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Insel R.A.,JDRF | Dunne J.L.,JDRF | Ziegler A.-G.,Helmholtz Center Munich | Ziegler A.-G.,TU Munich
Current Opinion in Endocrinology, Diabetes and Obesity | Year: 2015

Purpose of review The purpose of this review was to describe the potential for general childhood population-based screening of risk of symptomatic type 1 diabetes (T1D) Recent findings The earliest stages of T1D can be identified and risk and rate of progression to symptomatic disease can be estimated by the presence of multiple islet autoantibodies and glucose intolerance (dysglycemia) in individuals screened for risk. Screening for human leukocyte antigen risk genotypes in neonates with follow-up detection of islet autoantibodies in childhood has been explored. An alternative approach of general childhood population-based detection of autoantibodies at well child visits provides an approach to detect a high proportion of children who will develop T1D. The Fr1da study was launched in Bavaria in 2015 to explore this concept. Summary General childhood population-based screening for risk of T1D will allow detection of an at-risk population that can participate in natural history studies to better understand disease pathogenesis and intervention trials to prevent symptomatic disease and will provide a framework for public health-based prevention of childhood-onset T1D. © 2015 Wolters Kluwer Health, Inc. Source

Kowalski A.,JDRF
Diabetes Care | Year: 2015

Artificial pancreas (AP) systems, a long-sought quest to replicate mechanically islet physiology that is lost in diabetes, are reaching the clinic, and the potential of automating insulin delivery is about to be realized. Significant progress has been made, and the safety and feasibility of AP systems have been demonstrated in the clinical research center and more recently in outpatient "real-world" environments. An iterative road map to AP system development has guided AP research since 2009, but progress in the field indicates that it needs updating. While it is now clear that AP systems are technically feasible, it remains much less certain that they will be widely adopted by clinicians and patients. Ultimately, the true success of AP systems will be defined by successful integration into the diabetes health care system and by the ultimate metric: improved diabetes outcomes. ©2015 by the American Diabetes Association. Source

George Eisenbarth's pioneering and visionary research has provided a critical foundation that will be built on in the years ahead as we progress toward prevention of type 1 diabetes. His almost 30-year old model that type 1 diabetes was a chronic and predictable autoimmune disease with multiple identifiable progressive stages with a potential for interventions to prevent progression to symptomatic diabetes has stood the test of time. To deliver on the Eisenbarth vision and his "unfinished journey," the field needs: (1) to improve detection of risk of type 1 diabetes, (2) to improve staging and prediction of progression, (3) to perform smaller, shorter, practical, and an increased number of prevention clinical trials, and (4) to increase awareness of the potential for risk detection, staging, and prevention of type 1 diabetes and benefit/risk of prevention. © Copyright 2013, Mary Ann Liebert, Inc. 2013. Source

News Article | April 19, 2016
Site: http://www.biosciencetechnology.com/rss-feeds/all/rss.xml/all

