German working groups are planning for the future of diabetes therapy and regeneration of the insulin-producing cells.
Restoring the body's own insulin production is focus of research at the German Center for Diabetes Research. In addition to transplanting functioning organs or cells from human donors, animal tissue or stem cells could also serve as source for transplants in the future. New regenerative processes rely on dormant reserves in the patient's body. This goal can be achieved in different ways. One of them is the transplant of the entire pancreas from suitable donor - usually together with new kidney, as kidney disease can be secondary disease in diabetes.
A study of more than 12,000 people with type 1 diabetes shows how effective this therapy is: of those who had hoped for donor organs in vain, only 46 were left after 4-year waiting period % alive; in contrast, 91% of those successfully transplanted. However, the therapy cannot be carried out in all patients. For older patients and people with additional diseases of the cardiovascular system, transplant of islet cells from the pancreas is an option.
In Germany, the Dresden University Hospital - also partner of the DZD - is currently the only facility the islet cells can and may transplant. Experts from diabetology, vascular surgery and basic research work hand in hand. First, only the hormone-producing islet cells are removed from the donor's pancreas in complex process. In addition to beta cells, this also includes alpha cells that produce glucagon and signal to the liver that the glucose concentration is low, which stimulates gluconeogenesis. Both cell types form “clumps” of up to 1,500 cells. In the recipient's organism, the isolated and purified islet cells settle in the liver and start producing insulin.
An islet transplant is less stressful than transferring the entire pancreas. But in both cases, those affected have to take immunosuppressants for life.
German working groups are planning for the future of diabetes therapy and regeneration of the insulin-producing cells.
Restoring the body's own insulin production is focus of research at the German Center for Diabetes Research. In addition to transplanting functioning organs or cells from human donors, animal tissue or stem cells could also serve as source for transplants in the future. New regenerative processes rely on dormant reserves in the patient's body. This goal can be achieved in different ways. One of them is the transplant of the entire pancreas from suitable donor - usually together with new kidney, as kidney disease can be secondary disease in diabetes.
A study of more than 12,000 people with type 1 diabetes shows how effective this therapy is: of those who had hoped for donor organs in vain, only 46 were left after 4-year waiting period % alive; in contrast, 91% of those successfully transplanted. However, the therapy cannot be carried out in all patients. For older patients and people with additional diseases of the cardiovascular system, transplant of islet cells from the pancreas is an option.
In Germany, the Dresden University Hospital - also partner of the DZD - is currently the only facility the islet cells can and may transplant. Experts from diabetology, vascular surgery and basic research work hand in hand. First, only the hormone-producing islet cells are removed from the donor's pancreas in complex process. In addition to beta cells, this also includes alpha cells that produce glucagon and signal to the liver that the glucose concentration is low, which stimulates gluconeogenesis. Both cell types form “clumps” of up to 1,500 cells. In the recipient's organism, the isolated and purified islet cells settle in the liver and start producing insulin.
An islet transplant is less stressful than transferring the entire pancreas. But in both cases, those affected have to take immunosuppressants for life.The weakening of the body's own defense system, however, makes it more susceptible to infections and other diseases. Therefore, the benefits and risks of both interventions must be carefully weighed - especially since both procedures cannot guarantee permanent independence from additional insulin administration. Another stumbling block is the low willingness to donate organs.
"Bioreactor" produces insulin
That is why we are working on further alternatives. Instead of donor organ, palm-sized plastic capsule in the body of diabetes patients could in future take on the role of the pancreas. This "bioreactor", which Prof. Dr. Stefan Bornstein from the Dresden University Hospital and the Israeli biotech company Beta O2 developed it and optimized it for use on patients. It contains human islet cells that can measure glucose levels and produce insulin. They are surrounded by special Teflon membrane, which allows hormones and nutrients to pass unhindered, but prevents contact with the body's own immune cells. Immunosuppressive therapy can therefore be dispensed with. The artificial organ is planted under the abdominal wall and supplied with oxygen via port. After years of preliminary tests on animals, the capsule was transplanted to 63-year-old patient with type 1 diabetes. For ten months the donor cells worked as expected; the insulin dose could be reduced and the glucose levels were stable. Further clinical studies are planned.
