Diabetes and islet cells: The quest for a permanent cure
Not all diabetes researchers are obsessed with islet cells – just many of them. And for good reason. Diabetes destroys the islet cells that produce insulin, a hormone necessary to regulate blood sugar.
Researchers at the Diabetes Research Center at City of Hope, one of the most influential diabetes research programs in the world, are working on impressive array of approaches to diabetes treatment and cure, as detailed in a previous story. But the work on islet cells is impressive for its variety as well.
Here are some of the recent developments connected to islet cells.
Devising better treatment options for type 1 diabetes patients
Director of the Division of Diabetes, Endocrinology & Metabolism, Fouad Kandeel, M.D., Ph.D., is an international leader in the research effort to realize islet cell transplantation as a cure for people with type 1 diabetes, completely freeing them of the need for daily insulin injections.
In addition to perfecting clinical transplantation protocols, he has developed imaging methods that enable physicians to assess the health of islets after transplantation by visualizing them within the body in real-time. The ability to closely monitor the activity of transplanted islets will help improve efforts to prolong islet survival and function.
Kandeel is also leading investigations to determine whether growth factors (proteins that stimulate cells to grow and differentiate) could encourage transplanted islets to survive, grow and multiply, thus reducing the number of islets needed for successful transplantation. One long-term goal of this work is to identify individuals at early stages of the disease and then treat them with growth factors instead of islet cell transplantation — a solution that is gentler and less invasive for patients.
Kandeel is also developing a mobile device that combines a live glucose monitor with an automatic insulin delivery pump system. This “artificial pancreas” will free patients from periodic self-monitoring, as well as allow more accurate control of blood glucose levels.
Currently, City of Hope researchers are working with the device manufacturer to optimize performance, and preparations are being made to test the device in newly transplanted islet recipients in order to provide maximum protection of islets from the harmful effects of high blood sugar. In the near future, the device will be tested in an outpatient setting.
Blunting the autoimmune response in type 1 diabetes
Type 1 diabetes is caused by the body’s immune system destroying insulin-producing islet cells. Defu Zeng, M.D., associate professor in the Division of Diabetes, Endocrinology & Metabolism, has shown that this destruction could be fully halted and reversed in mouse models, research that could result in dramatic new treatment options for patients.
In a cover story in one of the world’s most prestigious medical journals, Science Translational Medicine, he reported on a combination strategy in which he first transplanted a healthy immune system into mice with type 1 diabetes — and then followed up with injections of growth factors that stimulate islet cell regeneration. This two-pronged approach reversed the immune system attack and stimulated beta cell regeneration, curing the disease.
The battle of the T cells: Arming the good guys
Chih-Pin Liu, Ph.D., a professor in the Department of Diabetes and Metabolic Diseases Research, also seeks to prevent immune system attack of islet cells. Liu is studying how a type of T cell known as pathogenic T cells attack islet cells and how regulatory T cells will block that attack. He discovered two genes that stimulate the production of the harmful pathogenic T cells.
Collaborating with Arthur Riggs, Ph.D., chair of the Department of Diabetes and Metabolic Diseases Research, Liu reported in the June issue of Proceedings of the National Academy of Sciences that silencing just one of these genes sparked a remarkable transformation: pathogenic T cells morphed into regulatory T cells. This study provides a potentially powerful new approach to develop new treatments to combat type 1 diabetes.
In parallel research, Liu is collaborating with Kandeel in translational studies to develop alternative ways to boost the number of regulatory T cells and use them to treat diabetes. Their goal is to develop ways to remove these beneficial immune cells from diabetic patients, expand them in culture and then readminister them to the patient.
In a promising finding, they have learned that the regulatory T cells fortified in culture are as potent as normal regulatory T cells in suppressing pathogenic T cells. Following completion of these preclinical studies, the researchers intend to move to first-in-human clinical trials in the near future. A paper on the study has been accepted for publication in the journal PLOS ONE.
Making islet cell transplantation available to more patients
A significant hurdle in making islet cell transplantation available to more people who need it is the limited supply of donor pancreases from which to harvest the insulin-producing islet cells. It is urgent that we realize methods of generating an unlimited supply of insulin-producing cells so that transplantation is available to all patients who would benefit.
One promising avenue of study under way at City of Hope is to generate insulin-producing cells from stem cells, rather than donated cells. H. Teresa Ku, Ph.D., an assistant professor in the Division of Diabetes, Endocrinology & Metabolism, is a stem cell expert who, in collaboration with Riggs, is optimizing technologies to differentiate stem cells (both embryonic and adult) into pancreatic cells suitable for transplant, which would circumvent the need for donor tissue.
Ku is also conducting research using biomarkers to identify pancreatic stem cells in the pancreas. If such pancreatic stem cells could be isolated — from a healthy donor or from patients themselves — they could be modified in the lab genetically or by growth factor treatment to increase their number before they are transplanted back into a patient where they could provide an unlimited source of healthy islet cells.
Yoko Mullen, M.D., Ph.D., research professor in the Department of Clinical Diabetes, Endocrinology & Metabolism, is conducting research to improve methods of harvesting islet cells from donor pancreases in order to maximize the number of healthy, viable cells available to patients, as well as help ensure that the fragile cells survive once they have been transplanted.
To maximize islet yields, she is exploring ways to minimize shock brought on by temperature change during pancreas transplantation and islet preparation by developing ways to protect islets. Some of those procedures could be also be used to protect islets from inflammation that occurs shortly after transplantation.
On a different front, her team is using manufactured hydrogels in protocols to transplant islets outside of the liver in order to avoid potential cellular toxicity associated with transplantation into the liver. The hope is that these procedures will achieve longer islet function and survival.
Islet cell transplantation program
City of Hope continues to make promising strides in realizing islet cell transplantation as a treatment for people with type 1 diabetes. To date, doctors at City of Hope have performed 45 islet transplantations in 20 type 1 diabetic patients.
Of the 12 patients who completed treatment under the islet transplantation protocol, all discontinued insulin injections at some time point in a two-year follow-up period, and eight remain off insulin injection at the program’s completion. Three patients await a second or third islet transplant in efforts to achieve insulin independence.
Not all donated islets are transplanted: We distribute a large number to researchers investigating diabetes treatment and diagnosis. In that effort, City of Hope coordinates the Integrated Islet Distribution Program (IIDP), an initiative funded by the National Institute of Diabetes, Digestive, and Kidney Diseases.
Joyce C. Niland, Ph.D., the Edward and Estelle Alexander Chair in Information Sciences and the chair of the Department of Research Information Sciences, serves as IIDP principal investigator. In the year ending in August 2012, delivery of 19 million islets overseen by the IIDP supported 260 projects led by investigators worldwide. Those researchers published over 360 high quality studies relevant to diabetes research.
Edited from the Diabetes Research Center Impact Report, February 2013.