature review current through: Dec 2022. | This topic last updated: Aug 26, 2022.

INTRODUCTION — The goal of transplantation in diabetes is to allow insulin independence, improve quality of life, and reduce secondary complications. Pancreas transplantation is most often performed with simultaneous kidney transplantation in selected patients with diabetes and end-stage kidney disease, who will already be required to take immunosuppressive therapy for the kidney graft [1]. Pancreas after kidney (PAK) and pancreas transplant alone (PTA) are performed less commonly. Islet cell transplantation is still under development but has been accepted by the transplant community as an efficacious method of restoring beta cell function and avoiding hypoglycemic reactions caused by exogenous insulin use in patients with 1 type diabetes.

This topic will briefly review the history, techniques, and clinical results of pancreas and pancreatic islet transplantation in hyperglycemic patients with longstanding type 1 diabetes mellitus, with a focus upon transplantation of islet or pancreatic tissue alone. Combined pancreas-kidney transplantation is discussed separately. (See "Pancreas-kidney transplantation in diabetes mellitus: Patient selection and pretransplant evaluation" and "Pancreas-kidney transplantation in diabetes mellitus: Benefits and complications".)

INDICATIONS FOR TRANSPLANTATION — The goals of transplantation are to restore glucose-regulated endogenous insulin secretion, arrest the progression of the complications of diabetes, and improve quality of life. Both pancreas and islet transplantation require lifelong immunosuppression to prevent rejection of the graft. Patients with end-stage kidney disease receiving simultaneous pancreas-kidney (SPK) or pancreas after kidney (PAK) transplants are already required to take immunosuppressive therapy for the kidney graft, and therefore the incremental effect of immunosuppressive therapy on quality of life is small. However, for patients receiving pancreas transplant alone (PTA), who have not yet developed advanced nephropathy, the benefit of preventing or slowing the progression of secondary complications must be balanced with the adverse effects of the immunosuppressive agents used in transplantation (eg, diarrhea, neutropenia, anemia, fatigue, hypertension, bone loss, susceptibility to infections and secondary cancers).

The American Diabetes Association (ADA) criteria for transplantation are as follows [2]:

SPK or PAK – Patients with type 1 diabetes and end-stage kidney disease who have had or plan to have a kidney transplant are candidates for pancreas transplantation. The successful transplantation of a pancreas will improve glycemia and may improve kidney survival. Most pancreatic transplants are performed in patients with diabetes and end-stage kidney disease. The majority of these patients receive SPK rather than PAK. (See "Pancreas-kidney transplantation in diabetes mellitus: Patient selection and pretransplant evaluation", section on 'Patient selection'.)

PTA – PTA is generally considered only in patients with serious progressive complications of diabetes in whom the quality of life is unacceptable. Such complications include:

A history of frequent, acute, severe metabolic complications (hypoglycemia, marked hyperglycemia, ketoacidosis)

Incapacitating clinical and emotional problems with exogenous insulin therapy

Consistent failure of insulin-based management to prevent acute complications

Islet – Islet transplantation is an evolving technology. This procedure is usually performed within the context of a controlled research study by experienced clinical transplant centers.

Pretransplant screening for cardiovascular disease in PTA is the same as for combined kidney-pancreas transplantation. (See "Pancreas-kidney transplantation in diabetes mellitus: Patient selection and pretransplant evaluation", section on 'Pretransplant evaluation'.)

PANCREAS VERSUS ISLET TRANSPLANTATION — There are no direct, randomized trials comparing the outcomes from whole organ versus islet transplantation. In addition, there are few observational studies comparing pancreas and islet transplantation procedures. In a report from a single center that performed 33 pancreas transplant alone (PTA) and 33 islet transplantation procedures, patients undergoing PTA had a higher rate of insulin independence (75 versus 57 percent) at an average of one-year follow-up [3]. The rate of long-term adverse events (length and frequency of hospitalization, reintervention for acute surgical or immunological complications, infections) was higher in the patients who received pancreas transplantation. In a second retrospective study comparing 15 PTA and 10 islet transplantation procedures, the rate of insulin independence at three years was similar (64 versus 70 percent) [4].

