Islet transplantation a decade later and strategies for filling a half-full glass

Abstract

Alloislet transplantation for the treatment of type 1 diabetes enjoyed highly favorable status in the first half of the last decade but declined in favor during the second half. In this Perspective, I will briefly review the literature published in this area from 2000 to 2010 for the purposes of extracting lessons we have learned, considering whether the procedure should be deemed a partial success or a partial failure, and offering several strategies to improve alloislet transplantation outcomes in the future. In the end, I hope to strike a positive note about where this procedure is going, and how it will be applied to establish insulin independence in patients with type 1 diabetes.

FIG. 1.

General method of intrahepatic islet transplantation. Islets are removed from a donated pancreas by collagenase digestion, followed by purification to separate the islets from exocrine tissue. Islets are then infused by gravity into a catheter lodged in the hepatic portal vein. Blood flow within the vein carries the islets into the liver tributaries where they lodge within the sinusoids and establish vascular connections. Reproduced with permission from ref. .

FIG. 2.

Comparison of rates of progress of alloislet transplantation versus pancreas transplantation as therapy for type 1 diabetes. The first alloislet transplant to be reported as successful appeared in 1980, 20 years earlier than the Edmonton series was reported. The first pancreas transplant to be reported as successful appeared in 1966, 18 years earlier than the 1984–1987 series was reported. At 15 months post-transplant, the Edmonton series of alloislet transplants for the years 2000–2005 compared favorably with the success rate of pancreas transplants for the years 1984–1987. Data from refs. and .

FIG. 3.

Nondiabetic control subjects have plasma glucagon responses to insulin-induced hypoglycemia during a stepped hypoglycemic clamp. This response is absent in patients with type 1 diabetes as well as patients who have received successful intrahepatic alloislet or autoislet transplantation. Reproduced from ref. .

FIG. 4.

Restoration of absent glucagon responses to hypoglycemia from intraheptic islets in rats after prolonged fasting. Liver glycogen depletion caused by prolonged fasting results in restoration of the glucagon response to hypoglycemia. Absence of glucagon responses recurs after refeeding. This abnormality in α-cell function does not occur in fed animals if islets are placed into nonhepatic sites. Reproduced with permission from ref. . *P < 0.05–0.01.