Beta cell transplantation and immunosuppression: can't live with it, can't live without it.
ABSTRACT Since the first diabetic was treated with insulin in 1922, millions of patients have relied on frequent insulin injections and glucose monitoring to combat the disease and its complications. Improved immunosuppressive regimens in islet transplantation developed in the Edmonton protocol raised the hopes of diabetics worldwide for a complete cure and insulin independence. However, transplant success has proven to be short-lived and accompanied by significant side effects. Using a clever genetic model for conditional ablation of pancreatic beta cells in vivo, Nir and colleagues show in this issue of the JCI that the immunosuppressant drugs clinically inhibit beta cell proliferation in the diabetic setting (see the related article beginning on page 2553). They also demonstrate that beta cells have a remarkable regenerative capacity and that normal beta cell mass can recover even in the setting of hyperglycemia. Their new mouse model should aid in the development of improved immunoregulatory strategies and in the elucidation of the molecular pathways that govern beta cell regeneration.
Full-textDOI: · Available from: Klaus H Kaestner, Jan 06, 2014
- SourceAvailable from: ncbi.nlm.nih.gov[Show abstract] [Hide abstract]
ABSTRACT: Transplantation of human pancreatic isolated islets can restore beta-cell function but it requires chronic immunosuppression. The outcome of islet transplantation mainly depends on both the quality of islet preparations, and the survival of the graft. The quality of islet preparations can be evaluated by the results of isolation, which determines the chance to achieve insulin independence. The survival of islet grafts is reflected by the amount of engrafted functional tissue that maintains metabolic control. Immunosuppressive therapy prevents the immunological rejection of grafts, but impairs their function and impedes their regenerative capacity. Therefore, the selection of high quality islet preparations and the reduction of toxic effects of immunosuppressive regimens might dramatically improve the outcomes. The application of stem cell therapy in islet transplantation may contribute to a better understanding of the mechanisms responsible for tissue homeostasis and immune tolerance. Xenogeneic islets may serve as an unlimited source if immune tolerance can be achieved. This may be a strategy to enable a substantial improvement in function while overcoming potentially deleterious risks.The Review of Diabetic Studies 02/2008; 5(3):136-43. DOI:10.1900/RDS.2008.5.136
- [Show abstract] [Hide abstract]
ABSTRACT: It remains controversial whether adult pancreatic ducts harbor facultative beta cell progenitors. Since neurogenin3 (Ngn3) is a key determinant of pancreatic endocrine cell neogenesis during embryogenesis, many studies have also relied upon Ngn3 expression as evidence of beta cell neogenesis in adults. Recently, however, Ngn3 as a marker of adult beta cell neogenesis has been called into question by reports of Ngn3 expression in fully-developed beta cells. Nevertheless, direct evidence as to whether Ngn3 activation in adult pancreatic duct cells may lead to duct-to-beta cell transdifferentiation is lacking. Here we studied two models of Ngn3 activation in adult pancreatic duct cells (low-dose alloxan treatment and pancreatic duct ligation) and lineage-traced Ngn3-activated duct cells by labeling them through intraductal infusion with a cell-tagging dye, CFDA-SE. No dye-labeled beta cells were found during the follow-up in either model, suggesting that activation of Ngn3 in duct cells is not sufficient to direct their transdifferentiation into beta cells. Therefore, Ngn3 activation in duct cells is not a signature for adult beta cell neogenesis.Journal of Biological Chemistry 07/2013; DOI:10.1074/jbc.M113.484022 · 4.60 Impact Factor