Data from pancreas and islet transplantation registries show a higher rate of insulin independence with pancreas transplantation (85 versus 50 percent at one year), but also a higher morbidity due to general surgery [5,6]. The islet transplantation procedure is less invasive, and therefore, it is associated with lower morbidity. However, rates of long-term success (defined by insulin independence) are lower. (See 'Outcomes' below and 'Metabolic outcomes' below.)

PANCREAS TRANSPLANTATION — Pancreas transplantation was first used for the treatment of diabetes in humans in 1966 [7]. The rates of graft and patient survival were low; as a result, very few procedures were performed in the early to mid-1970s. The subsequent introduction of better immunosuppressive regimens (particularly cyclosporine and anti-T-cell antibodies), new surgical techniques, and the selection of healthier recipients resulted in markedly improved outcomes. As a result, the number of pancreatic transplantations steadily increased each year in the United States, peaking at 1484 in 2004 [8,9]. In the United States during 2016, 791 simultaneous pancreas-kidney (SPK), 73 pancreas after kidney (PAK), and 73 pancreas transplant alone (PTA) transplants were performed [10]. The decrease in the number of pancreas transplants probably relates to improved results from insulin-based therapy since the Diabetes Control and Complications Trial (DCCT) findings and the consequently lower rates of secondary complications of chronic hyperglycemia.

Outcomes — The mortality, morbidity, and results of transplantation vary with operative experience and patient selection.

Patient survival

Based on 2004 to 2015 data, patient survival rates for SPK, PAK, or PTA ranged from 96 to 99 percent at one year, 89 to 91 percent at five years, and 70 to 80 percent at ten years postoperatively [10-12]. The majority of deaths in the first three months post-transplant and subsequently were due to cardiovascular or cerebrovascular disease.

There are few data on the survival benefit for transplanted compared with waitlisted patients. The following findings are based on retrospective analyses of transplantation registries from 1995 to 2003:

Survival for SPK recipients was much better than that of waitlisted patients who continue to receive dialysis [13]. The decreased mortality is due in part to the well-established survival benefit conferred by kidney transplantation alone (KTA; even without pancreas transplantation) compared with dialysis. (See "Pancreas-kidney transplantation in diabetes mellitus: Benefits and complications", section on 'Patient survival'.)

For PTA or PAK recipients, survival at four years was equivalent to that of patients on the waiting list (PTA 90.5 versus 87.3 percent for waitlisted patients, PAK 88.3 versus 81.7 percent) [13].

In another retrospective study of 11,572 patients with diabetes and preserved kidney function who were on a waiting list for pancreas transplantation, survival at four years was significantly worse for patients receiving PTA compared with waitlisted patients receiving conventional therapy (85.2 versus 92.1 percent) [14]. However, these data should be interpreted with caution as there could be important differences between the group transplanted with a pancreas alone and those on the waiting list (who, for example, may turn down a pancreas if feeling well) [15]. In addition, some patients from the waiting list group were counted more than once because they were registered on more than one list, and 8 percent of patients on the pancreas transplant waiting lists were removed from the waiting lists and underwent a kidney transplant first because of deteriorating kidney function. These differences could have biased the outcome of the study in favor of those on the waiting list.

Graft survival — Based on 2004 to 2015 data, early graft failure (within 90 days) occurred in approximately 8 to 9.4 percent of patients [10]. Five-year pancreas graft survival for SPK, PAK, and PTA was approximately 73, 65, and 53 percent, respectively [11]. Pancreas graft survival is inversely related to several donor variables, including age, body mass index, and cardiovascular death. Recipients of pancreas transplantation alone whose organs came from donors with poor donor risk indices had a lower rate of graft survival compared with recipients of SPK recipients (77 versus 88 percent at one year) [12,16].

