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The Edmonton Protocol
May 13th, 2009
Related Documents
Islet Transplantation in Seven Patients with Type 1 Diabetes Mellitus Using a Glucocorticoid-free Immunosuppressive Regimen (New England Journal of Medicine, July 27, 2000)
Diabetes cured! screamed the press. Few type 1 diabetics can forget the excitement that greeted the Edmonton Protocol’s publication and the surge of hope it engendered in 2000. Although the authors of the paper did little to encourage the hyperbole, it was hailed as a cure. It is not, but it is perhaps the most important milestone to date in the development of islet transplantation.
The appeal of treating diabetes with islet transplantation is intuitive: the disease is caused by the failure of native islets to secrete insulin, so just replace the islets and cure the disease – just like kidney transplantation cures kidney failure. But it turns out the islet transplantation faces three special difficulties. It is difficult to separate islets from the rest of the pancreas. Islets are sensitive to immune suppression drugs. And autoimmune disease is irrepressible.
The first clinical proof that islet transplantation could cure type 1 diabetes came using autografts following pancreatic trauma treated by pancreatectomy. These transplants are special because the islet recipient has no autoimmune disease (diabetes caused by pancreas/islet removal, not autoimmune rpocesses) and because the graft is an autograft there is no immune rejection. When the diseased pancreas is removed the pancreas is given to the islet laboratory; they digest the pancreas and purify the islets of Langerhans which are then infused into the liver of the patient. When enough islets are obtained the procedure prevents diabetes in the patient, and they can live a diabetes free life.
A similar situation provides a revealing contrast. The first successes in kidney transplantation occurred between identical twins who do not reject each other’s tissues because they are genetically identical (immunologically equivalent to autografts). In a procedure that was expected to work a type 1 diabetic identical twin received an implant of islets from his twin. Initially the graft cured diabetes but the islets were destroyed in a few weeks by the immune response in a repetition of the autoimmune disease that had caused type 1 diabetes in the first place.
Many years passed as islet transplant surgeons labored to make islet allografts work. By the late 1980′s workers at Washington University St. Louis and the University of Alberta managed to get a few patients off insulin using immune suppression regimens similar to those used in kidney transplantation. Efforts during the 1990′s to increase the success rate of the procedure met with limited success; during the 1990′s only about 12% of islet transplant recipients were insulin independent for a year and 8% for two years. Such a success rate did not justify the side effects and the expense.
So when Dr. Shapiro, a trained transplant surgeon specialized in liver transplant, moved to Edmonton to do research on improving islet transplantation the situation seemed bleak. Very few islet transplants were being performed worldwide. Dr. Shapiro teamed up with Jonathan Lakey, an Edmonton native and University of Alberta Ph.D. who had worked for years to improve human islet preparation methods, and they studied the data on the hundreds of transplants to date. They decided to try making a few changes.
First, Lakey and his colleagues had made many improvements in the islet isolation methods that improved both the number and quality of the islets. To minimize islet loss they decided to use islets as soon as available and not store them. Shapiro realized that combining islet with kidney transplants, the normal procedure, limited flexibility in the design of the immune suppression regimen. (continued after the figure)
Figure 3. Fluctuations in Blood Glucose Concentrations over a 24-Hour Period One Month Before Transplantation (Panel A) and after the Attainment of Insulin Independence (Panel B) in a Representative Patient. Each bar represents the median and the range. The broken lines represent blood glucose concentrations of 60 and 140 mg per deciliter (3.3 and 7.8 mmol per liter). To convert values for glucose to milimoles per liter multiply by 0.0555.
So they decided to treat certain people with severely complicated type 1 diabetes, namely those with hypoglycemia unawareness. These diabetics are at risk for sudden loss of consciousness without warning when their blood sugars dropped. Thus Dr. Shapiro was free to choose pharmaceuticals that would provide the needed immune suppression but would not harm islets. In particular it had become clear that glucocorticoid drugs were very toxic to islets. They were eliminated.
The first patient was implanted in March 1999 and was able to have good blood sugars without insulin injections. The first several patients treated under the new protocol – all off insulin – were described in the July 2000 paper. At that point four had been off insulin for over a year.
The quality of metabolic control was excellent, and from at least that perspective, the patients were cured. Figure 3 from the paper (reproduced above) shows the range and mean glucose before and after the transplants. Anyone with type 1 diabetes can look at the improvement and salivate!
I had known Jon Lakey for many years at that point, having worked with him on microencapsuled islet research. In 1999 I called him up and asked him to collaborate with our new effort on the macroencapsuled islets, the Islet Sheet. He demurred, saying that something big was happening in collaboration with a new surgeon there. We stayed in touch while working on the Islet Sheet elsewhere, so I knew something big would be published in 2000. It was, and the press went wild.