Beta cells from animals
Researchers at PLID are also experimenting with animal islet cells. The idea is obvious, given that diabetes patients have been supplied with pig insulin for decades. Shielded by the Teflon membrane, the animal cells in the bioreactor could deliver insulin without "calling on the affected person's immune system". If this approach should prove itself in practice, one would no longer have to rely on the rare organ donations. The hurdles for xenotransplantation are high. Anyone who wants to promote this form of therapy must meet strict safety requirements from the national and international health authorities. The aim is to reduce the risk of new pathogens entering the recipient's body with the foreign tissue.
Stem cells mature into beta cells
Another alternative is human stem cells: they can in mature into beta cells in the culture dish and release insulin in the body of diabetes patients. Numerous research institutions around the world are currently working at full speed on this option - including at the DZD partner Helmholtz Zentrum München. The cells that produce insulin are very similar to the body's own beta cells. They secrete insulin, but not yet in sufficient quantities.The weakening of the body's own defense system, however, makes it more susceptible to infections and other diseases. Therefore, the benefits and risks of both interventions must be carefully weighed - especially since both procedures cannot guarantee permanent independence from additional insulin administration. Another stumbling block is the low willingness to donate organs.
"Bioreactor" produces insulin
That is why we are working on further alternatives. Instead of donor organ, palm-sized plastic capsule in the body of diabetes patients could in future take on the role of the pancreas. This "bioreactor", which Prof. Dr. Stefan Bornstein from the Dresden University Hospital and the Israeli biotech company Beta O2 developed it and optimized it for use on patients. It contains human islet cells that can measure glucose levels and produce insulin. They are surrounded by special Teflon membrane, which allows hormones and nutrients to pass unhindered, but prevents contact with the body's own immune cells. Immunosuppressive therapy can therefore be dispensed with. The artificial organ is planted under the abdominal wall and supplied with oxygen via port. After years of preliminary tests on animals, the capsule was transplanted to 63-year-old patient with type 1 diabetes. For ten months the donor cells worked as expected; the insulin dose could be reduced and the glucose levels were stable. Further clinical studies are planned.
Beta cells from animals
Researchers at PLID are also experimenting with animal islet cells. The idea is obvious, given that diabetes patients have been supplied with pig insulin for decades. Shielded by the Teflon membrane, the animal cells in the bioreactor could deliver insulin without "calling on the affected person's immune system". If this approach should prove itself in practice, one would no longer have to rely on the rare organ donations. The hurdles for xenotransplantation are high. Anyone who wants to promote this form of therapy must meet strict safety requirements from the national and international health authorities. The aim is to reduce the risk of new pathogens entering the recipient's body with the foreign tissue.
Stem cells mature into beta cells
Another alternative is human stem cells: they can in mature into beta cells in the culture dish and release insulin in the body of diabetes patients. Numerous research institutions around the world are currently working at full speed on this option - including at the DZD partner Helmholtz Zentrum München. The cells that produce insulin are very similar to the body's own beta cells. They secrete insulin, but not yet in sufficient quantities.In addition, they can only be slightly stimulated by glucose. The maturation of beta-like cells generated from stem cells has yet to be fully understood and improved. This is why the identification of the maturation marker flattop is so important, as we can now understand this process and both improve the maturation of the beta cells in the culture dish and have starting point for the regeneration of the beta cells in diabetic patients.
Silence Stimulating reserves
Parallel to research on stem cells, the aim is to mobilize the self-healing powers in the pancreas of diabetes patients and stimulate them to form new, high-performance beta cells. The vision feeds on the fact that there are 2 types of beta cells: While some produce large amounts of insulin and react perfectly to changes in glucose - i.e. have the properties of mature beta cells - the others form kind of hidden reserve. Both cell types can now be differentiated using the protein marker Flattop (Nature 2016; 535 [7612]: 430–434). The molecule is part of the so-called Wnt signaling pathway, which primarily controls the development of tissues and the functions of cells.