The definition of pancreas graft survival has been variably defined by transplant centers (eg, persistence of complete insulin independence, persistence of C-peptide production) [11]. A consistent definition would strengthen future outcomes studies. In the United States, the United Network for Organ Sharing has proposed a new definition of graft failure (to be implemented in 2018), which includes the use of insulin ≥0.5 units/kg/day for 90 consecutive days [11,17].

In 2018, a classification of graft function was proposed by the International Pancreas and Islet Transplant Association and the European Pancreas and Islet Transplant Association [18]. The definitions are based on a combination of glycated hemoglobin (A1C), severe hypoglycemic events, insulin requirements, and C-peptide. With this proposed classification, optimal and good graft function are considered successful clinical outcomes.

Optimal graft function – Near-normal glycemic control (A1C ≤6.5 percent [48 mmol/mol]) without severe hypoglycemia or requirement for insulin or other antihyperglycemic therapy and with an increase in C-peptide compared with pretransplant.

Good graft function – A1C <7 percent (53 mmol/mol) without severe hypoglycemia and with a significant reduction in insulin requirements (>50 percent reduction, which should also be <0.5 units/kg/day) and an increase in C-peptide compared with pretransplant.

Marginal graft function – A1C ≥7 percent, the occurrence of any severe hypoglycemia, or less than a 50 percent reduction in insulin requirements, when there is an increase in C-peptide compared with pretransplant.

Failed graft – Absence of any evidence for clinically significant C-peptide production.

Metabolic effects — Both cross-sectional and prospective studies have shown that pancreatic transplantation can result in independence from exogenous insulin therapy and improvements in glucose metabolism, A1C values, acute insulin responses to intravenous glucose, and counterregulatory responses of serum glucagon and glucose to insulin-induced hypoglycemia [19-21]. These beneficial effects on glucose regulation, the result of restoring pancreatic islet function, are maintained for many years. Persistent improvement for 15 years is common in some centers [22].

Patients with well-functioning grafts have normal insulin responses to oral and intravenous glucose stimulation as well as to intravenous arginine and intravenous secretin [20,23-29]. However, owing to the systemic (rather than portal) venous drainage of the allograft basal and stimulated peripheral insulin concentrations are two to three times higher than normal [25,30]. Thus, the hepatic first-pass uptake and metabolism of insulin secreted into the portal vein are bypassed; in normal subjects, 50 to 90 percent of the insulin in portal venous blood undergoes first-pass hepatic degradation.

Post-transplantation hyperinsulinemia does not appear to have adverse effects on cardiovascular risk factors. Serum triglyceride and low-density lipoprotein (LDL) cholesterol concentrations tend to fall and serum high-density lipoprotein (HDL) cholesterol concentrations tend to rise in recipients of pancreatic transplants [31-33].

Glucose counterregulation after hypoglycemia is improved by pancreas transplantation [34-36]. This is an important benefit because patients who have had diabetes for many years before transplantation typically have abnormal glucose counterregulation due to decreased serum glucagon and epinephrine responses to hypoglycemia (see "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus"). The improvement in glucose counterregulation in recipients of pancreatic transplants is due to normalization of the glucagon counterregulatory response and improvement in the epinephrine counterregulatory response [36]. Recognition of symptoms of hypoglycemia also improves [36]. Hypoglycemia as a complication of pancreas transplantation has been reported [37], but it is usually mild [38].

Effects on the chronic complications of diabetes — The impact of successful pancreas transplantation and normalization of glycemia on the secondary complications of diabetes is reviewed briefly below and in detail elsewhere. Many of these studies involved patients who had undergone combined kidney-pancreas transplantation. (See "Pancreas-kidney transplantation in diabetes mellitus: Benefits and complications", section on 'Other potential benefits'.)

Following successful pancreas transplantation:

Recurrent and de novo diabetic nephropathy is prevented. PTA may reverse established diabetic lesions in patients with early diabetic nephropathy.

There is stabilization and, in some cases, improvement in peripheral and autonomic diabetic neuropathy.

