Those of us with diabetes are constantly looking for the "cure" for a disease that takes much of our time and robs us of our health. To this end, we bring you this article on islet cell transplantation.
The hypothesis that makes this research is based on the following information. Within the pancreas are small clusters of insulin-producing cells called islets of Langerhans. They make up only about 1-2% of the total pancreas and destruction of these cells leads to type 1 diabetes. The other 98% of the pancreas ( the exocrine portion) is associated with secretion of important digestive enzymes responsible for the breakdown of food. This functions normally for people with diabetes. Thus, only islet cells need to be replaced in people with type 1 diabetes. Notably, the exocrine tissue is the major source of surgical complications in pancreas transplants. Therefore, transplanting only the insulin-producing islets of Langerhans would correct blood glucose levels while avoiding the surgical complications.
The history of islet transplantation shows that between 1974 and 1997, approximately 300 islet transplants were performed in people with type 1 diabetes. The vast majority of islet transplantations were done in patients with established kidney transplants, or were performed simultaneously with a kidney transplant. The field was pioneered by Lacy and coworkers, who felt they had a cure at hand. Worldwide, due to transplantation, about 10% of the recipients were able to completely stop insulin injections and about one-third of the recipients benefited from significantly improved glucose control after transplantation. It is thought that patients who suffer from life threatening insulin reaction (hypoglycemia) could benefit immediately from transplant. Even islet recipients who still required some insulin after transplantation were more or less completely relieved of the worries related to hypoglycemia because of their ability to sense low blood sugars. The longest period of insulin independence after an islet transplant is 4 years now. In addition, there are recipients who have maintained normal glycated hemoglobin levels on low doses of insulin for more that 5 years. Today, the stage of research is similar to the point at which Banting and Best knew animal insulin could control diabetes in human.
How and How Much
Studies have shown that about 1 million functioning islets must be transplanted to produce enough insulin to replace the need for injections. The number of people who could benefit from transplants is larger that the number of living donors, so researchers around the world are exploring potential sources of islets from deceased organ donors, from animals such as pigs, and by producing cells through bioengineering. As with any transplantation, rejection is the biggest problem. The immune system is programmed to destroy bacteria, viruses, and tissue it recognizes as "foreign," including transplanted islets. Large doses of immunosuppressive drugs are necessary to stop the immune system from rejecting the transplant. For many people with diabetes, the risks of taking immunosuppressive drugs outweigh the benefits of islet transplantation (except for those who receive kidney transplants for end-stage renal disease and can benefit from a simultaneous pancreas transplant). Researchers are trying to develop methods of transplanting islets to reduce or eliminate the need for immunosuppression and the risk of rejection. Immunoisolation methods separate the islets from the immune system of the patient by coating cells or encapsulating them into microscopic containers. Immunoalteration tries to change the surface of islets so that the immune system does not notice or attack them.
Now lets look at current trends in research into islet transplantation. One way to circumvent the mounted autoimmune response is to engineer non-beta cells to express insulin. Dr. Raquel Faradji and co-workers have done just that, by engineering pituitary cells to produce insulin. To mimic the glucose-sensing apparatus of native beta cells, the scientists used recombinant adenoviruses to introduce into pituitary cells two molecules essential for glucose metabolism, namely the glucose transporter (GLUT2) and glucokinasa (GK). Although each of these factors individually had no effects on the metabolic profile, combined expression of both factors resulted in a doubling of glucose usage over the physiological range of normal in vivo glucose responsiveness. Although the pituitary cells produce insulin, the ability to release insulin in a glucose-related manner could not be demonstrated, and the investigators fell that further cell engineering to incorporate other glucose-signaling molecules may be required.
