Brian Flanagan, PhD, program director at the University of Minnesota’s Schulze Diabetes Institute explains how the experimental procedure works and the possibility of it being added as treatment modality for type 1s who struggle with hypo unawareness and quality-of-life issues.  
By: John Parkinson, Clinical Content Coordinator,
There are a subset of people with type 1 diabetes that struggle more than other type 1s. They suffer from hypoglycemia unawareness or have trouble maintaining blood sugars within the normal range. Even with their best efforts their health remains in danger and they have a limited quality-of-life due to the severity of the need for constant vigilance of their condition.
One of the more exciting, but lesser known surgical interventions addressing this subset of patients is the islet cell transplant. As it is in phase III clinical trials, it is technically considered an experimental procedure and it is very restrictive in who is eligible for the procedure. Nonetheless, these transplants have been showing some very good success rates in trials in offering patients a new lease on life. For example, immediately following the procedure, most patients no longer experience hypo unawareness, and at Schulze Diabetes Institute, almost 70% of islet recipients become insulin independent for a period of time after one or more transplants, the occurrence and duration of which varies depending on the individual patient. Schulze also reports that 50 percent of these patients remain insulin independent at five years.

The transplant requires islet cells that have been isolated from a pancreas of a deceased organ donor to be surgically implanted into the recipient’s liver.The operation, itself, is not a terribly invasive procedure, as compared to other organ transplants. It simply requires a small incision in the stomach area, and the deployment of a catheter to release the isolated islet cells into the liver for engraftment. The transplant takes between a half hour and one and half hours to complete.

The procedure has been performed and studied in a highly regulated manner by the Clinical Islet Transplantation (CIT) Consortium. This is a small select group of clinical centers in Europe, Canada, and the U.S., that have conducted studies around this form of transplantation and has been compiling data on patients postoperatively.  

One of the aims of the CIT Consortium is to improve the safety and long-term success methods for transplanting islets. Although the procedure is widely viewed as a successful, emerging treatment, it does have its challenges too.

For example, it sometimes requires a patient to undergo a second procedure if the islet cells are unable to restore insulin independence. Also, for anyone who has the transplant, as long as they have functional islets post-transplant they must be on a daily regimen of immunosuppressive drugs.

However, in looking at the big picture as it relates to islet cell transplantation this could be a viable surgical intervention for struggling type 1s that is FDA approved by as early as 2014--some are predicting.
Schulze is one of the clinical centers involved in the CIT Consortium. The institute is made up of researchers, nurses, clinicians, and surgeons who together work on new research pertaining to islet cell transplantation and clinical studies of the transplant. They have done nearly 50 transplant procedures in the last 11 years.

Brian Flanagan, PhD, is program director at Schulze and works closely with Bernhard Hering, MD, the director of Islet Transplantation program program. Dr. Flanagan recently sat down with to discuss how the procedure works, expectations for life post-operatively for patients who undergo the procedure, insights about the data of the transplant studies from Schulze, and thoughts about this procedure being approved in the U.S. Can you provide an overview of the islet transplant program at Schulze?
Dr. Flanagan: At Schulze, we really have two arms. We have a preclinical group, and they test new ways to overcome the current hurdles that are still facing islet transplantation in animal models.

Our other arm is the clinical group, where we conduct trials in patients using human islets. We have completed four clinical trials in the last 10 years, and we recently completed patient enrollment in a phase III clinical trial that was sponsored by the National Institutes of Health.

We have another phase III trial where we are enrolling patients right now. It is also part of the clinical consortium, and that trial is an islet after kidney trial. It is for patients who have had a kidney transplant and have type 1 diabetes and would benefit from having an islet transplant as well.

Our main focus is on islet cell transplantation for type 1 diabetes. We are continuing to look for alternative sources of tissue and ways to lessen the burden of immunosuppressive agents on patients and to improve insulin-independence rates. Ultimately, we would like to be able to induce immune tolerance so people don’t have to take these drugs. Can you describe the criteria for the type 1s who fit as a candidate for the islet transplant?

Dr. Flanagan: Islet transplantations are still considered experimental by insurance companies, so it is not a standard of care at the moment. The intent of the phase III trials is to obtain a standard of care status for this procedure. The FDA is regulating these transplants and because it is being done in clinical trials, you have a strict inclusion/exclusion criteria of who can and cannot participate.

The criteria can vary depending on the trial, center, and protocol. However, as general rules of thumb, transplant centers are looking for patients who are 18-65 years of age; people who have had type 1 diabetes for greater than five years; they are c-peptide negative; and their diabetes has a secondary complication like hypoglycemic unawareness.

Exclusion for participation would be for those with a body mass index greater than 30; if they are taking high doses of insulin; if their A1c is greater than 10; or if they have high levels of antibodies from another transplant or blood transfusions in the past because it will be difficult to get organ matches as the islet transplants come from human cadavers. Can you describe how the procedure works and what the expectations are for the patient post-operatively?

Dr. Flanagan: For people who are interested in the transplant, they would contact a center that is performing the transplants and they would be evaluated to see if they met the eligibility criteria. This includes an explanation of what the protocol and transplant procedures entail, and patients are given an opportunity to ask questions.

