Beta-cell transplantation in type 1 diabetes

To many people it appears that stem cells represent the magic answer in the treatment of many illnesses, including diabetes. However, there are many factors and risks that must be taken into account. Adding to the confusion, popular commercialization has already reached this particular field of therapy. The following observations are intended to offer people with diabetes and parents of children with diabetes a clearer picture as to the opportunities of beta-cell therapy, as well as the risks involved. It is also meant to warn of so-called miracle solutions that as yet lack sufficient scientific backing.  

Currently, the only possibility of causally treating type 1 diabetes is in the transplantation of the pancreatic beta cells. The resulting level of accuracy in blood sugar regulation has not yet been achieved even with the most modern insulin types and pump systems. The ability to control the release of insulin exactly as needed according to the intake of food has never been able to be perfectly imitated, despite the great progress that has been made in this kind of technology.

Beta-cell therapy, via the transplantation of the pancreas and individual pancreatic islets, is the clinical reality of today, albeit limited due to a lack of organ donors (especially for children and adolescents) and due to the complicated process of immunosuppression. The development of beta cells from the body’s own stem cells seems to present a promising solution. For those with diabetes, it gives hope of being able to do away with the need for tedious blood sugar monitoring and insulin injections. Although, to many people, it appears that stem cells represent a magic solution in the treatment of many illnesses, there are many factors and risks that must be taken into account. Adding to the confusion, popular commercialization has already reached this particular field of therapy. 

Do be sceptical
People with diabetes and parents of children with diabetes should weigh up all the chances as well as the risks, and to regard new therapies that have not as yet been adequately scientifically backed with some scepticism. Apart from pancreas transplantation, individual replacement of islet cells has become an established method, suitable especially for patients unable to reach the proper metabolic levels even with exogenous insulin. Pancreatic islets are taken from the donated organ and injected via the portal vein into the liver of the recipient. The success of this procedure has been optimized in clinics all over the world using the ‘Edmonton Protocol’.

Islet transplantation: Success rate
There are two reasons that have affected the success rate of pancreatic islet transplantations: (1) Nowadays, the number of transplanted islets is higher than it used to be. On average, two donors are needed to every recipient; and (2) Cortisone is no longer being used in the process of immunosuppression. After one year, 75 percent of patients no longer need exogenous insulin. Unfortunately, this number drops to around 10 percent after three years. The reason for this is due to the body’s own rejection of the islets as well as the continuing destruction of the beta cells that had already been going on prior to the transplantation. It seems that even the beta cells that originate from stem cells are susceptible to the attacks of the body’s aggressive autoimmune reactions (researchers are still in the process of finding a solution to this).

One may well view the lack of donor organs and the relatively low long-term success rate of islet transplantation with a critical eye. It is, however, clinical reality and it is available for the patients in special clinics across Germany. Furthermore, it is the very know-how in islet transplantation which forms the basis for beta-cell transplantation from stem cells, since the technical requirements are similar.
 
The research on embryonic and adult stem cells is very dynamic. In the past 10 years, it has moved from the experimental stage to the implementation stage for the successful treatment diabetes. With the use of growth factors, embryonic stem-cell lines are now able to produce insulin under laboratory cell-culture conditions, albeit only in a few studies and with mediocre results. In addition, embryonic stem cells harbour a potential risk of tumours that can develop from the embryonic residue tissue.

A new era in the production of stem cells began last year in which stem cells could be taken from the patient and developed into stem cell lines very similar to embryonic stem cells, but without the ethical considerations. These pluripotent stem cells can develop into many different cell types. This procedure will eventually present patients with the chance of undergoing individual cell therapy using various types of beta cells from their own bodies. But beware! Research on embryonic and pluripotent stem cells is only in the experimental stage. Serious prognoses regarding the time needed to clinical implementation is impossible, not least due to the risks involved.