The effect on diabetic retinopathy is not clear. While some studies have found no benefit in terms of halting or reversing the progression of advanced retinopathy after pancreas transplantation, other reports have noted stabilization or occasional regression of retinal lesions following successful pancreas transplantation.

Serum triglyceride and low-density lipoprotein (LDL) cholesterol concentrations tend to fall and serum high-density lipoprotein (HDL) cholesterol concentrations tend to rise.

Quality-of-life studies consistently demonstrate benefits, such as return to work and successful pregnancies, with no notable adverse effects on the fetus or the mother.

These findings regarding the effects of pancreas transplantation on diabetic microvascular disease must be interpreted in light of the fact that most patients undergoing pancreas transplantation have already had diabetes for over two decades and have advanced complications. Data are not available from prospective trials of patients undergoing pancreatic transplantation, compared with matched, stage-appropriate control populations.

Technique — The technique used for pancreas transplantation is the same whether or not a kidney is transplanted into the pelvic area at the same time. In the most common procedure, a whole pancreas, still attached to a small portion of the duodenum containing the ampulla of Vater, is taken from a cadaveric donor. The pancreas is placed laterally in the pelvis, with arterial anastomosis to a branch of the iliac artery and venous anastomosis to a branch of the iliac vein, which results in secreted insulin appearing first in the systemic (rather than the hepatic portal) circulation. A modification to this approach includes portal rather than systemic drainage of the endocrine pancreas.

The duodenal segment is connected to the urinary bladder or more commonly to a loop of bowel, which receives the pancreatic exocrine secretion. Bladder drainage has the advantage of providing a means to monitor urine amylase concentration to help detect allograft rejection but can also be complicated by metabolic acidosis, hematuria, and recurrent urinary tract infections. The native pancreas is left intact.

Although most patients receive a pancreas from a cadaver donor, occasional patients receive a segment of pancreas donated by a living-related donor who is willing to undergo a hemipancreatectomy [39].

Immunosuppression — Both pancreas and islet transplantation require lifelong immunosuppression to prevent rejection of the graft.

Conventional maintenance regimens consist of a combination of immunosuppressive agents that differ by mechanism of action. This strategy minimizes morbidity and mortality associated with each class of agent while maximizing overall effectiveness. Despite a diversity of protocols, most recipients of pancreatic transplants receive monoclonal or polyclonal anti-T-cell antibodies at the time of surgery and chronic immunosuppression therapy consisting of a calcineurin inhibitor (cyclosporine or tacrolimus) and an antimetabolite (mycophenolate mofetil or azathioprine). Since 2007, most patients have received tacrolimus and mycophenolate mofetil [10].

With the availability of new immunosuppressive drugs [40-43], some centers are performing pancreas transplants without antibody treatment, and avoidance of glucocorticoids is increasingly common [44-48]. Details concerning immunosuppressive regimens are discussed elsewhere. (See "Pancreas-kidney transplantation in diabetes mellitus: Surgical considerations and immunosuppression", section on 'Immunosuppression'.)

Causes of graft loss — The causes of pancreas transplant loss vary with the time after transplantation. Early graft loss, defined as loss occurring within hours or days after surgery, usually results from thrombosis, leaks, bleeding, infection, and pancreatitis (collectively referred to as technical failures). In one report of 211 patients undergoing pancreas transplant, technical graft failure occurred in 23 patients (11 percent), most commonly due to thrombosis [49]. Risk factors for technical failure included donor and recipient obesity and increased preservation time of the donor organ. Later graft loss after several weeks is more common and is most often caused by immunologic rejection [12,50].

Rejection — A transplanted pancreas can be rejected within days or after years of successful transplantation. Acute rejection of the pancreas is common, occurring in 60 to 80 percent of pancreas allografts [51,52]. Treatment involves hospitalization and intensive immunosuppressive therapy. The methods used to treat acute rejection of a pancreas transplanted alone are similar to those used to treat rejection of kidney-pancreas transplants. (See "Pancreas-kidney transplantation in diabetes mellitus: Patient selection and pretransplant evaluation".)