Flattop was present in around 80% of all beta cells. These cells determined the glucose content of their environment and released corresponding amount of insulin - so they behaved like mature beta cells. Conversely, beta cells, in which no flat top can be measured, have particularly high division rate. In the test model, these cells multiplied up to 4 times more often than the flattop-positive ones.
To investigate the assumption that the dividing cells without flattop are precursors of the metabolically active cells, genetic one was used Trick to track the fate of individual cells. This "lineage tracing" showed that the dividing reserve cells can mature into metabolically active cells. That was also the case when they were placed in an artificial three-dimensional environment, comparable to mini-organ. In addition, genetic analyzes confirmed that genes for the perception of the environment were mainly active in the flattop-negative cells, while metabolic programs were mainly running in cells with flattop.
The results suggest that the flat-top-negative cells are kind of reserve pool that is constantly being renewed and replenishing mature beta cells. In terms of perspective, there are two main aspects: On the one hand, the researchers hope that regeneration therapy will in future be able to stimulate the growth or maturation of these cells in patients with deficiency in functional beta cells.In addition, they can only be slightly stimulated by glucose. The maturation of beta-like cells generated from stem cells has yet to be fully understood and improved. This is why the identification of the maturation marker flattop is so important, as we can now understand this process and both improve the maturation of the beta cells in the culture dish and have starting point for the regeneration of the beta cells in diabetic patients.
Silence Stimulating reserves
Parallel to research on stem cells, the aim is to mobilize the self-healing powers in the pancreas of diabetes patients and stimulate them to form new, high-performance beta cells. The vision feeds on the fact that there are 2 types of beta cells: While some produce large amounts of insulin and react perfectly to changes in glucose - i.e. have the properties of mature beta cells - the others form kind of hidden reserve. Both cell types can now be differentiated using the protein marker Flattop (Nature 2016; 535 [7612]: 430–434). The molecule is part of the so-called Wnt signaling pathway, which primarily controls the development of tissues and the functions of cells.
Flattop was present in around 80% of all beta cells. These cells determined the glucose content of their environment and released corresponding amount of insulin - so they behaved like mature beta cells. Conversely, beta cells, in which no flat top can be measured, have particularly high division rate. In the test model, these cells multiplied up to 4 times more often than the flattop-positive ones.
To investigate the assumption that the dividing cells without flattop are precursors of the metabolically active cells, genetic one was used Trick to track the fate of individual cells. This "lineage tracing" showed that the dividing reserve cells can mature into metabolically active cells. That was also the case when they were placed in an artificial three-dimensional environment, comparable to mini-organ. In addition, genetic analyzes confirmed that genes for the perception of the environment were mainly active in the flattop-negative cells, while metabolic programs were mainly running in cells with flattop.
The results suggest that the flat-top-negative cells are kind of reserve pool that is constantly being renewed and replenishing mature beta cells. In terms of perspective, there are two main aspects: On the one hand, the researchers hope that regeneration therapy will in future be able to stimulate the growth or maturation of these cells in patients with deficiency in functional beta cells.On the other hand, one could try to promote the maturation of beta cells in the Petri dish via the signaling pathways "triggered" by Flattop, which is important for cell replacement therapy, but not yet fully possible. ▄
DOI: 10.3238 / PersDia.2017.05.19.05
Prof. Dr. rer. nat. Heiko Lickert Institute for Diabetes and Regeneration Research Helmholtz Center Munich Prof. Michele Solimena MD, PhD; Priv.-Doz. Dr. med. Barbara Ludwig DZD - Paul Langerhans Institute Dresden
Conflict of interest: Prof. Lickert holds patents for Flattop, PCT / EP2015 / 056664. Prof. Solimena and Priv.-Doz. Ludwig declare that there is no conflict of interest.
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