The Edmonton Protocol

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.

This entry was posted on Wednesday, May 13th, 2009 at 8:14 pm and is filed under Type 1 Diabetes Classic. You can follow any responses to this entry through the RSS 2.0 feed. You can skip to the end and leave a response. Pinging is currently not allowed.