Transplants of insulin-producing pancreas cells are a long hoped-for treatment for diabetes - and a new study shows they can protect the most seriously ill patients from a life-threatening complication of the disease, an important step toward U.S. approval. These transplants are used in some countries but in the U.S. they're available only through research studies. Armed with Monday's findings, researchers hope to license them for use in a small number of people with Type 1 diabetes who are most at risk for drops in blood sugar so severe they can lead to seizures, even death. "Cell-based diabetes therapy is real and works and offers tremendous potential for the right patient," said study lead author Dr. Bernhard Hering of the University of Minnesota, whose team plans to seek a Food and Drug Administration license for the therapy. In Type 1 diabetes, the immune system destroys the pancreatic cells responsible for making insulin, a hormone crucial to converting blood sugar into energy. About 1 million Americans have Type 1 diabetes and depend on regular insulin shots to survive but still can experience complications due to swings in their blood sugar. Diabetics who get kidney transplants sometimes also receive pancreas transplants at the same time, essentially curing their diabetes. But it's an uncommon and grueling operation, so scientists for years have worked on a minimally invasive alternative: Infusing patients with just islet cells, the insulin factories inside the pancreas. The questions: How best to obtain those islet cells from deceased donors, and who benefits most from transplants? When glucose levels drop too low, most people with Type 1 diabetes experience early warning signs - slurred speech, tremors, sweating, heart palpitations - so they know to eat or drink something for a quick sugar boost. But even with optimal care, about 30 percent eventually quit experiencing those symptoms, a condition called hypoglycemia unawareness. They can be in grave danger if their blood sugar plummets when no one else is around to help. Continuous glucose monitors can counteract that problem, but even those don't help everyone. The National Institutes of Health targeted that fraction of highest-risk patients, funding a study that gave 48 people at eight medical centers at least one islet cell transplant. A year later, 88 percent were free of severe hypoglycemia events, had their awareness of blood sugar dips restored, and harbored glucose levels in near-normal ranges. Two years later, 71 percent of participants still were faring that well, concluded the study published by the journal Diabetes Care. The goal wasn't insulin independence, which requires more functioning islet cells than merely restoring blood sugar awareness. But some patients - 52 percent after one year - no longer needed insulin shots and others used lower doses. "It's just an amazing gift," said Lisa Bishop of Eagle River, Wisconsin, who received new islet cells in 2010 and no longer needs insulin shots. Bishop recalls the terror of learning she'd become hypoglycemic unaware, and the difficulty of even holding a job. She hasn't had hypoglycemia since the transplant and says if her blood sugar occasionally dips a bit after exercise, "now my body senses it." Another key: The transplants have long been used experimentally but different hospitals use different methods to cull the islet cells from a donated pancreas and purify them - and it wasn't clear which worked best, explained Dr. Nancy Bridges, chief of the transplant branch at NIH's National Institute for Allergy and Infectious Diseases. The FDA made clear that there had to be a standard method for islet cell transplants if they were ever to be approved - which is necessary for insurance coverage - so the researchers developed that recipe, Bridges said. Side effects include bleeding and infection, and recipients need lifelong immune-suppressing drugs to avoid rejecting their new cells. Even if given the OK for more routine use, donated pancreas cells are in limited supply. Still, "it's a very beautiful study," said Dr. Julia Greenstein of the diabetes advocacy organization JDRF, who wasn't involved in the latest research. "For most people in the U.S., this was not an available choice, and this is the first step in making that an available choice."