Detection — Detection of pancreas rejection is made easier when a kidney has also been transplanted. An important clinical observation in kidney-pancreas transplantation recipients is that rejection of the pancreas graft is uncommon in the absence of concurrent kidney graft rejection (≤15 percent), and it tends to lag in severity behind the kidney [53]. As a result, measurements of serum creatinine are used to monitor for possible acute rejection of both grafts in patients with a functioning renal allograft. A relatively small increment in the serum creatinine is typically the first clinical sign of renal allograft rejection, although nonimmunologic causes must be excluded. (See "Kidney transplantation in adults: Clinical features and diagnosis of acute renal allograft rejection".)

As mentioned above, detection of rejection is more difficult with PTA. In the patient with bladder drainage, the indexes of rejection are:

Decreasing urinary amylase excretion (from the donor exocrine pancreas)

Increasing serum amylase concentrations

Increasing blood glucose concentrations

All of these markers are less sensitive than an increase in serum creatinine when there is a concurrent renal allograft. In particular, a rise in fasting blood glucose concentrations is a relatively late indicator of allograft destruction, and increasing serum enzymes, such as amylase, are nonspecific indicators of rejection [54,55].

When rejection is suspected, a cystoscopic-guided transduodenal pancreatic biopsy is the procedure of choice [56,57].

ISLET TRANSPLANTATION — Islet transplantation has been performed in patients with type 1 diabetes and in patients with chronic pancreatitis. In contrast to patients with type 1 diabetes, patients with chronic pancreatitis undergo islet transplantation in conjunction with total pancreatectomy, with infusion of their own islets (auto-islet transplantation), which does not require treatment with immunosuppressive drugs. (See 'Chronic pancreatitis' below.)

Type 1 diabetes — The less invasive procedure of islet transplantation in humans with diabetes is hoped to be safer and less costly than pancreas transplantation [58,59]. Much effort has been expended to establish techniques to maximize the yield and quality of islets isolated from various sources. This has resulted in improved techniques for organ procurement and standardization of methods for islet isolation. Typically, 500,000 or more islets isolated from cadaver pancreases are infused via a percutaneous catheter that is introduced into the liver and advanced retrograde to the portal vein of the recipient.

Metabolic outcomes — In the ninth report from the Collaborative Islet Transplant Registry (CITR), which included information on 1011 islet allograft recipients (819 islet alone, 192 islet after kidney, performed between 1999 and 2013), approximately 50 percent of adults with type 1 diabetes who received islet transplantation (alone or after kidney) were insulin independent at one year with declining rates over time (30 percent [islet alone], 20 percent [islet after kidney] at five years) [5]. Since 2000, more effective and less toxic immunosuppressive drug regimens and improved harvesting techniques have been developed in association with a significantly increased success rate of islet transplantation.

When 677 islet allograft recipients were analyzed by year of transplantation (214 recipients 1999 to 2002, 255 recipients 2003 to 2006, and 208 recipients 2007 to 2010), 55 percent of recipients from the most recent era remained insulin independent at two years [60]. Rates of insulin independence at three years after transplant improved from 27 to 37 to 44 percent, with the proportion of recipients receiving sequential islet infusions decreasing from 60 to 65 percent to <50 percent in the most recent era (see 'Islet donors' below). Over three to five years of follow-up, near-normal glycemic control (indicated by A1C <6.5 percent) was maintained by approximately 60 percent of recipients across all eras. While >90 percent of patients were experiencing severe hypoglycemia prior to transplant, >90 percent remained free of severe hypoglycemia events in all eras through five years of follow-up [60].

Adverse events — At least 50 percent of islet recipients experience at least one adverse event [5,61]. Adverse events are related to immunosuppression (neutropenia, elevated liver function tests, elevated serum creatinine) and procedural complications (intraperitoneal bleeding requiring transfusion or laparotomy).

