Islet Transplantation for Hypoglycemia Unawareness/Severe Hypoglycemia: Caveat Emptor.

Abstract

Current estimates are that 1.25 million Americans have type 1 diabetes (T1D) (1) caused by the gradual loss of nearly all pancreatic insulin-producing b-cells via a presumed T cell–mediated autoimmune process (2). Eventually, all with T1D display severely impaired endogenous insulin production (3) and are dependent upon injected insulin for survival. Because subcutaneously administered insulin displays sluggish “on” and delayed “off” kinetics compared with that from pancreatic b-cells, the glycemic control patients achieve using subcutaneous insulin is suboptimal. For too many individuals, chronic episodic hypoglycemia dulls the typical compensatory responses, leading to impaired hypoglycemia awareness. Absent the usual warning symptoms of a blood glucose too low to sustain higher cognitive functions, such individuals are susceptible to severe hypoglycemic events defined as those requiring assistance from others to recover. Some die as a result of severe and prolonged hypoglycemia (4). Severe hypoglycemia occurs with alarming frequency among patients with T1D (5). Scientists have long dreamed of restoring endogenous insulin production for those with T1D. One approach has been allogeneic pancreas transplantation. However, most pancreatic tissuemakes digestive enzymes, and any damage to the organ can lead to leakage and potentially serious complications. In the 1970s, investigators reasoned that isolated pancreatic islets (only about 2% of the pancreatic mass) might be transplanted via a percutaneous cannula avoiding surgical and other complications associated with pancreas transplantation (6). Early clinical islet transplantation results, however, were disappointing (7). Then in 2000, Shapiro et al. (8) reported seven consecutive T1D patients achieving 1-year insulin independence following islet transplantation, but serious issues remained. For instance, the only currently viable islet source is cadaveric donors. In 2015, the U.S. had only ;9,000 such donors, of which ;1,300 were deemed suitable for pancreas transplantation (9). Also, islets suitable for transplant are successfully isolated from approximately one-half of the donated organs, and many individuals with T1D receive islets from two or more donors. Even if all cadaveric pancreata were assigned for islet transplantation, on the basis of organ donor supply and other limitations, the procedure might benefit;2.000 U.S. patients each year. Moreover, islets are highly vascularized.Withwhole-pancreas transplantation, the donor organ is immediately revascularized, whereas isolated islets are separated from their vascular supply and take weeks to revascularize after transplantation (10). These and probably other factors (11,12) result in many transplanted isolated islets dying shortly after their infusion such that the recipient’s glycemic control is neither as robust or as long lasting as that achieved by pancreas transplantation. Last, recipients with T1D require immunosuppression to prevent both allograft rejection and recurrent anti–b-cell autoimmunity. The current standard treatment uses calcineurin phosphatase inhibitors with associated toxicities, e.g., an increased risk for infections and some cancers and too often progressive renal dysfunction (13). The critical question then is, “Can a cohort with T1D and recurrent severe hypoglycemia be identified with sufficiently high morbidity and mortality to justify the known risks associated with a transplant-based approach?” One large study evaluating whether pancreas transplantation improved survival for patients with T1D found a very Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Medical School, Worcester, MA

DOI: 10.2337/dci16-0008

1 Figure or Table

Cite this paper

@article{Harlan2016IsletTF, title={Islet Transplantation for Hypoglycemia Unawareness/Severe Hypoglycemia: Caveat Emptor.}, author={David M. Harlan}, journal={Diabetes care}, year={2016}, volume={39 7}, pages={1072-4} }