News Article
Site: http://www.biosciencetechnology.com/rss-feeds/all/rss.xml/all

In patients suffering from Type 1 diabetes, the immune system attacks the pancreas, eventually leaving patients without the ability to naturally control blood sugar. These patients must carefully monitor the amount of sugar in their blood, measuring it several times a day and then injecting themselves with insulin to keep their blood sugar levels within a healthy range. However, precise control of blood sugar is difficult to achieve, and patients face a range of long-term medical problems as a result. A better diabetes treatment, many researchers believe, would be to replace patients’ destroyed pancreatic islet cells with healthy cells that could take over glucose monitoring and insulin release. This approach has been used in hundreds of patients, but it has one major drawback — the patients’ immune systems attack the transplanted cells, requiring patients to take immunosuppressant drugs for the rest of their lives. Now, a new advance from MIT, Boston Children’s Hospital, and several other institutions may offer a way to fulfill the promise of islet cell transplantation. The researchers have designed a material that can be used to encapsulate human islet cells before transplanting them. In tests on mice, they showed that these encapsulated human cells could cure diabetes for up to six months, without provoking an immune response. Although more studies are needed, this approach “has the potential to provide diabetics with a new pancreas that is protected from the immune system, which would allow them to control their blood sugar without taking drugs. That’s the dream,” says Daniel Anderson, the Samuel A. Goldblith Associate Professor in MIT’s Department of Chemical Engineering, a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES), and a research fellow in the Department of Anesthesiology at Boston Children’s Hospital. Anderson is the senior author of two studies describing this method in the Jan. 25 issues of Nature Medicine and Nature Biotechnology. Researchers from Harvard University, the University of Illinois at Chicago, the Joslin Diabetes Center, and the University of Massachusetts Medical School also contributed to the research. Since the 1980s, a standard treatment for diabetic patients has been injections of insulin produced by genetically engineered bacteria. While effective, this type of treatment requires great effort by the patient and can generate large swings in blood sugar levels. At the urging of JDRF director Julia Greenstein, Anderson, Langer, and colleagues set out several years ago to come up with a way to make encapsulated islet cell transplantation a viable therapeutic approach. They began by exploring chemical derivatives of alginate, a material originally isolated from brown algae. Alginate gels can be made to encapsulate cells without harming them, and also allow molecules such as sugar and proteins to move through, making it possible for cells inside to sense and respond to biological signals. However, previous research has shown that when alginate capsules are implanted in primates and humans, scar tissue eventually builds up around the capsules, making the devices ineffective. The MIT/Children’s Hospital team decided to try to modify alginate to make it less likely to provoke this kind of immune response. “We decided to take an approach where you cast a very wide net and see what you can catch,” said Arturo Vegas, a former MIT and Boston Children’s Hospital postdoc who is now an assistant professor at Boston University. Vegas is the first author of the Nature Biotechnology paper and co-first author of the Nature Medicine paper. “We made all these derivatives of alginate by attaching different small molecules to the polymer chain, in hopes that these small molecule modifications would somehow give it the ability to prevent recognition by the immune system.” After creating a library of nearly 800 alginate derivatives, the researchers performed several rounds of tests in mice and nonhuman primates. One of the best of those, known as triazole-thiomorpholine dioxide (TMTD), they decided to study further in tests of diabetic mice. They chose a strain of mice with a strong immune system and implanted human islet cells encapsulated in TMTD into a region of the abdominal cavity known as the intraperitoneal space. The pancreatic islet cells used in this study were generated from human stem cells using a technique recently developed by Douglas Melton, a professor at Harvard University who is an author of the Nature Medicine paper. Following implantation, the cells immediately began producing insulin in response to blood sugar levels and were able to keep blood sugar under control for the length of the study, 174 days. “The really exciting part of this was being able to show, in an immune-competent mouse, that when encapsulated these cells do survive for a long period of time, at least six months,” said Omid Veiseh, a senior postdoc at the Koch Institute and Boston Children’s hospital, co-first author of the Nature Medicine paper, and an author of the Nature Biotechnology paper. “The cells can sense glucose and secrete insulin in a controlled manner, alleviating the mice’s need for injected insulin.” The researchers also found that 1.5-millimeter diameter capsules made from their best materials (but not carrying islet cells) could be implanted into the intraperitoneal space of nonhuman primates for at least six months without scar tissue building up. “The combined results from these two papers suggests that these capsules have real potential to protect transplanted cells in human patients,” said Robert Langer, the David H. Koch Institute Professor at MIT, a senior research associate at Boston’s Children Hospital, and co-author on both papers.  “We are so pleased to see this research in cell transplantation reach these important milestones.” Cherie Stabler, an associate professor of biomedical engineering at the University of Florida, said this approach is impressive because it tackles all aspects of the problem of islet cell delivery, including finding a source of cells, preventing an immune response, and developing a suitable delivery material. “It’s such a complex, multipronged problem that it’s important to get people from different disciplines to address it,” said Stabler, who was not involved in the research. “This is a great first step towards a clinically relevant, cell-based therapy for Type I diabetes.” The researchers now plan to further test their new materials in nonhuman primates, with the goal of eventually performing clinical trials in diabetic patients. If successful, this approach could provide long-term blood sugar control for such patients. “Our goal is to continue to work hard to translate these promising results into a therapy that can help people,” Anderson said. “Being insulin-independent is the goal,” Vegas said. “This would be a state-of-the-art way of doing that, better than any other technology could. Cells are able to detect glucose and release insulin far better than any piece of technology we’ve been able to develop.” The researchers are also investigating why their new material works so well. They found that the best-performing materials were all modified with molecules containing a triazole group — a ring containing two carbon atoms and three nitrogen atoms. They suspect this class of molecules may interfere with the immune system’s ability to recognize the material as foreign. The work was supported, in part, by the JDRF, the Leona M. and Harry B. Helmsley Charitable Trust, the National Institutes of Health, and the Tayebati Family Foundation. Other authors of the papers include MIT postdoc Joshua Doloff; former MIT postdocs Minglin Ma and Kaitlin Bratlie; MIT graduate students Hok Hei Tam and Andrew Bader; Jeffrey Millman, an associate professor at Washington University School of Medicine; Mads Gürtler, a former Harvard graduate student; Matt Bochenek, a graduate student at the University of Illinois at Chicago; Dale Greiner, a professor of medicine at the University of Massachusetts Medical School; Jose Oberholzer, an associate professor at the University of Illinois at Chicago; and Gordon Weir, a professor of medicine at the Joslin Diabetes Center.

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