A role for islet neogenesis in curing diabetes

Abstract

Endogenous insulin deficiency is the tie that binds all forms of diabetes. Definitive treatment or cure of type 1 and type 2 diabetes cannot occur without a durable reversal of relative or absolute endogenous insulin deficiency. Current efforts to restore physiological insulin secretion include (1) islet or pancreas transplant; (2) exogenous cell therapies, including differentiation of bone marrow cells and embryonic stem cells (ESCs); and (3) islet regeneration from endogenous pancreatic cells. Although they would represent advances, islet or beta cell transplant [1, 2], the artificial pancreas [3, 4], gene therapy [5], and even stem cell therapy [6, 7] cannot be considered restorative approaches unless the results are durable and have an acceptable safety profile. Islet transplantation, both alloand xeno-, as a means of reversing diabetes has been limited by graft durability and/ or donor supply, as well as the complications of surgery and immunosuppression. However, progress is being made to resolve these issues [1, 8]. Minimally invasive techniques for the transplant of donor islets into the liver have been developed, and extensive studies have refined the immunosuppression required for transplant survival. At present, the limiting problem for islet transplantation is obtaining sufficient islets for the broad application of the technique. It is hoped that work with stem cells will resolve this issue. Early studies showed that ESCs did not achieve terminal differentiation and had a low insulin content and a poor response to glucose. Growth of the islet-like clusters from ESCs was unbridled and, despite production of insulin, they failed to cure diabetic mice [9]. Israeli scientists found insulin-producing cells in embryoid bodies formed spontaneously from ESCs when they stop growing, but these did not make sufficient insulin to reverse diabetes [10]. Soria and colleagues used gene-trapping techniques to isolate insulin-producing cells and transfected an antibiotic resistance gene adjoined to the insulin promoter. When these cells formed three-dimensional structures, the cells increased insulin production to therapeutic levels but insulin secretion remained insensitive to glucose [11]. More recent Diabetologia (2009) 52:735–738 DOI 10.1007/s00125-009-1322-y