Although there were no post-transplantation deaths in a multinational study of 36 recipients, 38 serious adverse events occurred, and 18 required hospitalization [62]. Adverse events related to immunosuppression with sirolimus and tacrolimus were reported in all 26 diabetic patients undergoing allogeneic islet transplantation in one institution [63,64]. Four patients were withdrawn from immunosuppression due to serious toxicity; all patients experienced transient liver enzyme elevations, and most had sustained elevations in low-density lipoprotein (LDL) cholesterol.

Another potential consequence of islet transplantation is sensitization (development of donor specific antibodies) [61,65]. Because islets are obtained from multiple donors, islet transplant recipients are exposed to multiple human leukocyte antigen (HLA) mismatches. Multiple mismatches result in antibody formation, which may preclude the ability to undergo future transplantation (islet, kidney, pancreas) due to a decreased likelihood of finding a compatible graft.

In one series, 31 percent of islet transplant recipients developed new donor-specific HLA antibodies [65]. Discontinuation of immunosuppressants was associated with an abrupt rise in the appearance of HLA antibodies. Thus, the potential for an islet cell transplant to adversely affect the ability to receive a future transplant must be discussed routinely with all potential recipients.

Experimental techniques — Islet transplantation is an evolving therapy but has achieved its potential to reliably treat patients with severe hypoglycemia or labile type 1 diabetes. Techniques are being perfected to improve islet harvest, enhance engraftment, decrease apoptosis, use less toxic immunosuppressive regimens, induce immune tolerance, and noninvasively monitor islet cell fate after transplantation.

Islet donors — One of the limitations of islet transplantation is the need for multiple donors. Several studies suggest that insulin independence may be achieved with a single donor (as opposed to two to four donors) using fewer total islets [66-68]. In one report of eight patients, the improved success with fewer islets was attributed to an induction immunosuppression regimen that included antithymocyte globulin and etanercept (a tumor necrosis factor-alpha [TNFa] inhibitor) [68]. However, only obese donors (who have more islets than thin donors) were chosen in this study, and 10 of 18 of the donor pancreases still had to be discarded due to inadequate islet yield. Thus, the efficacy of single donor islet transplantation is still unproven.

Alternative islet sources — Harvesting sufficient numbers of healthy human pancreatic islets from cadavers is a major barrier to successful islet transplantation. Islets make up less than 2 percent of the mass of the adult human pancreas. Research is ongoing to identify alternative sources for beta cells.

Many studies, both in vitro and in vivo, have focused on identifying islet-producing stem cells and protocols to generate differentiated islets:

Transplantation of islets generated in vitro from cultures of mouse pancreatic ductal cells into diabetic mice resulted in reversal of insulin-dependent diabetes [69].

Human embryonic stem cells have been induced to differentiate in vitro into endodermal cells [70,71]. After implantation into mice, these cells generated glucose-responsive, insulin-producing cells [72]. Hypothetically, these endodermal cells could be further stimulated to differentiate into insulin-secreting beta cells in vitro, potentially producing the large quantities of beta cells needed for successful islet transplantation [73].

One group was able to demonstrate endocrine differentiation of nonendocrine pancreatic epithelial cells (NEPECs), transplanted along with fetal pancreas cells, into immunodeficient mice [74]. Insulin production was hypothesized to arise from endocrine stem or progenitor cells contained within the epithelial portion of the pancreas.

Injection of spleen cells together with an immune adjuvant into diabetic mice resulted in reversal of type 1 diabetes; the spleen was postulated to be a source of islet stem cells [75]. Subsequent studies, using the same immune adjuvant regimen (complete Freund's adjuvant), have successfully reproduced reversal of type 1 diabetes in up to 32 percent of the diabetic mice treated [76-78]. However, these investigators were unable to demonstrate evidence of allograft spleen cell survival and postulate that the immunosuppressive treatment allowed proliferation of small numbers of remaining islets in the mouse pancreas.

