Report from IPITA-TTS Opinion Leaders Meeting on the Future of β-Cell Replacement

At the time the first pancreas transplant was performed by Kelly and Lillehei in 1966, insulin therapy for diabetes was generally available but administered in a form that is known today as “conventional therapy.”1 In this era, as many as half of all juvenile onset diabetics did not reach the age of 55 years. Early mortality from accelerated cardiovascular disease, renal failure, and hypoglycemia-related events were commonplace. The early low success rate and mortality of pancreas transplantation by comparison were also suboptimal. As will be characterized in the succeeding 8 chapters, the outcome of “best medical therapy” with newer forms of insulin and insulin delivery systems along with dramatically improved outcomes of islet and pancreas transplantation and novel β-cell sources hold great promise for those afflicted. Among the great strides in diabetes research was the Diabetes Control and Complications Trial (DCCT).2 This trial, published in 1991, showed that intensive insulin therapy when compared with “conventional therapy” dramatically reduced the incidence and progression of the microvascular complications of diabetes, nephropathy, neuropathy, and retinopathy. Thus, with intensive insulin therapy, the mean hemoglobin A1C was improved to 7% compared with 8.3% in the conventional group. The improved microvascular outcomes and measured hemoglobin A1C came at a substantial price, namely, a greatly increased incidence of hypoglycemic events requiring third-party intervention. After 2 decades, the 2 groups have also diverged with respect to mortality; recent reanalysis of the original study groups demonstrates that those individuals who received intensive insulin therapy groups had lower overall mortality.3 Current best practice includes the availability of insulin pumps and newer forms of synthetic insulin as well as pharmaceutical agents that augment insulin action. Unfortunately, the widespread application of the therapeutic measures taken in the intensive therapy arm of the DCCT is not the norm. Analysis of data from the 67 centers reporting to the US type 1 diabetes (T1D) exchange shows that even today, more than 20 years after the DCCT, the average hemoglobin A1C for treated patients is 8.3%. Thus, outside of a clinical trial, such as the DCCT, actual practice achieves suboptimal outcomes. A remarkable report of the current state of diabetes care is published in the Journal of the American Medical Association in January 2015. This report shows that in a modern era of diabetes care, mortality remains higher than the general population. For men and women, the life expectancy for those reaching 20 years of age is 11.1 years and 12.9 years less than the general population, respectively.4 These sobering findings, which have been thoughtfully summarized in an accompanying editorial by Katz, provide a meaningful context for an international conference dedicated to summarize the current state of pancreas and islet transplantation and chart the way forward with an ambitious research agenda.5 The need for a cure for diabetes through transplantation, stem cell–based therapy, regeneration, newer insulin delivery systems, and devices that warn of hypoglycemia have been brought into sharp focus by these reports which show that the progress in care for diabetics has hit a plateau. Innovation will be required to improve the quality of life and lower morbidity and mortality for those with insulin-requiring diabetes. Against this backdrop, the International Pancreas and Islet Transplant Association (IPITA), in collaboration with the Transplantation Society (TTS), held a scientific workshop in Oxford England, May 7 to 9, 2014, to review the current status and needed research agenda of 8 current or nascent β-cell replacement therapies: whole organ pancreas transplantation, isolated islet transplantation, artificial pancreas (AP), immunological tolerance, xenotransplantation, encapsulation technologies, β cell regeneration, and stem cell derived β cells. Thirty-two scientists and clinicians representing 4 continents, 7 countries and 29 institutions, with dedicated expertise in these areas were recruited to participate in 8 topical workgroups along with representatives of the NIH (National Institute of Diabetes and Digestive and Kidney Disease, National Institute of Allergy and Infectious Disease), Diabetes Research and Wellness Foundation, the Juvenile Diabetes Research Foundation (JDRF) and industry. In advance of the meeting, the workgroups prepared summaries of their respective topic highlighting the state of their field and the research agenda needed to move the therapy forward to optimal clinical application. Presentation and full group discussion at the meeting generated revised summaries presented in the 8 sections below. These reports are followed by the results of a conference attendee survey examining how the participants view the future of β cell replacement therapies. ALLOGENEIC PANCREAS TRANSPLANTATION Current State of the Field Pancreas transplantation has been available as a cure for diabetes since its first application in 1966. The most common application is simultaneous pancreas-kidney (SPK) transplant for the uremic T1D patients who are free of major surgical risks. 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