Challenges facing islet transplantation for the treatment of type 1 diabetes mellitus

Abstract

Islet transplantation represents a most impressive recent advance in the search for a type 1 diabetes mellitus cure. While several hundred patients have achieved at least temporary insulin independence after receiving the islet "mini-organs" (containing insulin-producing β cells), very few patients remain insulin independent beyond 4 years after transplantation. In this review, we describe historic as well as technical details about the procedure and provide insight into clinical and basic research efforts to overcome existing hurdles for this promising therapy.Worldwide, more than 750 individuals with type 1 diabetes mellitus (T1DM) have received allogeneic islet transplants since 1974, in an effort to cure their chronic condition. Though this is still a small number (especially when compared with the estimated 1 million afflicted with T1DM and an additional 17 million with type 2 diabetes in the US, not to mention the estimated 140 million with diabetes worldwide), much has been learned, especially since the promising results of the Edmonton group were published in 2000 (1, 2). This report described 7 consecutive patients with T1DM who became insulin independent after receiving islet allografts, which reflects a success rate never previously achieved. The initial enthusiasm over the observation that islet transplantation can restore insulin-independent euglycemia to patients with long-standing T1DM has been dampened by complications associated with the procedure itself and the immunosuppression necessary to prevent rejection of the transplanted islets, as well as by the gradual loss of islet function and other problems arising from the placement of allogeneic islets in the liver (3, 4).At the same time, our understanding about the natural history of T1DM has changed. Epidemiological data indicate that the prognosis for survival among patients with T1DM is good and improving (5-7). Additional evidence strongly suggests that a significant minority with even long-standing T1DM continue to display islet function (8). For instance, we found that at least 40% of individuals with chronic T1DM (mean duration of 23 years) screened for our islet transplantation protocol had measurable circulating C-peptide levels, an equimolar by-product of endogenous insulin production (B.J. Digon et al., unpublished results). Similar percentages of patients with persistent C-peptide secretion have been documented in the literature (9-11), contrasted by a smaller number of individuals (11%) reported in the Diabetes Control and Complications Trial (12). Further, old (13) as well as more recent sporadic case reports (14) and other small studies (15) have suggested that diabetes can sometimes resolve and/or that pancreatic insulin production can at least be promoted in patients with longstanding T1DM. These studies have raised heretofore underexplored avenues for clinical investigation, which we will return to. Brief historyIn 1924, after approximately 40 years of unsuccessful attempts by various investigators to control diabetes using pa...

Facilitating Physiologic Self-Regeneration: A Step Beyond Islet Cell Replacement

“…The authors also reported that, BWithout further treatment, HbA 1c , and fasting glucose levels remained normal throughout the entire follow up of currently 4.5 years,'' and that serum autoantibodies to GAD65, IA-2, insulin, and ICA Bwere initially positive but showed a progressive decline or loss during follow-up.'' A similar case was recently reported by Rother and Harlan (15).…”

“…Islet transplantation can be carried out under local anesthesia using a relatively simple and low-risk procedure that a larger number of potential recipients can tolerate safely. In light of the proven feasibility of islet transplantation in animals and autotransplantations to prevent diabetes in patients in whom the pancreas had to be surgically removed, approximately 750 patients with T1D received allogeneic islet transplants between 1974 and 2000 (15).…”

“…For example, regeneration of endocrine pancreas function has been documented after partial pancreatectomy, and in streptozotocin (STZ)-treated animal models, including mice (39) and rats (40Y42), and there are sporadic reports involving spontaneous remission in T1D patients (15,43), as well as evidence for islet neogenesis in nondiabetic obese adult individuals (44). The potential of the pancreas to heal itself seems to be more efficient once autoimmunity is controlled (45).…”

Translational Molecular Imaging of Diabetes

“…However, the promise of allogeneic islet transplantation has been hindered by immunologic damage and death from hypoxia, the requirement for post-transplant immunosuppression, and limited supply of pancreatic islets [64]. Even with improved protocols, long-term survival of the grafts is bleak, with most recipients requiring additional exogenous insulin therapy or a second transplant within a short time to meet their metabolic needs [65].…”

Cystic cholangiomas after transplantation of pancreatic islets into the livers of diabetic rats

“…Recent advances in immunosuppressive regimens, beginning with a glucocorticoid-free therapy established by the Edmonton Group in Canada [51] and improved islet preparation techniques have meanwhile substantially contributed to the excellent long-term metabolic control in transplanted patients [46][47][48][49]. More than 750 patients have been treated so far, and further improvement of the immunosuppression protocols to reduce the risk of complications is one of the major future challenges [46,47].…”