Before stem cell-derived beta cells can be considered for use in human trials, it will need to be demonstrated that such cells will provide normal physiologic responses to changes in glucose, will maintain genetic stability after transplantation, and will not be teratogenic [79].

Xenotransplantation — Xenotransplantation of islets has also been evaluated. Intraportal transplantation of islets cultured from pigs into diabetic nonhuman primates (macaques) treated with monoclonal antibodies to suppress T cell activation led to reversal of diabetes for over 100 days [80]. Significant morbidity was associated with the immunosuppression regimen used, and clinical potential for xenograft islet transplants remains uncertain.

Engraftment site — The majority of islet transplantations are performed via infusion into the portal vein with subsequent engraftment in the liver. Several findings, in addition to the risk of bleeding during intraportal catheterization, suggest that the liver may not be the optimal site for islet infusion [58]:

Intrahepatic islet transplant grafts (auto- or allografts) are unable to secrete glucagon in response to sustained hypoglycemia, though they can respond to an arginine stimulus [81-83]. One possible explanation for this defect in alpha cell production of glucagon is that the intrahepatic alpha cells do not perceive hypoglycemia, because they are flooded by free glucose secondary to hypoglycemia-induced increases in glycogenolysis. For this reason, some advocate use of nonhepatic as well as hepatic sites for islet transplantation, with the goal of preserving alpha cell function to protect the recipient from severe hypoglycemia [84].

Intrahepatic islets are exposed to environmental toxins and high immunosuppressive drug concentrations that can impair beta cell function.

Islets for intrahepatic infusion must be purified to avoid injecting a large tissue volume into the liver (which may result in obstruction of portal flow and portal hypertension). However, roughly 50 to 70 percent of the islet mass can be lost during the purification process.

Alternate sites, such as the omentum, peritoneal cavity, or bone marrow, are being considered to avoid some of these issues [83,85-87].

Microencapsulation — Techniques to provide immunoisolation for transplanted islets are also under investigation. As an example, microencapsulation is a process whereby individual islets are surrounded with thin membranes that are permeable to insulin but not to native antibodies. Microencapsulation may reduce the need for immunosuppressive agents [88]. However, there are still many unsolved technical issues with the process of microencapsulation, including the ability of cytokines to freely pass through the membrane and damage transplanted islets.

One group of researchers has treated two type 1 diabetic patients with a preparation of microencapsulated human islets injected into the peritoneum [89]. These patients were not treated with immunosuppressive medications. At six-month and one-year follow-up, C-peptide was detectable in both patients; they continued to require exogenous insulin, but overall metabolic control of their diabetes improved, with a decrease in hypoglycemic episodes.

Monitoring islet engraftment — Islet transplantation results in transient insulin independence. The fate of infused donor islets is poorly understood. A method of monitoring islets after transplantation would provide information on the accuracy of infusions, success of early engraftment, and long-term survival. In a small number of patients, scanning with positron-emission tomography (PET) combined with computed tomography (CT) allowed visualization of islet survival and distribution after transplantation [90]. This technique may be useful for evaluating alternative sites of implantation or for developing strategies to improve intrahepatic transplantation.

Magnetic resonance imaging (MRI), when combined with a process called magnetoencapsulation, may also be useful for monitoring islet cell survival [91]. Magnetoencapsulation is a technique that simultaneously provides immunoisolation and magnetic resonance tracking of grafted cells. In animal studies, islets incorporated into magnetocapsules and infused intraperitoneally were shown to be functional [91]. In separate animal studies, magnetocapsules infused into the portal vein under real-time MRI monitoring were visualized as areas of hypointensity within the liver, which can be followed longitudinally to determine graft survival [91]. In human studies, laboratory measurements of beta cell mass prior to islet implantation correlated highly with measures of insulin secretory reserve post-transplantation using the clinical technique of glucose potentiation of arginine-induced insulin secretion [92].

