One More Step Along the Road

Diabetes mellitus (DM) is a multifactorial metabolic disorder resulting in insulin deficiency. Insulin injections, the only life-sustaining therapy available for ∼70 years since Banting, Best, and Collip (1) discovered and purified insulin in 1921–22, ameliorated the outward symptoms of type 1 DM. Soon it became apparent that DM was really a chronic illness with long-term complications like retinopathy, nephropathy, neuropathy, and vasculopathy. Whole organ pancreas or purified islet transplantation ameliorated diabetes and restored stable metabolic glucose control in type 1 diabetic patients. Currently, the 1-year survival rate after simultaneous kidney/pancreas transplantation stands at 95% for patients, 89–92% for kidney, and 85–87% for the pancreas; pancreas graft survival rates are ∼70% at 5 years and ∼ 50% at 10 years (2). In comparison with whole organ transplants, islet transplantation is a much safer transplant procedure but early outcomes showed a very low islet graft survival period. A landmark study published by Shapiro et al. in 2000 reported a new approach to islet transplantation (3). The Edmonton group had made many improvements to the islet isolation process and infusion technique into the liver. They also enrolled a different patient group into their transplant program: nonuremic type 1 diabetic patients with labile diabetes who suffered from severe hypoglycemic unawareness. Seven consecutive patients were grafted with >10,000 islet equivalents per kilogram of body weight, administered into the liver as two or even three infusions. The islets were isolated from sequential donors and prepared in the absence of xenogeneic proteins. The immunosuppressive protocol included monoclonal antibody induction therapy and was steroid free. This protocol achieved insulin independence in all seven patients at 1 year and was heralded as the beginning of a new era for islet grafting. Following this promising success, new islet transplant centers were formed in Europe and North America and state-of-the-art islet isolation units were built; an International Multi Centre Trial confirmed the reproducibility of the Edmonton protocol and consequently high rates of 1-year graft survival and insulin independence have been reproduced in several experienced centers. Over 500 islet transplants were performed worldwide over the next few years resulting in further advances in islet isolations, implantation procedures, and immunosuppressive protocols. Recent results of a 5-year follow-up of the Edmonton patients (4) showed that only a small proportion of patients were still insulin independent (∼10%) and that most patients needed exogenous insulin therapy to control their glucose levels. Despite this partial islet graft function shown by C-peptide secretion, labile diabetes and hypoglycemic events were much reduced compared with patients who had lost all graft function. Similar results were reported from other transplant centers in North America and Europe. In this issue of Transplantation, Badet et al. report the outcome of a phase 1–2 clinic trial study of islet transplantation in patients with brittle diabetes. This data comes from a European single islet isolation center with five remote transplant and follow-up centers. Pancreata and purified islet tissue were transported between these centers. The primary outcome of achieving insulin independence over a period of 2 years was not achieved in all patients but the secondary outcome of successful metabolic control as measured by a composite score was reached. Measurements of hypoglycemic score and the beta score, as recommended by the Edmonton group, as well as real-life metabolic profiles, are reported and related to islet numbers transplanted after first and second grafts. Unfortunately, quality-of-life data is not included in this article and but will be published elsewhere. The current main indications for solitary islet transplantation are labile diabetes with proven recurrent hypoglycemic events requiring frequent hospitalization and absence of the usual warning signs of impeding hypoglycemia. The goal of islet transplantation for this condition, long-term (>5 years) insulin independence, has been achieved only in a small number of patients worldwide, but perhaps insulin independence should not be the main goal. With a fully functioning islet graft—but more importantly, also with a partial functioning islet graft—insulin supply is still under physiological control and thus the occurrence of hypoglycemia is greatly diminished. A single infusion with highly functioning islets isolated from one donor could achieve insulin independence, as described by Hering et al. (5), but could also entail sufficient islet mass to give adequate glucose control if it is followed with aggressive exogenous insulin therapy and dietary restrictions to support this marginal islet mass. But major immunosuppressive agents like FK506 and CyA have a proven record of diabetogenicity and may confound the problem of limited islet mass and insulin storage capacity, resulting in islet exhaustion and potential disruption of insulin synthesis. New and different immunosuppressive agents with fewer side effects are entering clinical pilot trials and may prove to be more effective and less toxic in islet transplantation. Other hurdles to islet survival and function—such as undiagnosed acute and chronic rejection, recurrent autoimmunity, or failure of long-term islet regeneration, mostly due to immunosuppressive agents—need to be overcome because they are likely to result in further deterioration of function. Currently, the major benefits of a functioning graft in nonuremic patients are improved glycemic control and reduction of hypoglycemic attacks, the stabilization of HbA1c, no more insulin injections, and renewed quality of life. This has to be weighed against the increased risk of infection, the risk of adverse renal outcomes (6), and malignancy from potent immunosuppressive therapy needed to suppress allograft rejection. Are patients aware that multiple insulin injections may still be necessary and dietary restriction may still apply just to keep the surviving, marginal islet mass functioning for a longer period? Moreover, islets are infused into the portal vein and washed into the liver—directly into the “lion's mouth,” an organ full of dendritic cells, Kupffer cells, macrophages, and other immune cells, only too keen to clear up dead, disrupted, or slightly damaged tissue. Some marginally surviving tissue may be cleared away in a “bystander” action. The liver is also the main site of accumulation of toxic substances for clearance, some of which may be specifically toxic to islets. Other implantation sites may be better adjusted to accommodate the islet tissue with respect to revascularization and oxygen supply, preventing necrosis of larger islets. Infusions of small islets may be more able to survive in the liver and, because the islets are infused into the portal vein, blockage of the sinusoids by large islets can potentially result in many small foci of thrombosis within parts of the liver in contrast to smaller islets. These factors need to be fully discussed with prospective islet transplant candidates. The report in Transplantation discusses these issues. It may spark further discussions and decision making in the transplant community of the merits of repeated islet transplantation for patients with hypoglycemic unawareness. The introduction of the Edmonton protocol and the many improvements made over the last 5 years by other transplant centers has improved islet transplantation dramatically and given a better quality of life to many patients. Now we need to improve and optimize the long-term success—not only one more but, unfortunately, several more steps along the steep and stony road ahead.

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