I have great respect for Dr. Gordon Weir, who was my first endocrinologist before he moved on to Boston and Joslin. In a newly funded program, Drs. Gordon Weir, Bonner-Weir and Lipes of Joslin are working with colleagues at Howard Hughes Medical Institute/Children's Hospital in Boston, Beth Israel Deaconess Medical center, and Massachusetts general Hospital to use gene therapy to improve available beta cells for transplantation. A number of genes will be tested; some to make beta cells more resistant to immune attacks, others to modify the response by the recipient. Using such approaches, pig islets will be transplanted into rodents and then into monkeys. Such experiments should lead to a better understanding of whether pig islets can be a source for human transplantation. The same researchers area also studying the abnormal insulin secretion of insulin in rodents. A number of rodent models have been evaluated and researchers have focused their recent efforts on understanding the biochemical changes in activity and function that occur in transplanted islets. Using immunofluorescence and confocal microscopy, the researchers have discovered that glucokinasa, an enzyme thought to be the glucose sensor linked to glucose transport in the cells, is shifted from one location to another by glucose stimulation. They continue to explore the theory that beta cells exposed to the metabolic changes of diabetes undergo drastic changes in insulin secretion and beta cell growth capacity. These include reductions in the expression of the glucose transporter GLUT2 and the important beta-cell transcription factor IDX-1.
Dr. Fred Levine and colleagues have developed a strategy to induce significant expansion of fetal islet cell clusters (ICC's) to generate a large source of cells for transplantation. However, a difficult problem is the loss of functional islet cells resulting from damage incurred during their preparation. A number of strategies have been postulated to prevent apoptosis (cell death). Cells are exposed to caspase inhibitors which gave a 2-fold increase in the survival of ICC's and insulin content. However in doing this, the researchers observed that they have a limited capacity to replicate without losing differentiated function. Accordingly, the scientists used a strategy to bypass cellular senescence by genitally introducing genes into ICC's through a retroviral vector containing the SV40 T-antigen and human telemerase (H-TERT). This process resulting in immortalization of the expanded cells led to the development of cell lines. Further characterization of the cell lines showed that they do not express insulin but produce somatostatin. The investigators are now using genetic engineering to sequentially introduce factors that induce insulin gene transcription into the cells, to rescue their ability to express insulin. It is hoped that these models may constitute valuable sources of functional islet cells for transplantation.
There is no way that we can share with you all of the research that is going on in this field. But, one interesting study by Yang has an approach to protect beta cells from autoimmune reactions. He and his colleagues have used adenoviral vectors to introduce the uteroglobin gene into islets transplanted onto pre-diabetic BB rates. It is known that uteroglobin is a protein expressed during pregnancy that confers immunologic tolerance and prevents inflammatory reactions.
How do you find out more about islet transplantation?
The centers in this country are at Minnesota at the Minnesota Institute which works closely with the University of Chicago. In North Carolina, researchers are collaborating with those at the university of Alberta and the University of Tennessee Medical Center. We have shared the results of the Diabetes Research Institute of the university of Miami, most especially those monkeys that were "cured of diabetes". Finally, we have examined in this paper the research at the Joslin Diabetes center by Dr. Gordon Weir. Enrollment has begun for clinical trials involving patients with renal failure who need a kidney or kidney-pancreas transplant, or patients with diabetes who need a pancreatic islet transplant. Trials involving patients who have already received a transplant are planned as well. If you are interested in enrolling in one of these clinical studies, call NIH Clinical Center's Patients Recruitment and Public Liaison Office at 1-800-411-1222. For more information see the National Institute of Diabetes and Digestive and Kidney Disease at www.niddk.nih.gov. You can find much information at the Islet Foundation at www.med.uni-giessen.de/itr/ or www.insulin-free.org, the Diabetes Research Institute, Joslin Diabetes Clinic, and the other hospitals cited. Be well, and hope that these brilliant men and women with the funding they so rightfully deserve can find out how to help us to throw away our syringes in our life times. If you know your representative or even if you don't, write them a letter today to ask about funding for diabetes research. Now you have some information to understand the process with, and that the cure is out there. It's complicated but we continue to take small steps forward toward our goal.
Next month, we'll be talking about the new long-acting insulin for treatment of type 1 and type 2 diabetes just approved by the FDA.