With Jon Lakey’s encouragement I went to the American Diabetes Association meeting in June of 2000 to meet Dr. Shapiro. He was gracious and very interested in the potential of the Islet Sheet, and agreed to collaborate with us. Working with Jon and James in 2000-2001 was our most productive period in the development of the Islet Sheet.
So what has come of the Edmonton Protocol? It has continued to evolve, with changes in both islets and drug regimen. But it has foundered on the oldest, most basic problem: autoimmunity. In the right hands the initial success can always be nearly 100%. However, the failure of the grafts is much higher for islets during the following years. At five years, 80% of transplanted kidneys function but less than 10% of type 1 diabetes patients with islets are insulin independent.
So the next breakthrough in islet transplantation must be eliminating loss of islets to autoimmune attack. The two likely candidates are more specific immune suppression and encapsulation. But thanks to the work of the Edmonton group we know that the metabolic disease called type 1 diabetes can be cured in everyone with islet transplantation.
I just discovered today that the islet transplants don’t work longterm. My daughter is type 1, 16 years old and I had hoped she would get the transplant within a few years. What will the next step be, will there be hope in her lifetime?
Megan–
Islet transplants work long-term for a small number of people, but mostly insulin independence is gone in a few years. This is in contrast to solid organs. After five years, about 80% of kidneys function; after five years, about 15% of islet transplants function well.
Researchers have identified a half dozen problems with the current islet transplant protocols. For example, a large number of islets (about half) are lost within a few days of implantation into the liver (an unnatural site for islets).
It is our hope that the Islet Sheet will support islet function for years.
Enjoy reading about success and improvements. Now I wish to ask for someone to respond to a question that is of major importance: can a type 2 diabetic patient be treated with the Pancreatic Islet Transplantation? My mother has beena diabetic for over 20 years and there has been an increase in medication (from taking pills to injecting insulin daily). Her condition lingers on the critical side and I want to help her. Is there any hope that such a procedure could be part of the miracle to wellness for my Mom?
Freddie, not with the methods we have today. Your mother and almost everyone with type 2 diabetes needs much more insulin than the usual type 1 diabetic. So the number of islets — which is just enough for type 1 — is not enough for type 2. What is needed most in type 2 diabetes is better methods to increase sensitivity to insulin so less insulin is needed.
I am a type one diabetic who is looking into getting the islet cell transplant ASAP. I often have problems with my blood sugar, and i have had diabetes for 10 years. Is there anyway i could get the transplant without having to wait 5 years? even though you need to be 18 for most studies, i was hoping there was another way for me to get the transplant. I hate my diabetes and the fact that the pump is too much technology for me and shots hurt doesn’t help it. I already know from what i read that sometimes it doesn’t work completely, but i would be fine with having to give myself shots occasionally. do you know of another way?
Hi Jessi–
I don’t think there is any transplant program that takes someone as young as you. And they can’t violate protocol – in a clinical trial that is breaking the law! But frankly I don’t think you want to take the required drugs the rest of your life. Try to get the resources to control your blood sugar better. It is hard work but it is worth it.
Just wondering how close we are to seeing islet transplants as a possible treatment to type 1 diabetes. I’m not sure what the history is with moving clinical trials toward treatments. I have 4 siblings with complications , thankfully I have none. Another treatment or even a cure is such a great hope to look forward to. Thank you.
Jamie, islet transplantation continues at a low level a some academic research centers like University of Minnesota. The Solving Diabetes Project hopes that the use of the Islet Sheet will make the benefits of islet transplantation available to many more people.
any closer to having this become a reality in 2010?
Demetri-
You can see a list of all the islet transplantation clinical protocols here:
http://clinicaltrials.gov/ct2/results?term=islet
Scott
Are you still researching a cure for Type 1? My 12 year old niece was just diagnosed last week.
Praying there’s a cure soon. 
Yes! See the link for the latest.
http://www.solvingdiabetes.org/2010/10/10/progress-in-rat-studies-learning-to-make-a-rat-really-diabetic/
Hi Scott and all readers . I was #127 Islet Cell Recipient patient in Edmonton Alberta back in June 23 2010, I have a real problem when I hear the medical profession talk about long term success rates with islet cell transplant and being insulin independent , It’s not about being off insulin ,”which I have been for 148 days today ”January 1 2011” and the first 44 days after transplant had remarkably good blood control. After 25yrs of no control and hypoglycemic unawareness ,Some type 1 insulin dependant have good control ,doesn’t mean the ones who don’t didn’t struggle and did this to them selves .I beleive long term illness’ss like type 1 is a self treat diease on a daily basis .My life was like skating on ice hearing a crack not knowing where the crack was or how close the crack is and when I might fall through the ice, and hope someone see’s me if I do, and not judge me ..