If at that point they are found to be eligible and still interested, they get wait listed. When a donor’s islet cells becomes available, the surgical candidate is brought in two days in advance of the operation and are given immunosuppressive agents to prepare their body for the transplant.

During the transplant procedure, the patient is under conscious sedation--not fully sedated. A small incision is made in the patient’s abdomen, the islets are infused into the patient’s liver, and after the procedure, the patient is monitored for two to three days in the hospital, depending on how well they are feeling.They then resume a normal life.

Because these patients are in a clinical protocol, we ask that they come back at certain time periods for follow-up visits postoperatively. It depends on the specifics of the clinical protocol, but these can be at one week, two weeks, a month, etc.

During these visits, we draw blood and perform some testing on the individuals to make sure their islets are functioning correctly. That follow-up period might be two years, but if things are going well, we like to follow our patients for as long as possible, especially in those who want to be involved in long term observations. How long are the patients on the immunosuppressive agents?

Dr. Flanagan: The agents are taken for as long as the islets continue to function. We have patients who 10 and 11 years after their transplant remain insulin-independent. Those individuals are still taking their medicine twice daily. If you lose grafts and islets stop working, the immunosuppressive drugs get withdrawn. You had said the transplant is experimental, but how would you characterize it? Can we call it a cure for type 1 diabetes?

Dr. Flanagan: As far as the transplant itself, what we know is the minute the islets are infused, the hypoglycemic unawareness is resolved immediately. From a quality of life perspective, this is a game changer for patients. What we usually see over the first several weeks or months for patients postop is that they wean themselves off of insulin because their islets start to graft into the liver and then they start sensing blood glucose and making insulin.

This doesn’t happen overnight. It can be 2 to 3 months usually.

Patient expectations’ are part of how the procedure is viewed too. If the patient is expecting a return to hypoglycemia awareness, and the the transplants work immediately it is very encouraging. If they are expecting an insulin free life, that may occur more slowly, or not at all.

As with all emerging therapies there will be successes and failures along the way and the risks/benefit ratio should be carefully considered by people who want to undertake islet transplants. Schulze has been involved in the CIT Consortium. Can you detail what it is exactly and what Schulze have done as part of the consortium?

Dr. Flanagan: The idea behind the consortium is to develop a series of islet transplant protocols that would be conducted at a number of sites in the U.S., Canada, and Europe. Two of those protocols are in phase III clinical studies. The intent of the phase III trials is to obtain third-party reimbursement for this procedure. What this entails is demonstrating that this procedure is a treatment and is no longer experimental. 
We were asked to do a number of things. Our contribution to the consortium is to perform transplants, provide clinical protocols, and to provide knowledge and support to the phase III trials that are being untaken.

For example, we helped define one of the phase III trials. We have currently transplanted 15 patients as part of this consortium, and we will continue to follow these patients for the next two to five years, depending on the trial and the protocol they are in.

The second islet trial is the islet after kidney transplant. We are still enrolling patients in that. How many patients altogether has Schulze performed the procedure on, and can you share any general data or findings?

Dr. Flanagan: Since 2000, we have transplanted 47 patients with a total of 62 infusions. What you have is that some patients may need a second infusion. Most patients are able to do one, but depending on the individual and their insulin needs, it make take a second infusion.

We do know that about 70 percent of patients become insulin-independent, post-transplant, and of them, 50 percent of the these patients are protected from hyperglycemia for five years after the transplant. Although some of them might be back on a little insulin.

However, one of the challenges that remain is that we know at five years, only 50 percent of these patients who are insulin-independent, remain so. Therefore, we know there is a loss of insulin-independence as time goes by. As long as some people are making some insulin from the transplanted grafts, their hyperglycemia is resolved. They may still be on some insulin injections.

While I would not consider it always as a cure, I would say it certainly has the ability to be a game changer in the lives of people with hypoglycemia unawareness.

What is exciting for us is that these outcomes now mirror what you typically see in patients who have had a solitary whole pancreas transplant. Now, we have a therapy that is equivalent at least as far as outcomes are concerned to pancreas transplantation.

One advantage of the islet cell transplant is that it is a much less invasive procedure. What are the remaining challenges for FDA approval?

Dr. Flanagan: The phase III trials are underway. In one of the trials, the patient enrollment is complete. It is anticipated that the data from this trial will be collected in the next year and a half to two years, and that data will be submitted to the FDA and then to the CMS in 2013 or 2014. We would expect to see reimbursement for this procedure in that patient population in 2014.

I think there are two major hurdles that still confront the field. One is the need for a universal, replensishable source of tissue for transplantation, because human islets are obtained from deceased human donors, and there are just not enough islets from this source.

The second one is finding approaches to remove the long-term use of immunosuppressive agents. They are toxic and detrimental to the body; however, they are the same agents a patient would use if he or she had another organ transplant. We do know if we can move away from these agents, we can certainly improve the outcomes of the procedure. We can also improve the quality of life and make this much easier to undergo. ran a story last week about Kathy White who underwent the islet cell transplant at Schulze. You can read about her experience here