Nearly 600 diabetes patients worldwide have now received islet transplants, and enough patients have been transplanted that long-term benefits can be documented. Islet cell transplants have resulted in significant benefits to people with very complicated forms of type 1 diabetes: for instance, at least half of the transplant recipients exhibit stabilization or reversal of their diabetic eye and nerve diseases. Overall, islet transplant patients report a significant improvement in their quality of life. However, challenges remain, and we need additional funding for NIH programs and NIH/CMS sponsored clinical trials to test new protocols and fully understand how to maximize this proven treatment so it is an appropriate therapy for all who suffer from type 1 diabetes.

ISLET TRANSPLANTATION
Type 1 diabetes results from the immune-mediated destruction of insulin-producing beta cells that are clustered with other cell types in 'islets' found in the pancreas. A cure for type 1 diabetes therefore requires restoring beta cell function either by replacement with transplantation or by beta cell regeneration. Organ transplantation has revolutionized the treatment of heart, lung, and kidney disease, among other conditions, in an almost "miraculous" way. However, transplantation of pancreatic islets as a therapy for type 1 diabetes has lagged behind. Significant hurdles stand in the way of realizing the potential of islet transplantation as a safe, effective, and widely-available therapeutic option for type 1 diabetes: a severe shortage of donor islet cells; the recurrence of autoimmunity and the development of allo (non-self) immunity — resulting in a loss of graft function over time; and problems associated with the chronic use of immunosuppressive drugs that are toxic. Indeed, the last concern alone currently precludes islet transplantation in children.

HOPE AND PROGRESS THROUGH RESEARCH
Since 1999, considerable progress has been made in the use of islet transplantation to treat people with "brittle" or difficult to control type 1 diabetes. These individuals live with the constant threat of hypoglycemia unawareness (a disabling inability to anticipate and treat low blood sugar that, if left untreated, can result in death) and are at high risk for other diabetes-related complications such as blindness, kidney disease, and nerve damage.

Several groups have demonstrated that islet transplantation can reverse hypoglycemia unawareness. Indeed, in many centers, approximately 80 percent of islet-treated recipients are insulin independent one year after transplantation. Data indicate that most recipients can resume important everyday activities free of insulin shots. Even patients who must resume insulin therapy take, on average, only one-half the dose of insulin required before transplantation and still maintain better glucose control. For many patients, the progression towards diabetic eye or nerve disease is halted and, in some cases, even reversed after transplantation.

The National Institutes of Health (NIH) is sponsoring a multi-center study extending islet transplantation to a more diverse group of recipients using different and hopefully less toxic immunosuppression. In collaboration with the Centers for Medicare and Medicaid Services (CMS), the NIH is also exploring the potential benefits of islet transplantation in persons with end stage kidney disease who have previously received kidney transplants. These clinical trials should lead to an FDA approved biologic license and make the islet transplantation procedure more broadly accessible for patients nationwide.

The confidence of the diabetes healthcare community in the procedure is highlighted by the 40 or so islet transplant programs across the U.S. that are now conducting or are in the process of starting clinical trials.

Multiple immunosuppressive drugs are being tested in combination to define an optimal drug cocktail that will prevent rejection of the transplanted islets, without the induction of intolerable side effects.

CELL AND REGENERATIVE MEDICINE FOR TYPE 1 DIABETES
Type 1 diabetes results from immune-mediated destruction of the insulin-producing beta cells that are clustered with other cell types in "islets" found in the pancreas. Replacement of a patient's lost beta cells, either through transplantation of islets from an external source or through regeneration of islets within a patient's own pancreas, is required to restore glucose control and cure type 1 diabetes. While researchers have made dramatic progress in transplanting islets, there are simply not enough donor islets available to treat the entire population of individuals with type 1 diabetes. A safe, abundant, and renewable source of islets for transplantation is required. Also, drugs that can stimulate re-growth or regeneration of beta cells in the pancreas are urgently needed.

HOPE AND PROGRESS THROUGH RESEARCH
Adult and embryonic stem cells represent a remarkably promising source of renewable cells to treat type 1 diabetes, if they can be coaxed into becoming glucose-responsive, insulin-producing cells. Similarly, the development of regenerative treatments capable of restoring beta cells without the need for transplantation requires an understanding of how such cells are normally formed in the adult pancreas. Once known, such information might be used to design drugs that induce the process in type 1 diabetes patients.

Scientists have recently developed a far more detailed knowledge of normal beta cell development and have uncovered multiple pathways by which new beta cells are formed within the body. Genes that regulate growth, differentiation, and replication of beta cells have been identified through the efforts of the Beta Cell Biology Consortium.

To develop a source of beta cells for replacement, embryonic stem cells must be guided through a stepwise process that mimics normal human development. Several research groups have reported conditions that direct human embryonic stem cells to turn into definitive endoderm — the first step in development of the pancreas.

Adult stem cells derived from the pancreas have been shown to differentiate to cells that have some characteristics of a functional, insulin-producing beta cell.

Evidence indicating the potential for pancreatic beta cell regeneration has been obtained from studies in animal models of diabetes.

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