In December 2012, a study published in The Journal of the American Medical Association reported that people with type 1 diabetes (T1D) or who are at increased risk of developing the disease have smaller pancreases than people not at risk. Researchers studied pancreases from three groups of deceased donors: individuals with T1D, those with autoantibodies indicating risk of developing T1D, and people without T1D or autoantibodies (the control group). Pancreases from donors with T1D weighed 50 percent as much as pancreases from nondiabetic donors who were not at risk for T1D. Similarly, pancreases from donors at risk for T1D were also smaller than expected, weighing 75 percent as much as control pancreases.
JDRF is excited about this study for two important reasons. First, the lower weight of some pancreases may be attributable to a smaller number of insulin-producing beta cells. Thus, the findings provide compelling evidence that people at risk of developing T1D may already have fewer beta cells in their pancreases even before changes in blood-glucose levels are detectable.
Second, the study was made possible by a unique research resource supported by JDRF at the University of Florida—the Network for Pancreatic Organ Donors with Diabetes (nPOD). By using pancreases donated to nPOD, the study investigators were able to directly measure differences in pancreas size by weight for the first time. Previous studies relied on ultrasound techniques to gauge organ size, introducing the potential for other variables.
This study of pancreas weight is just the latest example of how nPOD is supporting new advances and insights in T1D research. Since its inception, nPOD has transformed from a promising but untested idea to an invaluable and expanding resource for the broad diabetes-research community.
Building an unprecedented resource for T1D research
In 2007, JDRF took a calculated risk by creating nPOD to collect and distribute pancreatic and other tissues from deceased organ donors with T1D, as well as those without the disease but with multiple antibodies indicating high risk for developing the disease. Some people disputed the importance of studying T1D in human tissues, and many were skeptical that such a network could be established and that it could obtain and process enough suitable pancreatic tissue to make the effort worthwhile.
Today, nPOD is proving those early skeptics wrong. Indeed, the network is challenging some of our most basic understandings of human T1D and changing the culture of scientific collaboration within the T1D-research community along the way. Building on its successes, nPOD is now poised for an exciting new era of scientific discovery and expansion.
Rewriting the textbooks on T1D
So far, nPOD has provided more than 30,000 samples of human pancreatic and other tissues, including spleen, lymph nodes, and blood, for more than 80 research projects at institutions around the world. According to Mark Atkinson, Ph.D., Eminent Scholar for Diabetes Research at the University of Florida and nPOD executive director, those samples are having a major impact on T1D research.
“There was a notion that a lot of what could be learned from human tissues we had learned three or four decades ago and that there was little new to be discovered,” Dr. Atkinson states. “To my thinking, that notion has effectively been blown out of the water. I think we’re at the precipice, thanks to nPOD, of being able to change much of what’s been put into textbooks and review articles on type 1 diabetes in terms of how the disease develops and what are its potential causes.”
In January 2012, more than 100 investigators gathered in Miami, FL, to discuss some of those paradigm-shifting research findings at the Fourth Annual nPOD Scientific Meeting. Richard A. Insel, M.D., JDRF chief scientific officer, attended the meeting and was impressed by the new research opportunities that nPOD has generated. “nPOD has allowed our investigators to think beyond a mouse model of type 1 diabetes,” he reports. “This has catalyzed interest in human type 1 diabetes because now investigators have access to tissue samples that, until this time, they did not have. That is very gratifying.”
One advance that caught the attention of both Dr. Atkinson and Dr. Insel is the finding that surprisingly little of the inflammation known as “insulitis” can be found in pancreatic tissue from humans with multiple autoantibodies or “pre-T1D.” This observation has been made in a series of studies by Dr. Atkinson, Peter In’t Veld, Ph.D., of the Brussels Free University, and others and is very different from what researchers see in mice with T1D.
In mice, insulitis is widespread throughout the pancreas from the beginning of the autoimmune process until nearly all of the islets are destroyed and T1D is established. With nPOD samples, researchers can find insulitis only in small regions of pancreases from autoantibody-positive donors. Instead, these pancreases appear to have regions of healthy islets with no signs of insulitis alongside other islets that are missing their insulin-producing beta cells. These studies suggest that beta cell destruction might be more of a “hit and run” process in human T1D rather than a continuous event, as it is in mice. For Dr. Atkinson, that discovery “is absolutely a dogma changer in terms of our understanding of type 1 diabetes.”
Another fascinating study, from Roberto Gianani, M.D., and the late George Eisenbarth, M.D., Ph.D., of the University of Colorado, Denver revealed that not all cases of T1D are the same. Researchers analyzing nPOD samples from donors with long-standing T1D found that some individuals still have beta cells remaining in their pancreases and that at least two distinct patterns of those residual cells could be identified. This heterogeneity suggests that there may be two or more forms of human T1D that have distinct disease pathways, all leading to a common requirement for insulin treatment.