To the medical profession what option do we have currently as a type 1, education, monitors did that 20 times a day, wait for a kidney,heart,liver blindness,ampution, when the Governments talk about Diabetes being a burden on health care ,,,first and foremost the burden is living with this disease , And now we have an option ,and what do health care providers say its not enough evidence to make it a standard of care. REALLY…..we need a professional who has the vision as Fredrick Banting did back in 1921 REALLY almost 100 years ago.
Bob Inglis patient 127 Edmonton Protocol.
Dr. Denis Faustmas out of Mass General who is currently initiating a phase II trial, of a new treatment, where in 2001 she was able to successfully reverse Type 1 (end stage) diabetes in mice. I do believe in being proactive about managing my diabetes, and I continue to research daily to remain current with the progress being made. Although diabetic care and management has made leaps and bounds, it has not come far enough – I’m still hearing of Doctors and Educators who are advocating for improper nutrition, and they are largely misinformed. Nutrition is absolutely vital to sustaining “normal” glucose control for Type 1 diabetics, often many doctors/educators encourage the increase of insulin injections (money generating), if the patient is unwilling to modify their nutritional intake. The role of nutrition could be very important in how our immune system came to destroy our insulin producing cells. I’ve read many theories, linking wheat and sugar (both promoting “yeast” in the body) as potential culprits, as well as environmental triggers and toxins that we breathe in. Many of us have questions and might feel frustrated as to why this happened in our body and not another’s? No firms answers can be found, but we can continue to ask, and we can continue to research and in the meantime find out as much as you can about what you’re eating and how it affects your blood glucose levels (which ultimately determines your insulin requirements). Ask your Doctor/Dieticians/Educators questions and challenge their answers and advice, its been my experience that generic professionals and GP’s are often misinformed, and suffer a disadvantage when it comes to offering nutritional advice and insulin dosing (they don’t have diabetes) they are citing their information from where? Ask them, and ask them how effective that advice has proven to be. Text-books can be wrong.
The information below is taken from Denise Faustman’s “Clinical Trials” page…
The BCG Human Clinical Trial Program is testing whether using Bacillus Calmette-Guérin (BCG), an inexpensive generic drug that temporarily elevates TNF levels in the body, will reduce or eliminate the disease-causing T cells in patients living with type 1 diabetes.
Under the direction of Denise Faustman, MD, PhD, director of the MGH Immunology Lab, and David Nathan, MD, director of the MGH Diabetes Center, an FDA-approved, Phase I human clinical trial was conducted and demonstrated that vaccination with BCG is safe in individuals with type 1 diabetes. The next step is to conduct a Phase II study, in which we will need to identify the “best” dose of BCG and the best schedule for giving this potential new therapy and achieving the desired effects.
Scott,
Can you elaborate on the types of drugs a patient is required to take when undergoing the islet transplantation clinical trial? Are these drugs harmful, must they be taken indefinitely? And what are the purpose of such drugs?
Furthermore, my husband currently (29 year old with Diabetes Type 1) has Crohn’s Disease. Would this diminish his chances of being able to participate in such a trial? If not, how does one go about joining an islet transplantation clinical trial?
Thanks,
Hannah
Hannah–
If you click through to the PDF file above, under methods you will read
sirolimus, tacrolimus, and daclizumab.
The first two are immune suppression drugs, and the third is an antibody. The antibody is used at the time of implant, and the other two for the rest of your life. The drugs are pills and the antibody is administered by injection.
Speaking of a cure, someone i know in edmonton had a successful pancreas transplant, yes the entire pancreas was transplanted, and he’s doing remarkably well. He had type 1 diabetes all his life, and now he can live life free of insulin. Could you please elaborate on this procedure in more detail Scott King, thank you.
i have only just found out about the edmonton protocol and i was reading on some websites about the criteria that patients need to meet in order to be considered for the procedure, something about having DKA multiple times means that one will not be considered, i was curious as to what qualifies as “multiple times”? And i’m assuming that one’s immune system will be effected due to taking immune suppression drugs, does this mean that some one that has undergone the treatment would be more prone to viruses and alike compared to a type 1 diabetic (that is more prone anyway) that hasn’t?
We are so close to a cure!! I an 47 yrs old have just been diagnosed with Diabetes Type 2 (not on insulin but taking tablets). I know it will get worse as I get older. I am hoping for a cure in my lifetime. Would the islet transplantation work on Type 2?