Adult stem cells have the ability to develop into certain tissues under laboratory conditions. These cells can be taken from bone marrow or tissue with regenerative potential. No carcinogenic abnormalities have been observed so far in adult stem cells. Until now, three types of tissue have been found as suitable candidates for extracting stem cells for use in diabetes therapy.

Diabetes therapy using stem cells from three tissue types
First possible source
Located in the pancreas are the cells that make up the duct system, which is responsible for diverting the digestive juices to the intestines. Here, a special cell type can be found that has the potential to develop into an insulin-producing cell (differentiation). The islet-like formations that can be built from these duct cells, however, contain lower amounts of insulin as compared to normal beta cells. Due to their slow rates of cell division, a relatively large number of duct cells is necessary to obtain normal blood sugar levels in rats with type 1 diabetes.

Second possible source
The second alternative lies in stem cells drawn from bone marrow. Under laboratory conditions, these bone marrow stem cells can be made to differentiate into neuronal cells, muscle cells, liver cells, and insulin-producing cells. In special bone-marrow stem cell centres, these cells have already been used in the treatment of heart attack in clinical studies that have received permission to be performed by the ethics commission. The stem cells are infused intravenously, or injected directly into the heart muscle. Apart from the improvement in heart function, it is not yet exactly clear by which mechanism the heart muscle actually recovers.

Third possible source: The liver
As third source for the differentiation of stem cells into beta cells is the liver which, per se, possesses a high regenerative potential. In animal experiments, insulin-producing cells have been developed that have been able to normalize the diabetic metabolic state.

Is cell transplantation really necessary?
Beta cells do not necessarily have to be introduced from an external source. They can also regenerate by themselves, as has been observed under experimental conditions. Thus arises the provoking question as to whether cell transplantation is at all necessary. It has been known for quite some time that the operative removal of certain sections of the pancreas results in an increase in the number of beta cells due to a stimulatory effect on beta-cell regeneration. This applies to duct cells as well as beta cells that possess regenerative potential. A beta-cell multiplication from individual pancreatic islets has only been achieved so far in experiments on rodents—not, however, in human islet cells. Nevertheless, there is no doubt that the human endocrine pancreas is able to regenerate. Further research is needed in order to find the exact mechanism by which the process of cell regeneration occurs. To this end, experiments on transgenic animal models are constantly making key findings in the process of beta-cell differentiation. 

Stem-cell therapy for diabetes: No routine matter
The success of experimental stem-cell research raises the question as to whether these cells are actually available for diabetic patients. There are many complexities and questions yet to be answered as to all the mechanisms involved. We need to perform further clinical studies to find the answers, especially in view of the fact that success has already been achieved in the treatment of heart attack by the introduction of bone-marrow stem cells. Stem-cell therapy is by no means a routine procedure, even though the extraction of stem cells from bone marrow is already established.

One should also be aware of the fact that the cost for individual stem-cell therapy must be, at least in part, paid for by the patient. The German Diabetes Society (DDG) rejects the commercialization of stem-cell therapy due to the false expectations it provokes in the patients and their families. Many of the claims have no scientific backing.

Final statement
Recently, there have been many advertisements in non-scientific publications as well as in Internet claiming to be able to treat diabetes with individual stem-cell therapy. Therapy protocols and risks are not at all detailed. Many of the claims are not scientifically sound. In addition to this, the patient is expected to carry much of the cost. This leads to question as to how much is based on scienctific fact and how much is based on commercial gain. The DDG rejects any commercialization of stem-cell therapy for diabetes, due to the false expectations it provokes in the patients as well as their relatives. The progress made in recent years in the area of islet transplantation and the development of adult stem cells will lead to further clinical studies founded on basic research. For those patients who would like to obtain information on the possibilities of stem-cell therapy and islet transplantation should refer to their treatment centres or their clinics in which their physicians are located. They will assist you in contacting the relevant clinical centres that carry out basic research in the area of stem-cell therapy.

Prof. Markus Tiedge MD
Institut für Med. Biochemie und Molekularbiologie, Universität Rostock
E-Mail: markus.tiedge(at)med.uni-rostock(dot)de