Chronic pancreatitis — Common consequences of chronic pancreatitis include severe chronic abdominal pain, weight loss, diarrhea, poor quality of life, and narcotic use. Progressive inflammation of acinar tissue may affect endocrine tissue function, thereby progressively damaging the islets of Langerhans, resulting in diabetes. The course of the disease is often punctuated by repeated pancreatic duct stenting and/or partial pancreatectomy. Some patients undergo total pancreatectomy for pain relief, which leads to immediate and total insulin-deficient diabetes. In the 1980s, surgeons at the University of Minnesota reasoned that the resected pancreas could be used for islet isolation and infusion of the islets into the patients' liver to effect auto-islet transplantation that would prevent onset of diabetes [93]. Auto-islet transplantation does not require treatment with immunosuppressive drugs.

Metabolic outcomes

Insulin independence – In contrast to most early studies of transplantation of islet allografts in patients with diabetes, islet autograft transplantation has been successful in nondiabetic adults and children with chronic painful pancreatitis [93-95]. Many islet autograft recipients have normoglycemia and normal serum insulin responses to oral and intravenous glucose and intravenous arginine soon after transplantation. These outcomes can last for many years after transplantation [94,96,97].

In an initial series, 10 of 14 patients receiving more than 300,000 islets were insulin independent two years after transplantation [98], a finding verified by a later series in a much larger group of recipients [99]. The magnitude of beta function after total pancreatectomy and islet autotransplantation (TPIAT) has been shown to be similar to that of normal individuals when the secretion data are normalized to the number of islets transplanted [92]. Differences in outcomes can be explained by the following factors:

Use of freshly isolated islets (often within three to four hours of pancreas resections) as opposed to the longer periods of time required to harvest islets from human donors

Absence of underlying autoimmune disease directed at beta cell destruction, as is present in type 1 diabetes

Absence of the need for immunosuppressive drugs, which are often toxic to beta cells

Hypoglycemia – Patients who undergo TPIAT very frequently experience bouts of hypoglycemia associated with exercise and meals [84]. One study reported a lack of glucagon responses during an insulin clamp and hypoglycemia, as was earlier reported in type 1 diabetic recipients of allo-islet transplants [100]. This lack of glucagon responses was not observed in a subgroup of patients whose auto-islets were placed into both intrahepatic and nonhepatic sites. The mechanism of the failure of intrahepatic islets to secrete glucagon during hypoglycemia may therefore be related to intrahepatic glycogenolysis and release of free glucose intrahepatically that inhibited release of intrahepatic islet glucagon [83]. In subsequent studies of intrahepatic auto-islet recipients, there was no increase in endogenous glucose production during moderate exercise [101], and the glucagon response was absent during postprandial hypoglycemia [102].

SUMMARY

The goals of transplantation are to restore glucose-regulated endogenous insulin secretion, arrest the progression of the complications of diabetes, and improve quality of life. (See 'Introduction' above.)

Transplantation is generally considered only in patients with serious progressive complications of diabetes in whom the quality of life is unacceptable. This includes patients with end-stage kidney disease who have had or plan to have a kidney transplant. The successful simultaneous transplantation of a pancreas will improve glycemia and may improve kidney survival. (See 'Indications for transplantation' above.)

Patients without substantial renal disease are candidates for pancreas transplantation alone if they have a history of frequent, acute, severe metabolic complications (hypoglycemia, marked hyperglycemia, ketoacidosis); incapacitating clinical and emotional problems with exogenous insulin therapy; and consistent failure of insulin-based management to prevent acute complications. (See 'Indications for transplantation' above.)

Islet transplantation is an evolving technology. The procedure is usually performed within the context of a controlled research study. (See 'Indications for transplantation' above.)

Keeping in mind that there have been no direct, randomized trials comparing the outcomes from whole organ versus islet transplantation, pancreas transplantation appears to have a higher rate of insulin independence than islet transplantation. Whole organ transplantation is associated with higher morbidity due to general surgery than islet transplantation, which remains an experimental procedure in the United States. (See 'Pancreas versus islet transplantation' above.)

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Topic 1767 Version 23.0

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