The scientific progress being made with nPOD tissues is providing new clues for scientists to decipher what is really happening in human T1D before, during, and after the destruction of pancreatic beta cells. This is important because many potential treatments that were based on our knowledge of the disease process in mice and other animal models have not worked as hoped in human clinical trials. JDRF’s chief scientific officer is encouraged by the progress he sees with nPOD-supported research. “In the long term, I expect that the discoveries will make a real difference in the development of new treatments targeting all stages of the disease process in humans,” Dr. Insel says. “My hope is that these findings, which have been advanced through nPOD, will lead to new therapies and approaches for human type 1 diabetes.”
Setting a new standard of scientific collaboration
One of the most difficult problems in T1D research is understanding the possible role of viruses in the development of T1D. Individual researchers have found evidence that infection with certain viruses—Coxsackie viruses in particular—might be associated with T1D, but the link has never been proven beyond a doubt. Now, nPOD is proactively tackling this question by fostering the assembly of a “Viral Working Group” of investigators with a common interest in viruses and T1D but unique scientific perspectives and technologies.
Alberto Pugliese, M.D., head of the Immunogenetics Program at the Diabetes Research Institute at the University of Miami and nPOD co-executive director, notes that the Viral Working Group represents a new model of scientific collaboration for the field. “What’s never been possible before is to have the people who are trying to address this question actually looking at the same tissues, comparing notes, and sharing reagents,” he explains. “We’re going to have ongoing sharing of data and make collective decisions about how best to use these nPOD resources to advance the science.”
Dr. Pugliese has noticed a “tremendous enthusiasm” from the approximately 30 researchers who participate in the Viral Working Group. nPOD plans to build on that success and extend the working-group model of active communication and collaboration to other unresolved questions in T1D research, such as understanding “hit and run” insulitis in the human pancreas.
Expanding the collection
The nPOD staff works closely with nearly all of the 58 organ-procurement organizations in the United States to find the rare and difficult-to-obtain tissues that are vital for research on human T1D. Of 193 donor pancreases accepted by nPOD through April 2012, fewer than 10 percent are from donors with multiple autoantibodies who had not yet been diagnosed with T1D. Organs from this group are extremely important for research on the destruction of beta cells by the immune system in the early stages of the disease, but they can be found only by screening many thousands of donors. It is also not a simple task to find organ donors with recent-onset T1D, which could provide insights into the mechanisms of onset of overt clinical T1D that typically follows an incubation period of several years after onset of the beta cell–specific autoimmunity.
To increase the recovery of organs for T1D research, nPOD is pilot testing a new program called nPOD-Europe (nPOD-E). By partnering with sites in Italy, Finland, Spain, and Sweden, nPOD-E will be able to screen a much larger number of organ donors in search of rare pancreases from donors with pre-T1D or recent-onset T1D.
A second pilot program, nPOD-Transplantation (nPOD-T), is recovering pancreases and other tissues from organ donors with T1D who have had pancreas transplants. These organs and tissues will help researchers address key questions that cannot be answered with the general nPOD collection.
For example, all transplant recipients must take drugs to suppress their immune systems and prevent organ rejection. Researchers want to know if this chronic suppression of the immune system allows beta cells to regenerate in the recipient’s original, native pancreas. If beta cell regeneration is observed in individuals with pancreas transplants, then it could point the way to new therapies to stimulate beta cell regeneration in all people with T1D.
Moreover, transplant patients may develop recurrent T1D. Studies in the pancreas transplant, therefore, represent a complementary approach to the study of the causes of T1D. Initial studies in pancreas-transplant recipients with recurrent T1D show that despite the presence of insulitis, a large number of beta cells are still present while the patients are already frankly hyperglycemic and the transplanted pancreas fails to produce insulin in response to stimulation tests. This suggests that the transplanted pancreases have not lost all or most of their beta cells, as is typical in people with T1D. Rather, a large proportion of beta cells in those pancreases may have become incapable of producing insulin, a finding that points to additional mechanisms of beta cell dysfunction.
The expansion of the nPOD collection through nPOD-E and nPOD-T will enhance this already unique and valuable resource for T1D research by allowing more investigators to study rare tissues, ask interesting questions, and get better answers in the search for a cure.
The community’s gratitude
Running nPOD is a 24-hour, 365-day job. Teodora P. Staeva, Ph.D., JDRF’s scientific program director of immune therapies, appreciates the hard work and commitment of the nPOD team that manages this complex operation.
“Through the leadership of Dr. Atkinson and Dr. Pugliese, nPOD has grown to heights beyond our wildest imagination and is setting an example of how collaborative research in T1D should be done on human samples,” Dr. Staeva says. “I personally am very grateful and also very proud of what they’ve been able to accomplish. I feel confident that this will continue to bear great fruit for the community.”
Importantly, nPOD’s success also relies on the thousands of individuals who contribute to our national organ-donation system each year. The enthusiasm of JDRF, the nPOD staff, and the T1D research community is tempered with deep gratitude and respect for the organ donors and their families who make nPOD possible.
“There is a feeling that researchers have when they’re studying tissues from deceased donors,” Dr. Pugliese explains. “They really understand that this is a gift. We try to maximize the potential benefit that comes from these tissues and make sure that they are not wasted but are used to the fullest. This act of generosity helps set the stage for sharing and collaborating.”